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1. Increased risk of breast cancer in neurofibromatosis type 1: current insights

Author: Howell SJ, Hockenhull K, Salih Z, and Evans DG
Subjects: breast cancer, neurofibromatosis type 1, NF1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Sacha J Howell,1 Kimberley Hockenhull,1 Zena Salih,1 D Gareth Evans2,3 1Department of Medical Oncology, The Christie NHS Foundation Trust, 2Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, 3Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by mutation/deletion of the NF1 gene. The gene product, neurofibromin, is a tumor suppressor which represses the activity of the Ras oncogene. Central nervous system (CNS) tumors have long been associated with NF1, but their association with several other malignancies has been demonstrated. In this review, we summarize the epidemiological data that irrefutably support a link between NF1 and an increased risk of early-onset breast cancer, to levels at which annual mammography is currently recommended in national high-risk screening programs. We discuss the reasons for the observed adverse breast cancer prognosis in NF1 cases, including late presentation and more aggressive tumor subtypes, and recommend that a collaborative breast screening study be initiated to better serve this currently underserved population of women. Keywords: breast cancer, neurofibromatosis type 1, NF1
Published: 2017

2. Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing.

Author: Rowlands, CF, Allen, S, Balmaña, J, Domchek, SM, Evans, DG, Hanson, H, Hoogerbrugge, N, James, PA, Nathanson, KL, Robson, M, Tischkowitz, M, Foulkes, WD, Turnbull, C, Rowlands, CF, Allen, S, Balmaña, J, Domchek, SM, Evans, DG, Hanson, H, Hoogerbrugge, N, James, PA, Nathanson, KL, Robson, M, Tischkowitz, M, Foulkes, WD, and Turnbull, C
Abstract: BACKGROUND: Germline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to patients with 'population-type' breast cancer in mainstream oncology clinics, with wide variation in the genes included. PATIENTS AND METHODS: Weighted meta-analysis was carried out for three population-based case-control studies (BRIDGES, CARRIERS and UK Biobank) comprising in total 101 397 women with breast cancer and 312 944 women without breast cancer, to quantify 37 putative breast cancer susceptibility genes (BCSGs) for the frequency of pathogenic variants (PVs) in unselected, 'population-type' breast cancer cases and their association with breast cancer and its subtypes. RESULTS: Meta-analysed odds ratios (ORs) and frequencies of PVs in 'population-type' breast cancer cases were generated for BRCA1 (OR 8.73, 95% confidence interval (CI) 7.47-10.20; 1 in 101), BRCA2 (OR 5.68, 95% CI 5.13-6.30; 1 in 68) and PALB2 (OR 4.30, 95% CI 3.68-5.03; 1 in 187). For both CHEK2 (OR 2.40, 95% CI 2.21-2.62; 1 in 73) and ATM (OR 2.16, 95% CI 1.93-2.41; 1 in 132) subgroup analysis showed a stronger association with oestrogen receptor-positive disease. The magnitude of association and frequency of PVs were low for RAD51C (OR 1.53, 95% CI 1.29-2.04; 1 in 913), RAD51D (OR 1.76, 95% CI 1.29-2.41; 1 in 1079) and BARD1 (OR 2.34, 95% CI 1.85-2.97; 1 in 672); frequencies and associations were higher when the analysis was restricted to triple-negative breast cancers. The PV frequency in 'population-type' breast cancer cases was very low for 'syndromic' BCSGs TP53 (1 in 1844), STK11 (1 in 11 525), CDH1 (1 in 2668), PTEN (1 in 3755) and NF1 (1 in 1470), with metrics of association also modest ranging from OR 3.62 (95% CI 1.98-6.61) for TP53 down to OR 1.60 (95% CI 0.48-5.30) for STK11. CONCLUSIONS: These metrics reflecting 'population-type' breast cancer will be informative in defining the appropriate gene set as we continue to expand to germline t
Published: 2024

3. Closing the Loops on Southern Ocean Dynamics: From the Circumpolar Current to Ice Shelves and From Bottom Mixing to Surface Waves

Author: Bennetts, LG, Shakespeare, CJ, Vreugdenhil, CA, Foppert, A, Gayen, B, Meyer, A, Morrison, AK, Padman, L, Phillips, HE, Stevens, CL, Toffoli, A, Constantinou, NC, Cusack, JM, Cyriac, A, Doddridge, EW, England, MH, Evans, DG, Heil, P, Hogg, AMC, Holmes, RM, Huneke, WGC, Jones, NL, Keating, SR, Kiss, AE, Kraitzman, N, Malyarenko, A, McConnochie, CD, Meucci, A, Montiel, F, Neme, J, Nikurashin, M, Patel, RS, Peng, J-P, Rayson, M, Rosevear, MG, Sohail, T, Spence, P, Stanley, GJ, Bennetts, LG, Shakespeare, CJ, Vreugdenhil, CA, Foppert, A, Gayen, B, Meyer, A, Morrison, AK, Padman, L, Phillips, HE, Stevens, CL, Toffoli, A, Constantinou, NC, Cusack, JM, Cyriac, A, Doddridge, EW, England, MH, Evans, DG, Heil, P, Hogg, AMC, Holmes, RM, Huneke, WGC, Jones, NL, Keating, SR, Kiss, AE, Kraitzman, N, Malyarenko, A, McConnochie, CD, Meucci, A, Montiel, F, Neme, J, Nikurashin, M, Patel, RS, Peng, J-P, Rayson, M, Rosevear, MG, Sohail, T, Spence, P, and Stanley, GJ
Abstract: A holistic review is given of the Southern Ocean dynamic system, in the context of the crucial role it plays in the global climate and the profound changes it is experiencing. The review focuses on connections between different components of the Southern Ocean dynamic system, drawing together contemporary perspectives from different research communities, with the objective of closing loops in our understanding of the complex network of feedbacks in the overall system. The review is targeted at researchers in Southern Ocean physical science with the ambition of broadening their knowledge beyond their specific field, and aims at facilitating better‐informed interdisciplinary collaborations. For the purposes of this review, the Southern Ocean dynamic system is divided into four main components: large‐scale circulation; cryosphere; turbulence; and gravity waves. Overviews are given of the key dynamical phenomena for each component, before describing the linkages between the components. The reviews are complemented by an overview of observed Southern Ocean trends and future climate projections. Priority research areas are identified to close remaining loops in our understanding of the Southern Ocean system.
Published: 2024

4. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author: Blein, S, Bardel, C, Danjean, V, McGuffog, L, Healey, S, Barrowdale, D, Lee, A, Dennis, J, Kuchenbaecker, KB, Soucy, P, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Gerdes, AM, Ejlertsen, B, Nielsen, FC, Hansen, TVO, Osorio, A, Benitez, J, Conejero, RA, Segota, E, Weitzel, JN, Thelander, M, Peterlongo, P, Radice, P, Pensotti, V, Dolcetti, R, Bonanni, B, Peissel, B, Zaffaroni, D, Scuvera, G, Manoukian, S, Varesco, L, Capone, GL, Papi, L, Ottini, L, Yannoukakos, D, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brady, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Cook, J, Adlard, J, Barwell, J, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Tischkowitz, M, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Cole, T, Godwin, AK, Isaacs, C, Claes, K, De Leeneer, K, Meindl, A, Gehrig, A, Wappenschmidt, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Plendl, H, Kast, K, Rhiem, K, Ditsch, N, Arnold, N, Varon-Mateeva, R, Schmutzler, RK, Preisler-Adams, S, Markov, NB, Wang-Gohrke, S, de Pauw, A, Lefol, C, Lasset, C, Leroux, D, Rouleau, E, Damiola, F, and Dreyfus, H
Subjects: Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Published: 2015

5. Use of risk-reducing surgeries in a prospective cohort of 1,499 BRCA1 and BRCA2 mutation carriers

Author: Chai, X, Friebel, TM, Singer, CF, Evans, DG, Lynch, HT, Isaacs, C, Garber, JE, Neuhausen, SL, Matloff, E, Eeles, R, Tung, N, Weitzel, JN, Couch, FJ, Hulick, PJ, Ganz, PA, Daly, MB, Olopade, OI, Tomlinson, G, Blum, JL, Domchek, SM, Chen, J, and Rebbeck, TR
Subjects: Oncology & Carcinogenesis, Oncology and Carcinogenesis, Clinical Sciences
Abstract: Inherited mutations in BRCA1 or BRCA2 (BRCA1/2) confer very high risk of breast and ovarian cancers. Genetic testing and counseling can reduce risk and death from these cancers if appropriate preventive strategies are applied, including risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). However, some women who might benefit from these interventions do not take full advantage of them. We evaluated RRSO and RRM use in a prospective cohort of 1,499 women with inherited BRCA1/2 mutations from 20 centers who enrolled in the study without prior cancer or RRSO or RRM and were followed forward for the occurrence of these events. We estimated the age-specific usage of RRSO/RRM in this cohort using Kaplan–Meier analyses. Use of RRSO was 45 % for BRCA1 and 34 % for BRCA2 by age 40, and 86 % for BRCA1 and 71 % for BRCA2 by age 50. RRM usage was estimated to be 46 % by age 70 in both BRCA1 and BRCA2 carriers. BRCA1 mutation carriers underwent RRSO more frequently than BRCA2 mutation carriers overall, but the uptake of RRSO in BRCA2 was similar after mutation testing and in women born since 1960. RRM uptake was similar for both BRCA1 and BRCA2. Childbearing influenced the use of RRSO and RRM in both BRCA1 and BRCA2. Uptake of RRSO is high, but some women are still diagnosed with ovarian cancer before undergoing RRSO. This suggests that research is needed to understand the optimal timing of RRSO to maximize risk reduction and limit potential adverse consequences of RRSO.
Published: 2014

6. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Author: Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, Adlard, J, Davidson, R, Cole, T, Cook, J, Paterson, J, Douglas, F, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Rogers, MT, Donaldson, A, Dorkins, H, Godwin, AK, Bove, B, Stoppa-Lyonnet, D, Houdayer, C, Buecher, B, de Pauw, A, Mazoyer, S, Calender, A, Leone, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SF, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MB, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, M-K, Kaulich, DG, Hansen, TVO, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, and Piedmonte, M
Published: 2012

7. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Author: Mulligan, AM, Couch, FJ, Barrowdale, D, Domchek, SM, Eccles, D, Nevanlinna, H, Ramus, SJ, Robson, M, Sherman, M, Spurdle, AB, Wappenschmidt, B, Lee, A, McGuffog, L, Healey, S, Sinilnikova, OM, Janavicius, R, Hansen, TV, Nielsen, FC, Ejlertsen, B, Osorio, A, Muñoz-Repeto, I, Durán, M, Godino, J, Pertesi, M, Benítez, J, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Cattaneo, E, Bonanni, B, Viel, A, Pasini, B, Papi, L, Ottini, L, Savarese, A, Bernard, L, Radice, P, Hamann, U, Verheus, M, Meijers-Heijboer, HEJ, Wijnen, J, Gómez García, EB, Nelen, MR, Kets, CM, Seynaeve, C, Tilanus-Linthorst, MMA, van der Luijt, RB, Os, TV, Rookus, M, Frost, D, Jones, JL, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Adlard, J, Davidson, R, Cook, J, Donaldson, A, Dorkins, H, Gregory, H, Eason, J, Houghton, C, Barwell, J, Side, LE, McCann, E, Murray, A, Peock, S, Godwin, AK, Schmutzler, RK, Rhiem, K, Engel, C, Meindl, A, Ruehl, I, Arnold, N, Niederacher, D, Sutter, C, Deissler, H, Gadzicki, D, Kast, K, Preisler-Adams, S, Varon-Mateeva, R, Schoenbuchner, I, Fiebig, B, Heinritz, W, Schäfer, D, Gevensleben, H, and Caux-Moncoutier, V
Abstract: Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers. © 2011 Mulligan et al.; licensee BioMed Central Ltd.
Published: 2011

8. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

Author: Antoniou, AC, Cunningham, AP, Peto, J, Evans, DG, Lalloo, F, Narod, SA, Risch, HA, Eyfjord, JE, Hopper, JL, Southey, MC, Olsson, H, Johannsson, O, Borg, A, Passini, B, Radice, P, Manoukian, S, Eccles, DM, Tang, N, Olah, E, Anton-Culver, H, Warner, E, Lubinski, J, Gronwald, J, Gorski, B, Tryggvadottir, L, Syrjakoski, K, Kallioniemi, O-P, Eerola, H, Nevanlinna, H, Pharoah, PDP, and Easton, DF
Subjects: Breast Cancer, Ovarian Cancer, Cancer, Genetics, Genetic Testing, Rare Diseases, Prevention, Aetiology, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, 2.6 Resources and infrastructure (aetiology), Adult, Age Factors, Aged, Breast Neoplasms, Female, Genes, BRCA1, Genes, BRCA2, Genetic Carrier Screening, Genetic Predisposition to Disease, Humans, Middle Aged, Models, Genetic, Mutation, Neoplasms, Second Primary, Ovarian Neoplasms, BRCA1, BRCA2, cancer risk model, genetic testing, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract: Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).
Published: 2008

9. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies

Author: Antoniou, AC, Pharoah, PDP, Narod, S, Risch, HA, Eyfjord, JE, Hopper, JL, Olsson, H, Johannsson, O, Borg, A, Pasini, B, Radice, P, Manoukian, S, Eccles, DM, Tang, N, Olah, E, Anton-Culver, H, Warner, E, Lubinski, J, Gronwald, J, Gorski, B, Tulinius, H, Thorlacius, S, Eerola, H, Nevanlinna, H, Syrjäkoski, K, Kallioniemi, O-P, Thompson, D, Evans, C, Peto, J, Lalloo, F, Evans, DG, and Easton, DF
Subjects: Breast Cancer, Ovarian Cancer, Rare Diseases, Cancer, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Breast Neoplasms, Female, Founder Effect, Genes, BRCA1, Genes, BRCA2, Heterozygote, Humans, Incidence, Jews, Meta-Analysis as Topic, Middle Aged, Mutation, Ovarian Neoplasms, Penetrance, Prevalence, Risk Assessment, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.
Published: 2005

10. Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases

Author: Figlioli, G, Billaud, A, Wang, Q, Bolla, MK, Dennis, J, Lush, M, Kvist, A, Adank, MA, Ahearn, TU, Antonenkova, NN, Auvinen, P, Behrens, S, Bermisheva, M, Bogdanova, N, Bojesen, SE, Bonanni, B, Bruening, T, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Czene, K, Devilee, P, Doerk, T, Eriksson, M, Fasching, PA, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Glendon, G, Garcia, EG, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Hahnen, E, Hamann, U, Hillemanns, P, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jakubowska, A, Khusnutdinova, EK, Kristensen, VN, Lindblom, A, Loizidou, MA, Lubinski, J, Mannermaa, A, Maurer, T, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, M, Radice, P, Rashid, MU, Rhenius, V, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shah, MT, Southey, MC, Tomlinson, I, Truong, T, van Veen, EM, Wendt, C, Yang, XR, Michailidou, K, Dunning, AM, Pharoah, PDP, Easton, DF, Andrulis, IL, Evans, DG, Hollestelle, A, Chang-Claude, J, Milne, RL, Peterlongo, P, Figlioli, G, Billaud, A, Wang, Q, Bolla, MK, Dennis, J, Lush, M, Kvist, A, Adank, MA, Ahearn, TU, Antonenkova, NN, Auvinen, P, Behrens, S, Bermisheva, M, Bogdanova, N, Bojesen, SE, Bonanni, B, Bruening, T, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Czene, K, Devilee, P, Doerk, T, Eriksson, M, Fasching, PA, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Glendon, G, Garcia, EG, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Hahnen, E, Hamann, U, Hillemanns, P, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jakubowska, A, Khusnutdinova, EK, Kristensen, VN, Lindblom, A, Loizidou, MA, Lubinski, J, Mannermaa, A, Maurer, T, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, M, Radice, P, Rashid, MU, Rhenius, V, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shah, MT, Southey, MC, Tomlinson, I, Truong, T, van Veen, EM, Wendt, C, Yang, XR, Michailidou, K, Dunning, AM, Pharoah, PDP, Easton, DF, Andrulis, IL, Evans, DG, Hollestelle, A, Chang-Claude, J, Milne, RL, and Peterlongo, P
Abstract: FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.
Published: 2023

11. A Likelihood Ratio Approach for Utilizing Case-Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2

Author: Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, Michailidou, K, Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, and Michailidou, K
Abstract: A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.
Published: 2023

12. Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author: Kast, KM, John, EL, Hopper, J, Andrieu, N, Nogues, C, Mouret-Fourme, E, Lasset, C, Fricker, J-P, Berthet, P, Mari, V, Salle, LK, Schmidt, M, Ausems, MGEM, Garcia, EBG, van de Beek, IR, Wevers, M, Evans, DG, Tischkowitz, M, Lalloo, F, Cook, J, Izatt, L, Tripathi, V, Snape, K, Musgrave, H, Sharif, S, Murray, JV, Colonna, SV, Andrulis, IL, Daly, MB, Southey, MC, de la Hoya, M, Osorio, A, Foretova, L, Berkova, D, Gerdes, A-M, Olah, E, Jakubowska, A, Singer, CF, Tan, Y, Augustinsson, A, Rantala, J, Simard, J, Schmutzler, RK, Milne, RL, Phillips, K-A, Terry, MB, Goldgar, D, van Leeuwen, FE, Mooij, TM, Antoniou, AC, Easton, DF, Rookus, MA, Engel, C, Kast, KM, John, EL, Hopper, J, Andrieu, N, Nogues, C, Mouret-Fourme, E, Lasset, C, Fricker, J-P, Berthet, P, Mari, V, Salle, LK, Schmidt, M, Ausems, MGEM, Garcia, EBG, van de Beek, IR, Wevers, M, Evans, DG, Tischkowitz, M, Lalloo, F, Cook, J, Izatt, L, Tripathi, V, Snape, K, Musgrave, H, Sharif, S, Murray, JV, Colonna, SV, Andrulis, IL, Daly, MB, Southey, MC, de la Hoya, M, Osorio, A, Foretova, L, Berkova, D, Gerdes, A-M, Olah, E, Jakubowska, A, Singer, CF, Tan, Y, Augustinsson, A, Rantala, J, Simard, J, Schmutzler, RK, Milne, RL, Phillips, K-A, Terry, MB, Goldgar, D, van Leeuwen, FE, Mooij, TM, Antoniou, AC, Easton, DF, Rookus, MA, and Engel, C
Abstract: INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.
Published: 2023

13. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Author: Mueller, SH, Lai, AG, Valkovskaya, M, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Abu-Ful, Z, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baert, T, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Brucker, SY, Buys, SS, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Chung, WK, Colonna, S, Cornelissen, S, Couch, FJ, Czene, K, Daly, MB, Devilee, P, Dork, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Gago-Dominguez, M, Gao, Y-T, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Gentry-Maharaj, A, Grassmann, F, Guenel, P, Gundert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Harkness, EF, Harrington, PA, Hartikainen, JM, Hartman, M, Hein, A, Ho, W-K, Hooning, MJ, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Huo, D, Investigators, A, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kang, D, Khusnutdinova, EK, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Mannermaa, A, Manoochehri, M, Margolin, S, Matsuo, K, Mavroudis, D, Menon, U, Muir, K, Murphy, RA, Nevanlinna, H, Newman, WG, Niederacher, D, O'Brien, KM, Obi, N, Offit, K, Olopade, O, Olshan, AF, Olsson, H, Park, SK, Patel, A, Perou, CM, Peto, J, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Ramachandran, D, Rashid, MU, Rennert, G, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneider, MO, Scott, C, Shah, M, Sharma, P, Shen, C-Y, Shu, X-O, Simard, J, Surowy, H, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Vachon, CM, Vijai, J, Weinberg, CR, Wendt, C, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Yang, XR, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Easton, DF, Hemingway, H, Hamann, U, Kuchenbaecker, KB, Mueller, SH, Lai, AG, Valkovskaya, M, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Abu-Ful, Z, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baert, T, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Brucker, SY, Buys, SS, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Chung, WK, Colonna, S, Cornelissen, S, Couch, FJ, Czene, K, Daly, MB, Devilee, P, Dork, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Gago-Dominguez, M, Gao, Y-T, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Gentry-Maharaj, A, Grassmann, F, Guenel, P, Gundert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Harkness, EF, Harrington, PA, Hartikainen, JM, Hartman, M, Hein, A, Ho, W-K, Hooning, MJ, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Huo, D, Investigators, A, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kang, D, Khusnutdinova, EK, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Mannermaa, A, Manoochehri, M, Margolin, S, Matsuo, K, Mavroudis, D, Menon, U, Muir, K, Murphy, RA, Nevanlinna, H, Newman, WG, Niederacher, D, O'Brien, KM, Obi, N, Offit, K, Olopade, O, Olshan, AF, Olsson, H, Park, SK, Patel, A, Perou, CM, Peto, J, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Ramachandran, D, Rashid, MU, Rennert, G, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneider, MO, Scott, C, Shah, M, Sharma, P, Shen, C-Y, Shu, X-O, Simard, J, Surowy, H, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Vachon, CM, Vijai, J, Weinberg, CR, Wendt, C, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Yang, XR, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Easton, DF, Hemingway, H, Hamann, U, and Kuchenbaecker, KB
Abstract: BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.
Published: 2023

14. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

Author: Morra, A, Schreurs, MAC, Andrulis, IL, Anton-Culver, H, Augustinsson, A, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brauch, H, Broeks, A, Buys, SS, Camp, NJ, Castelao, JE, Cessna, MH, Chang-Claude, J, Chung, WK, Collaborators, N, Colonna, SV, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dörk, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Evans, DG, Fasching, PA, Fehm, TN, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, Genkinger, J, Grassmann, F, Gündert, M, Hahnen, E, Haiman, CA, Hamann, U, Harrington, PA, Hartikainen, JM, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Investigators, A, Investigators, K, Jakubowska, A, Janni, W, Jernström, H, John, EM, Johnson, N, Jones, ME, Kristensen, VN, Kurian, AW, Lambrechts, D, Marchand, LL, Lindblom, A, Lubiński, J, Lux, MP, Mannermaa, A, Mavroudis, D, Mulligan, AM, Muranen, TA, Nevanlinna, H, Nevelsteen, I, Neven, P, Newman, WG, Obi, N, Offit, K, Olshan, AF, Park-Simon, T-W, Patel, AV, Peterlongo, P, Phillips, K-A, Plaseska-Karanfilska, D, Polley, EC, Presneau, N, Pylkäs, K, Rack, B, Radice, P, Rashid, MU, Rhenius, V, Robson, M, Romero, A, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schuetze, S, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Tapper, WJ, Teras, LR, Tollenaar, RAEM, Tomczyk, K, Tomlinson, I, Troester, MA, Vachon, CM, van Veen, EM, Wang, Q, Wendt, C, Wildiers, H, Winqvist, R, Ziogas, A, Hall, P, Pharoah, PDP, Adank, MA, Hollestelle, A, Schmidt, MK, Hooning, MJ, Morra, A, Schreurs, MAC, Andrulis, IL, Anton-Culver, H, Augustinsson, A, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brauch, H, Broeks, A, Buys, SS, Camp, NJ, Castelao, JE, Cessna, MH, Chang-Claude, J, Chung, WK, Collaborators, N, Colonna, SV, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dörk, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Evans, DG, Fasching, PA, Fehm, TN, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, Genkinger, J, Grassmann, F, Gündert, M, Hahnen, E, Haiman, CA, Hamann, U, Harrington, PA, Hartikainen, JM, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Investigators, A, Investigators, K, Jakubowska, A, Janni, W, Jernström, H, John, EM, Johnson, N, Jones, ME, Kristensen, VN, Kurian, AW, Lambrechts, D, Marchand, LL, Lindblom, A, Lubiński, J, Lux, MP, Mannermaa, A, Mavroudis, D, Mulligan, AM, Muranen, TA, Nevanlinna, H, Nevelsteen, I, Neven, P, Newman, WG, Obi, N, Offit, K, Olshan, AF, Park-Simon, T-W, Patel, AV, Peterlongo, P, Phillips, K-A, Plaseska-Karanfilska, D, Polley, EC, Presneau, N, Pylkäs, K, Rack, B, Radice, P, Rashid, MU, Rhenius, V, Robson, M, Romero, A, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schuetze, S, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Tapper, WJ, Teras, LR, Tollenaar, RAEM, Tomczyk, K, Tomlinson, I, Troester, MA, Vachon, CM, van Veen, EM, Wang, Q, Wendt, C, Wildiers, H, Winqvist, R, Ziogas, A, Hall, P, Pharoah, PDP, Adank, MA, Hollestelle, A, Schmidt, MK, and Hooning, MJ
Abstract: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09-1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words).
Published: 2023

15. A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Author: Middha, PK, Wang, X, Behrens, S, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baert, T, Freeman, LEB, Becher, H, Beckmann, MW, Benitez, J, Bojesen, SE, Brauch, H, Brenner, H, Brooks-Wilson, A, Campa, D, Canzian, F, Carracedo, A, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Cordina-Duverger, E, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dossus, L, Dugue, P-A, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Giles, GG, Gonzalez-Neira, A, Grassmann, F, Grundy, A, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, SE, Harkness, EF, Holleczek, B, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Ingvar, C, Isaksson, K, Jernstroem, H, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lacey, JV, Lambrechts, D, Larson, NL, Larsson, S, Le Marchand, L, Lejbkowicz, F, Li, S, Linet, M, Lissowska, J, Martinez, ME, Maurer, T, Mulligan, AM, Mulot, C, Murphy, RA, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, O'Brien, KM, Olson, JE, Patel, AV, Prentice, R, Rees-Punia, E, Rennert, G, Rhenius, V, Ruddy, KJ, Sandler, DP, Scott, CG, Shah, MT, Shu, X-O, Smeets, A, Southey, MC, Stone, J, Tamimi, RM, Taylor, JA, Teras, LR, Tomczyk, K, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Weinberg, CR, Wildiers, H, Willett, W, Winham, SJ, Wolk, A, Yang, X, Zamora, MP, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Garcia-Closas, M, Schmidt, MK, Kraft, P, Milne, RL, Lindstroem, S, Easton, DF, Chang-Claude, J, Middha, PK, Wang, X, Behrens, S, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baert, T, Freeman, LEB, Becher, H, Beckmann, MW, Benitez, J, Bojesen, SE, Brauch, H, Brenner, H, Brooks-Wilson, A, Campa, D, Canzian, F, Carracedo, A, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Cordina-Duverger, E, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dossus, L, Dugue, P-A, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Giles, GG, Gonzalez-Neira, A, Grassmann, F, Grundy, A, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, SE, Harkness, EF, Holleczek, B, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Ingvar, C, Isaksson, K, Jernstroem, H, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lacey, JV, Lambrechts, D, Larson, NL, Larsson, S, Le Marchand, L, Lejbkowicz, F, Li, S, Linet, M, Lissowska, J, Martinez, ME, Maurer, T, Mulligan, AM, Mulot, C, Murphy, RA, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, O'Brien, KM, Olson, JE, Patel, AV, Prentice, R, Rees-Punia, E, Rennert, G, Rhenius, V, Ruddy, KJ, Sandler, DP, Scott, CG, Shah, MT, Shu, X-O, Smeets, A, Southey, MC, Stone, J, Tamimi, RM, Taylor, JA, Teras, LR, Tomczyk, K, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Weinberg, CR, Wildiers, H, Willett, W, Winham, SJ, Wolk, A, Yang, X, Zamora, MP, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Garcia-Closas, M, Schmidt, MK, Kraft, P, Milne, RL, Lindstroem, S, Easton, DF, and Chang-Claude, J
Abstract: BACKGROUND: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. METHODS: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. RESULTS: Assuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). CONCLUSIONS: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.
Published: 2023

16. FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

Author: Figlioli, G, Billaud, A, Ahearn, TU, Antonenkova, NN, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blok, MJ, Bogdanova, NV, Bonanni, B, Burwinkel, B, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chanock, SJ, Czene, K, Devilee, P, Doerk, T, Engel, C, Eriksson, M, Fasching, PA, Figueroa, JD, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Guendert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harrington, PA, He, W, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jager, A, Jakubowska, A, Khusnutdinova, EK, Ko, Y-D, Kristensen, VN, Lindblom, A, Lissowska, J, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, MI, Rashid, MU, Rhenius, V, Rookus, MA, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sironen, R, Southey, MC, Suvanto, M, Tollenaar, RAEM, Tomlinson, I, Truong, T, van der Kolk, LE, van Veen, EM, Wappenschmidt, B, Yang, XR, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Lush, M, Michailidou, K, Pharoah, PDP, Wang, Q, Adank, MA, Schmidt, MK, Andrulis, IL, Chang-Claude, J, Nevanlinna, H, Chenevix-Trench, G, Evans, DG, Milne, RL, Radice, P, Peterlongo, P, Figlioli, G, Billaud, A, Ahearn, TU, Antonenkova, NN, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blok, MJ, Bogdanova, NV, Bonanni, B, Burwinkel, B, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chanock, SJ, Czene, K, Devilee, P, Doerk, T, Engel, C, Eriksson, M, Fasching, PA, Figueroa, JD, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Guendert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harrington, PA, He, W, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jager, A, Jakubowska, A, Khusnutdinova, EK, Ko, Y-D, Kristensen, VN, Lindblom, A, Lissowska, J, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, MI, Rashid, MU, Rhenius, V, Rookus, MA, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sironen, R, Southey, MC, Suvanto, M, Tollenaar, RAEM, Tomlinson, I, Truong, T, van der Kolk, LE, van Veen, EM, Wappenschmidt, B, Yang, XR, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Lush, M, Michailidou, K, Pharoah, PDP, Wang, Q, Adank, MA, Schmidt, MK, Andrulis, IL, Chang-Claude, J, Nevanlinna, H, Chenevix-Trench, G, Evans, DG, Milne, RL, Radice, P, and Peterlongo, P
Abstract: Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.
Published: 2023

17. Young age at first pregnancy does protect against early onset breast cancer in BRCA1 and BRCA2 mutation carriers

Author: Evans, DG, Harkness, EF, Howel, S., Woodward, ER, Howell, A., and Lalloo, F.
Published: 2017
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18. A digital pathway for genetic testing in UK NHS cancer patients: BRCA-DIRECT randomised study internal pilot

Author: Torr, B, Jones, C, Choi, S, Allen, S, Kavanaugh, G, Garrett, A, MacMahon, S, Loong, L, Reay, A, Yuan, L, Valganon Petrizan, M, Monson, K, Perry, N, Fallowfield, L, Jenkins, V, Gold, R, Taylor, A, Gabe, R, Wiggins, J, Lucassen, A, Manchanda, R, Gandhi, A, George, A, Hubank, M, Kemp, Z, Evans, DG, Bremner, S, and Turnbull, C
Abstract: Background\ud Germline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing.\ud \ud Methods\ud We designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing of BRCA1/BRCA2/PALB2 (BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected breast cancer patients and gathered preliminary data from a randomised comparison of delivery of pre-test information digitally (fully-digital pathway) or via telephone consultation with a genetics professional (partially-digital pathway).\ud \ud Results\ud Uptake of genetic testing was 98.4%, with good satisfaction reported for both the fully- and partially-digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with
Published: 2022

19. A Genome-Wide Gene-Based Gene-Environment Interaction Study of Breast Cancer in More than 90,000 Women

Author: Wang, X, Chen, H, Kapoor, PM, Su, Y-R, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Michailidou, K, Pharoah, PDP, Hopper, JL, Southey, MC, Koutros, S, Freeman, LEB, Stone, J, Rennert, G, Shibli, R, Murphy, RA, Aronson, K, Guenel, P, Truong, T, Teras, LR, Hodge, JM, Canzian, F, Kaaks, R, Brenner, H, Arndt, V, Hoppe, R, Lo, W-Y, Behrens, S, Mannermaa, A, Kosma, V-M, Jung, A, Becher, H, Glies, GG, Haiman, CA, Maskarinec, G, Scott, C, Winham, S, Simard, J, Goldberg, MS, Zheng, W, Long, J, Troester, MA, Love, MI, Peng, C, Tamimi, R, Eliassen, H, Garcia-Closas, M, Figueroa, J, Ahearn, T, Yang, R, Evans, DG, Howell, A, Hall, P, Czene, K, Wolk, A, Sandler, DP, Taylor, JA, Swerdlow, AJ, Orr, N, Lacey, JV, Wang, S, Olsson, H, Easton, DF, Milne, RL, Hsu, L, Kraft, P, Chang-Claude, J, Lindstroem, S, Wang, X, Chen, H, Kapoor, PM, Su, Y-R, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Michailidou, K, Pharoah, PDP, Hopper, JL, Southey, MC, Koutros, S, Freeman, LEB, Stone, J, Rennert, G, Shibli, R, Murphy, RA, Aronson, K, Guenel, P, Truong, T, Teras, LR, Hodge, JM, Canzian, F, Kaaks, R, Brenner, H, Arndt, V, Hoppe, R, Lo, W-Y, Behrens, S, Mannermaa, A, Kosma, V-M, Jung, A, Becher, H, Glies, GG, Haiman, CA, Maskarinec, G, Scott, C, Winham, S, Simard, J, Goldberg, MS, Zheng, W, Long, J, Troester, MA, Love, MI, Peng, C, Tamimi, R, Eliassen, H, Garcia-Closas, M, Figueroa, J, Ahearn, T, Yang, R, Evans, DG, Howell, A, Hall, P, Czene, K, Wolk, A, Sandler, DP, Taylor, JA, Swerdlow, AJ, Orr, N, Lacey, JV, Wang, S, Olsson, H, Easton, DF, Milne, RL, Hsu, L, Kraft, P, Chang-Claude, J, and Lindstroem, S
Abstract: BACKGROUND: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene-environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. METHODS: We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P<0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. RESULTS: After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE=4.44×10-6). CONCLUSION: In this transcriptome-informed genome-wide gene-environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. IMPACT: Our study suggests a limited role of gene-environment interactions in breast cancer risk.
Published: 2022

20. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author: Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, Chatterjee, N, Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, and Chatterjee, N
Abstract: BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Published: 2022

21. Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci

Author: Chen, H, Fan, S, Stone, J, Thompson, DJ, Douglas, J, Li, S, Scott, C, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Li, C, Peters, U, Hopper, JL, Southey, MC, Nguyen-Dumont, T, Nguyen, TL, Fasching, PA, Behrens, A, Cadby, G, Murphy, RA, Aronson, K, Howell, A, Astley, S, Couch, F, Olson, J, Milne, RL, Giles, GG, Haiman, CA, Maskarinec, G, Winham, S, John, EM, Kurian, A, Eliassen, H, Andrulis, I, Evans, DG, Newman, WG, Hall, P, Czene, K, Swerdlow, A, Jones, M, Pollan, M, Fernandez-Navarro, P, McConnell, DS, Kristensen, VN, Rothstein, JH, Wang, P, Habel, LA, Sieh, W, Dunning, AM, Pharoah, PDP, Easton, DF, Gierach, GL, Tamimi, RM, Vachon, CM, Lindstrom, S, Chen, H, Fan, S, Stone, J, Thompson, DJ, Douglas, J, Li, S, Scott, C, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Li, C, Peters, U, Hopper, JL, Southey, MC, Nguyen-Dumont, T, Nguyen, TL, Fasching, PA, Behrens, A, Cadby, G, Murphy, RA, Aronson, K, Howell, A, Astley, S, Couch, F, Olson, J, Milne, RL, Giles, GG, Haiman, CA, Maskarinec, G, Winham, S, John, EM, Kurian, A, Eliassen, H, Andrulis, I, Evans, DG, Newman, WG, Hall, P, Czene, K, Swerdlow, A, Jones, M, Pollan, M, Fernandez-Navarro, P, McConnell, DS, Kristensen, VN, Rothstein, JH, Wang, P, Habel, LA, Sieh, W, Dunning, AM, Pharoah, PDP, Easton, DF, Gierach, GL, Tamimi, RM, Vachon, CM, and Lindstrom, S
Abstract: BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.
Published: 2022

22. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author: Barnes, DR, Silvestri, V, Leslie, G, McGuffog, L, Dennis, J, Yang, X, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Belotti, M, Benitez, J, Berthet, P, Boonen, SE, Borg, A, Bozsik, A, Brady, AF, Brennan, P, Brewer, C, Brunet, J, Bucalo, A, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cassingham, H, Christensen, LL, Cini, G, Claes, KBM, Cook, J, Coppa, A, Cortesi, L, Damante, G, Darder, E, Davidson, R, de la Hoya, M, De Leeneer, K, de Putter, R, Del Valle, J, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Fostira, F, Frone, M, Frost, D, Gallagher, D, Gehrig, A, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gregory, H, Gross, E, Hahnen, E, Hamann, U, Hansen, TVO, Hanson, H, Hentschel, J, Horvath, J, Izatt, L, Izquierdo, A, James, PA, Janavicius, R, Jensen, UB, Johannsson, OT, John, EM, Kramer, G, Kroeldrup, L, Kruse, TA, Lautrup, C, Lazaro, C, Lesueur, F, Lopez-Fernandez, A, Mai, PL, Manoukian, S, Matrai, Z, Matricardi, L, Maxwell, KN, Mebirouk, N, Meindl, A, Montagna, M, Monteiro, AN, Morrison, PJ, Muranen, TA, Murray, A, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Tu, N-D, Niederacher, D, Olah, E, Olopade, O, Palli, D, Parsons, MT, Pedersen, IS, Peissel, B, Perez-Segura, P, Peterlongo, P, Petersen, AH, Pinto, P, Porteous, ME, Pottinger, C, Pujana, MA, Radice, P, Ramser, J, Rantala, J, Robson, M, Rogers, MT, Ronlund, K, Rump, A, Sanchez de Abajo, AM, Shah, PD, Sharif, S, Side, LE, Singer, CF, Stadler, Z, Steele, L, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Tommasi, S, Toss, A, Trainer, AH, Tripathi, V, Valentini, V, van Asperen, CJ, Venturelli, M, Viel, A, Vijai, J, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Whaite, A, Zanna, I, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Ottini, L, Barnes, DR, Silvestri, V, Leslie, G, McGuffog, L, Dennis, J, Yang, X, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Belotti, M, Benitez, J, Berthet, P, Boonen, SE, Borg, A, Bozsik, A, Brady, AF, Brennan, P, Brewer, C, Brunet, J, Bucalo, A, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cassingham, H, Christensen, LL, Cini, G, Claes, KBM, Cook, J, Coppa, A, Cortesi, L, Damante, G, Darder, E, Davidson, R, de la Hoya, M, De Leeneer, K, de Putter, R, Del Valle, J, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Fostira, F, Frone, M, Frost, D, Gallagher, D, Gehrig, A, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gregory, H, Gross, E, Hahnen, E, Hamann, U, Hansen, TVO, Hanson, H, Hentschel, J, Horvath, J, Izatt, L, Izquierdo, A, James, PA, Janavicius, R, Jensen, UB, Johannsson, OT, John, EM, Kramer, G, Kroeldrup, L, Kruse, TA, Lautrup, C, Lazaro, C, Lesueur, F, Lopez-Fernandez, A, Mai, PL, Manoukian, S, Matrai, Z, Matricardi, L, Maxwell, KN, Mebirouk, N, Meindl, A, Montagna, M, Monteiro, AN, Morrison, PJ, Muranen, TA, Murray, A, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Tu, N-D, Niederacher, D, Olah, E, Olopade, O, Palli, D, Parsons, MT, Pedersen, IS, Peissel, B, Perez-Segura, P, Peterlongo, P, Petersen, AH, Pinto, P, Porteous, ME, Pottinger, C, Pujana, MA, Radice, P, Ramser, J, Rantala, J, Robson, M, Rogers, MT, Ronlund, K, Rump, A, Sanchez de Abajo, AM, Shah, PD, Sharif, S, Side, LE, Singer, CF, Stadler, Z, Steele, L, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Tommasi, S, Toss, A, Trainer, AH, Tripathi, V, Valentini, V, van Asperen, CJ, Venturelli, M, Viel, A, Vijai, J, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Whaite, A, Zanna, I, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Ottini, L
Abstract: BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
Published: 2022

23. Rare germline copy number variants (CNVs) and breast cancer risk

Author: Dennis, J, Tyrer, JP, Walker, LC, Michailidou, K, Dorling, L, Bolla, MK, Wang, Q, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, Collee, JM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, Jager, A, Jakubowska, A, John, EM, Johnson, N, Jones, ME, Jung, A, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Larson, NL, Linet, M, Ogrodniczak, A, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Milne, RL, Muranen, TA, Murphy, RA, Nevanlinna, H, Olson, JE, Olsson, H, Park-Simon, T-W, Perou, CM, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shibli, R, Smeets, A, Soucy, P, Southey, MC, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Teras, LR, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wendt, C, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Simard, J, Dunning, AM, Pharoah, PDP, Easton, DF, Dennis, J, Tyrer, JP, Walker, LC, Michailidou, K, Dorling, L, Bolla, MK, Wang, Q, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, Collee, JM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, Jager, A, Jakubowska, A, John, EM, Johnson, N, Jones, ME, Jung, A, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Larson, NL, Linet, M, Ogrodniczak, A, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Milne, RL, Muranen, TA, Murphy, RA, Nevanlinna, H, Olson, JE, Olsson, H, Park-Simon, T-W, Perou, CM, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shibli, R, Smeets, A, Soucy, P, Southey, MC, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Teras, LR, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wendt, C, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Simard, J, Dunning, AM, Pharoah, PDP, and Easton, DF
Abstract: Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
Published: 2022

24. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author: Li, S, Silvestri, V, Leslie, G, Rebbeck, TR, Neuhausen, SL, Hopper, JL, Nielsen, HR, Lee, A, Yang, X, McGuffog, L, Parsons, MT, Andrulis, IL, Arnold, N, Belotti, M, Borg, A, Buecher, B, Buys, SS, Caputo, SM, Chung, WK, Colas, C, Colonna, S, Cook, J, Daly, MB, de la Hoya, M, de Pauw, A, Delhomelle, H, Eason, J, Engel, C, Evans, DG, Faust, U, Fehm, TN, Fostira, F, Fountzilas, G, Frone, M, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Gehrig, A, Glendon, G, Goldgar, DE, Golmard, L, Greene, MH, Hahnen, E, Hamann, U, Hanson, H, Hassan, T, Hentschel, J, Horvath, J, Izatt, L, Janavicius, R, Jiao, Y, John, EM, Karlan, BY, Kim, S-W, Konstantopoulou, I, Kwong, A, Lauge, A, Lee, JW, Lesueur, F, Mebirouk, N, Meindl, A, Mouret-Fourme, E, Musgrave, H, Yie, JNY, Niederacher, D, Park, SK, Pedersen, IS, Ramser, J, Ramus, SJ, Rantala, J, Rashid, MU, Reichl, F, Ritter, J, Rump, A, Santamarina, M, Saule, C, Schmidt, G, Schmutzler, RK, Senter, L, Shariff, S, Singer, CF, Southey, MC, Stoppa-Lyonnet, D, Sutter, C, Tan, Y, Teo, SH, Terry, MB, Thomassen, M, Tischkowitz, M, Toland, AE, Torres, D, Vega, A, Wagner, SA, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Spurdle, AB, Easton, DF, Chenevix-Trench, G, Ottini, L, Antoniou, AC, Li, S, Silvestri, V, Leslie, G, Rebbeck, TR, Neuhausen, SL, Hopper, JL, Nielsen, HR, Lee, A, Yang, X, McGuffog, L, Parsons, MT, Andrulis, IL, Arnold, N, Belotti, M, Borg, A, Buecher, B, Buys, SS, Caputo, SM, Chung, WK, Colas, C, Colonna, S, Cook, J, Daly, MB, de la Hoya, M, de Pauw, A, Delhomelle, H, Eason, J, Engel, C, Evans, DG, Faust, U, Fehm, TN, Fostira, F, Fountzilas, G, Frone, M, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Gehrig, A, Glendon, G, Goldgar, DE, Golmard, L, Greene, MH, Hahnen, E, Hamann, U, Hanson, H, Hassan, T, Hentschel, J, Horvath, J, Izatt, L, Janavicius, R, Jiao, Y, John, EM, Karlan, BY, Kim, S-W, Konstantopoulou, I, Kwong, A, Lauge, A, Lee, JW, Lesueur, F, Mebirouk, N, Meindl, A, Mouret-Fourme, E, Musgrave, H, Yie, JNY, Niederacher, D, Park, SK, Pedersen, IS, Ramser, J, Ramus, SJ, Rantala, J, Rashid, MU, Reichl, F, Ritter, J, Rump, A, Santamarina, M, Saule, C, Schmidt, G, Schmutzler, RK, Senter, L, Shariff, S, Singer, CF, Southey, MC, Stoppa-Lyonnet, D, Sutter, C, Tan, Y, Teo, SH, Terry, MB, Thomassen, M, Tischkowitz, M, Toland, AE, Torres, D, Vega, A, Wagner, SA, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Spurdle, AB, Easton, DF, Chenevix-Trench, G, Ottini, L, and Antoniou, AC
Abstract: PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management. METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment. RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.
Published: 2022

25. Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes

Author: Mavaddat, N, Dorling, L, Carvalho, S, Allen, J, Gonzalez-Neira, A, Keeman, R, Bolla, MK, Dennis, J, Wang, Q, Ahearn, TU, Andrulis, IL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Briceno, I, Bruning, T, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Christiansen, H, Czene, K, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Geisler, J, Giles, GG, Guenel, P, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Hartikainen, JM, Hartman, M, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, EK, Kristensen, VN, Li, J, Lim, SH, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Taib, NAM, Morra, A, Muir, K, Obi, N, Osorio, A, Park-Simon, T-W, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Thorne, H, Tomlinson, I, Torres, D, Truong, T, Yip, CH, Spurdle, AB, Vreeswijk, MPG, Dunning, AM, Garcia-Closas, M, Pharoah, PDP, Kvist, A, Muranen, TA, Nevanlinna, H, Teo, SH, Devilee, P, Schmidt, MK, Easton, DF, Mavaddat, N, Dorling, L, Carvalho, S, Allen, J, Gonzalez-Neira, A, Keeman, R, Bolla, MK, Dennis, J, Wang, Q, Ahearn, TU, Andrulis, IL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Briceno, I, Bruning, T, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Christiansen, H, Czene, K, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Geisler, J, Giles, GG, Guenel, P, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Hartikainen, JM, Hartman, M, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, EK, Kristensen, VN, Li, J, Lim, SH, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Taib, NAM, Morra, A, Muir, K, Obi, N, Osorio, A, Park-Simon, T-W, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Thorne, H, Tomlinson, I, Torres, D, Truong, T, Yip, CH, Spurdle, AB, Vreeswijk, MPG, Dunning, AM, Garcia-Closas, M, Pharoah, PDP, Kvist, A, Muranen, TA, Nevanlinna, H, Teo, SH, Devilee, P, Schmidt, MK, and Easton, DF
Abstract: IMPORTANCE: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. DESIGN, SETTING, AND PARTICIPANTS: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021. EXPOSURES: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. MAIN OUTCOMES AND MEASURES: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. RESULTS: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subt
Published: 2022

26. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author: Hakkaart, C, Pearson, JF, Marquart, L, Dennis, J, Wiggins, GAR, Barnes, DR, Robinson, BA, Mace, PD, Aittomaki, K, Andrulis, IL, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Belhadj, S, Berger, L, Blok, MJ, Boonen, SE, Borde, J, Bradbury, AR, Brunet, J, Buys, SS, Caligo, MA, Campbell, I, Chung, WK, Claes, KBM, Collonge-Rame, M-A, Cook, J, Cosgrove, C, Couch, FJ, Daly, MB, Dandiker, S, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Dhawan, M, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Easton, DF, Ehrencrona, H, Engel, C, Evans, DG, Faust, U, Feliubadalo, L, Fostira, F, Friedman, E, Frone, M, Frost, D, Garber, J, Gayther, SA, Gehrig, A, Gesta, P, Godwin, AK, Goldgar, DE, Greene, MH, Hahnen, E, Hake, CR, Hamann, U, Hansen, TVO, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kemp, Z, Kirk, J, Konstantopoulou, I, Koudijs, M, Kwong, A, Laitman, Y, Lalloo, F, Lasset, C, Lautrup, C, Lazaro, C, Legrand, C, Leslie, G, Lesueur, F, Mai, PL, Manoukian, S, Mari, V, Martens, JWM, McGuffog, L, Mebirouk, N, Meindl, A, Miller, A, Montagna, M, Moserle, L, Mouret-Fourme, E, Musgrave, H, Nambot, S, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nguyen-Dumont, T, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, OI, Osorio, A, Ott, C-E, Park, SK, Parsons, MT, Pedersen, IS, Peixoto, A, Perez-Segura, P, Peterlongo, P, Pocza, T, Radice, P, Ramser, J, Rantala, J, Rodriguez, GC, Ronlund, K, Rosenberg, EH, Rossing, M, Schmutzler, RK, Shah, PD, Sharif, S, Sharma, P, Side, LE, Simard, J, Singer, CF, Snape, K, Steinemann, D, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Trainer, AH, Tripathi, V, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Viel, A, Walker, L, Weitzel, JN, Wevers, MR, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, Walker, LC, Hakkaart, C, Pearson, JF, Marquart, L, Dennis, J, Wiggins, GAR, Barnes, DR, Robinson, BA, Mace, PD, Aittomaki, K, Andrulis, IL, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Belhadj, S, Berger, L, Blok, MJ, Boonen, SE, Borde, J, Bradbury, AR, Brunet, J, Buys, SS, Caligo, MA, Campbell, I, Chung, WK, Claes, KBM, Collonge-Rame, M-A, Cook, J, Cosgrove, C, Couch, FJ, Daly, MB, Dandiker, S, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Dhawan, M, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Easton, DF, Ehrencrona, H, Engel, C, Evans, DG, Faust, U, Feliubadalo, L, Fostira, F, Friedman, E, Frone, M, Frost, D, Garber, J, Gayther, SA, Gehrig, A, Gesta, P, Godwin, AK, Goldgar, DE, Greene, MH, Hahnen, E, Hake, CR, Hamann, U, Hansen, TVO, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kemp, Z, Kirk, J, Konstantopoulou, I, Koudijs, M, Kwong, A, Laitman, Y, Lalloo, F, Lasset, C, Lautrup, C, Lazaro, C, Legrand, C, Leslie, G, Lesueur, F, Mai, PL, Manoukian, S, Mari, V, Martens, JWM, McGuffog, L, Mebirouk, N, Meindl, A, Miller, A, Montagna, M, Moserle, L, Mouret-Fourme, E, Musgrave, H, Nambot, S, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nguyen-Dumont, T, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, OI, Osorio, A, Ott, C-E, Park, SK, Parsons, MT, Pedersen, IS, Peixoto, A, Perez-Segura, P, Peterlongo, P, Pocza, T, Radice, P, Ramser, J, Rantala, J, Rodriguez, GC, Ronlund, K, Rosenberg, EH, Rossing, M, Schmutzler, RK, Shah, PD, Sharif, S, Sharma, P, Side, LE, Simard, J, Singer, CF, Snape, K, Steinemann, D, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Trainer, AH, Tripathi, V, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Viel, A, Walker, L, Weitzel, JN, Wevers, MR, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, and Walker, LC
Abstract: The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
Published: 2022

27. Cancer risk and tumour spectrum in 172 patients with a germline SUFU pathogenic variation: a collaborative study of the SIOPE Host Genome Working Group

Author: Guerrini-Rousseau, L, Masliah-Planchon, J, Waszak, SM, Alhopuro, P, Benusiglio, PR, Bourdeaut, F, Brecht, IB, Del Baldo, G, Dhanda, SK, Garre, ML, Gidding, CEM, Hirsch, S, Hoarau, P, Jorgensen, M, Kratz, C, Lafay-Cousin, L, Mastronuzzi, A, Pastorino, L, Pfister, SM, Schroeder, C, Smith, MJ, Vahteristo, P, Vibert, R, Vilain, C, Waespe, N, Winship, IM, Evans, DG, Brugieres, L, Guerrini-Rousseau, L, Masliah-Planchon, J, Waszak, SM, Alhopuro, P, Benusiglio, PR, Bourdeaut, F, Brecht, IB, Del Baldo, G, Dhanda, SK, Garre, ML, Gidding, CEM, Hirsch, S, Hoarau, P, Jorgensen, M, Kratz, C, Lafay-Cousin, L, Mastronuzzi, A, Pastorino, L, Pfister, SM, Schroeder, C, Smith, MJ, Vahteristo, P, Vibert, R, Vilain, C, Waespe, N, Winship, IM, Evans, DG, and Brugieres, L
Abstract: BACKGROUND: Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome. METHODS: To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline SUFU PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with SUFU PV (89 patients) using the Nelson-Aalen estimator. RESULTS: Overall, 117/172 (68%) SUFU PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated. CONCLUSION: Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.
Published: 2022

28. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Author: Moller, P, Seppala, T, Dowty, JG, Haupt, S, Dominguez-Valentin, M, Sunde, L, Bernstein, I, Engel, C, Aretz, S, Nielsen, M, Capella, G, Evans, DG, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J-P, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Half, E, Lopez-Koestner, F, Alvarez-Valenzuela, K, Scott, RJ, Katz, L, Laish, I, Vainer, E, Vaccaro, CA, Carraro, DM, Gluck, N, Abu-Freha, N, Stakelum, A, Kennelly, R, Winter, D, Rossi, BM, Greenblatt, M, Bohorquez, M, Sheth, H, Tibiletti, MG, Lino-Silva, LS, Horisberger, K, Portenkirchner, C, Nascimento, I, Rossi, NT, da Silva, LA, Thomas, H, Zarand, A, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, P, Therkildsen, C, Lindberg, LJ, Thorlacius-Ussing, O, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hueneburg, R, de Vargas, AF, Latchford, A, Gerdes, A-M, Backman, A-S, Guillen-Ponce, C, Snyder, C, Lautrup, CK, Amor, D, Palmero, E, Stoffel, E, Duijkers, F, Hall, MJ, Hampel, H, Williams, H, Okkels, H, Lubinski, J, Reece, J, Ngeow, J, Guillem, JG, Arnold, J, Wadt, K, Monahan, K, Senter, L, Rasmussen, LJ, van Hest, LP, Ricciardiello, L, Kohonen-Corish, MRJ, Ligtenberg, MJL, Southey, M, Aronson, M, Zahary, MN, Samadder, NJ, Poplawski, N, Hoogerbrugge, N, Morrison, PJ, James, P, Lee, G, Chen-Shtoyerman, R, Ankathil, R, Pai, R, Ward, R, Parry, S, Debniak, T, John, T, van Overeem Hansen, T, Caldes, T, Yamaguchi, T, Barca-Tierno, V, Garre, P, Cavestro, GM, Weitz, J, Redler, S, Buettner, R, Heuveline, V, Hopper, JL, Win, AK, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, J, Buchanan, DD, Thibodeau, SN, ten Broeke, SW, Hovig, E, Nakken, S, Pineda, M, Duenas, N, Brunet, J, Green, K, Lalloo, F, Newton, K, Crosbie, EJ, Mints, M, Tjandra, D, Neffa, F, Esperon, P, Kariv, R, Rosner, G, Pavicic, WH, Kalfayan, P, Torrezan, GT, Bassaneze, T, Martin, C, Moslein, G, Ahadova, A, Kloor, M, Sampson, JR, Jenkins, MA, Moller, P, Seppala, T, Dowty, JG, Haupt, S, Dominguez-Valentin, M, Sunde, L, Bernstein, I, Engel, C, Aretz, S, Nielsen, M, Capella, G, Evans, DG, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J-P, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Half, E, Lopez-Koestner, F, Alvarez-Valenzuela, K, Scott, RJ, Katz, L, Laish, I, Vainer, E, Vaccaro, CA, Carraro, DM, Gluck, N, Abu-Freha, N, Stakelum, A, Kennelly, R, Winter, D, Rossi, BM, Greenblatt, M, Bohorquez, M, Sheth, H, Tibiletti, MG, Lino-Silva, LS, Horisberger, K, Portenkirchner, C, Nascimento, I, Rossi, NT, da Silva, LA, Thomas, H, Zarand, A, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, P, Therkildsen, C, Lindberg, LJ, Thorlacius-Ussing, O, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hueneburg, R, de Vargas, AF, Latchford, A, Gerdes, A-M, Backman, A-S, Guillen-Ponce, C, Snyder, C, Lautrup, CK, Amor, D, Palmero, E, Stoffel, E, Duijkers, F, Hall, MJ, Hampel, H, Williams, H, Okkels, H, Lubinski, J, Reece, J, Ngeow, J, Guillem, JG, Arnold, J, Wadt, K, Monahan, K, Senter, L, Rasmussen, LJ, van Hest, LP, Ricciardiello, L, Kohonen-Corish, MRJ, Ligtenberg, MJL, Southey, M, Aronson, M, Zahary, MN, Samadder, NJ, Poplawski, N, Hoogerbrugge, N, Morrison, PJ, James, P, Lee, G, Chen-Shtoyerman, R, Ankathil, R, Pai, R, Ward, R, Parry, S, Debniak, T, John, T, van Overeem Hansen, T, Caldes, T, Yamaguchi, T, Barca-Tierno, V, Garre, P, Cavestro, GM, Weitz, J, Redler, S, Buettner, R, Heuveline, V, Hopper, JL, Win, AK, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, J, Buchanan, DD, Thibodeau, SN, ten Broeke, SW, Hovig, E, Nakken, S, Pineda, M, Duenas, N, Brunet, J, Green, K, Lalloo, F, Newton, K, Crosbie, EJ, Mints, M, Tjandra, D, Neffa, F, Esperon, P, Kariv, R, Rosner, G, Pavicic, WH, Kalfayan, P, Torrezan, GT, Bassaneze, T, Martin, C, Moslein, G, Ahadova, A, Kloor, M, Sampson, JR, and Jenkins, MA
Abstract: OBJECTIVE: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. METHODS: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. RESULTS: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. CONCLUSIONS: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
Published: 2022

29. Incorporating progesterone receptor expression into the PREDICT breast prognostic model

Author: Grootes, I, Keeman, R, Blows, FM, Milne, RL, Giles, GG, Swerdlow, AJ, Fasching, PA, Abubakar, M, Andrulis, IL, Anton-Culver, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Bonanni, B, Briceno, I, Burwinkel, B, Camp, NJ, Castelao, JE, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Ernst, K, Evans, DG, Figueroa, JD, Fink, V, Floris, G, Fox, S, Gabrielson, M, Gago-Dominguez, M, Garcia-Saenz, JA, Gonzalez-Neira, A, Haeberle, L, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hein, A, Hooning, MJ, Hou, M-F, Howell, SJ, Ito, H, Jakubowska, A, Janni, W, John, EM, Jung, A, Kang, D, Kristensen, VN, Kwong, A, Lambrechts, D, Li, J, Manoochehri, M, Margolin, S, Matsuo, K, Taib, NAM, Mulligan, AM, Nevanlinna, H, Newman, WG, Offit, K, Osorio, A, Park, SK, Park-Simon, T-W, Patel, A, Presneau, N, Pylkas, K, Rack, B, Radice, P, Rennert, G, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schochter, F, Schoemaker, MJ, Shen, C-Y, Shibli, R, Sinn, P, Tapper, WJ, Tawfiq, E, Teo, SH, Teras, LR, Torres, D, Vachon, CM, van Deurzen, CHM, Wendt, C, Williams, JA, Winqvist, R, Elwood, M, Schmidt, MK, Pharoah, PDP, Grootes, I, Keeman, R, Blows, FM, Milne, RL, Giles, GG, Swerdlow, AJ, Fasching, PA, Abubakar, M, Andrulis, IL, Anton-Culver, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Bonanni, B, Briceno, I, Burwinkel, B, Camp, NJ, Castelao, JE, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Ernst, K, Evans, DG, Figueroa, JD, Fink, V, Floris, G, Fox, S, Gabrielson, M, Gago-Dominguez, M, Garcia-Saenz, JA, Gonzalez-Neira, A, Haeberle, L, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hein, A, Hooning, MJ, Hou, M-F, Howell, SJ, Ito, H, Jakubowska, A, Janni, W, John, EM, Jung, A, Kang, D, Kristensen, VN, Kwong, A, Lambrechts, D, Li, J, Manoochehri, M, Margolin, S, Matsuo, K, Taib, NAM, Mulligan, AM, Nevanlinna, H, Newman, WG, Offit, K, Osorio, A, Park, SK, Park-Simon, T-W, Patel, A, Presneau, N, Pylkas, K, Rack, B, Radice, P, Rennert, G, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schochter, F, Schoemaker, MJ, Shen, C-Y, Shibli, R, Sinn, P, Tapper, WJ, Tawfiq, E, Teo, SH, Teras, LR, Torres, D, Vachon, CM, van Deurzen, CHM, Wendt, C, Williams, JA, Winqvist, R, Elwood, M, Schmidt, MK, and Pharoah, PDP
Abstract: BACKGROUND: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2). METHOD: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance. RESULTS: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted. CONCLUSION: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.
Published: 2022

30. Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author: Dorling, L, Carvalho, S, Allen, J, Parsons, MT, Fortuno, C, Gonzalez-Neira, A, Heijl, SM, Adank, MA, Ahearn, TU, Andrulis, IL, Auvinen, P, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bremer, M, Briceno, I, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Collee, JM, Czene, K, Dennis, J, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Glendon, G, Guenel, P, Gundert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, E, Kim, S-W, Ko, Y-D, Kristensen, VN, Lakeman, IMM, Li, J, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Luccarini, C, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Mohd Taib, NA, Muir, K, Nevanlinna, H, Newman, WG, Oosterwijk, JC, Park, SK, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Surowy, H, Suvanto, M, Tomlinson, I, Torres, D, Truong, T, van Asperen, CJ, Waltes, R, Wang, Q, Yang, XR, Pharoah, PDP, Schmidt, MK, Benitez, J, Vroling, B, Dunning, AM, Teo, SH, Kvist, A, de la Hoya, M, Devilee, P, Spurdle, AB, Vreeswijk, MPG, Easton, DF, Dorling, L, Carvalho, S, Allen, J, Parsons, MT, Fortuno, C, Gonzalez-Neira, A, Heijl, SM, Adank, MA, Ahearn, TU, Andrulis, IL, Auvinen, P, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bremer, M, Briceno, I, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Collee, JM, Czene, K, Dennis, J, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Glendon, G, Guenel, P, Gundert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, E, Kim, S-W, Ko, Y-D, Kristensen, VN, Lakeman, IMM, Li, J, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Luccarini, C, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Mohd Taib, NA, Muir, K, Nevanlinna, H, Newman, WG, Oosterwijk, JC, Park, SK, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Surowy, H, Suvanto, M, Tomlinson, I, Torres, D, Truong, T, van Asperen, CJ, Waltes, R, Wang, Q, Yang, XR, Pharoah, PDP, Schmidt, MK, Benitez, J, Vroling, B, Dunning, AM, Teo, SH, Kvist, A, de la Hoya, M, Devilee, P, Spurdle, AB, Vreeswijk, MPG, and Easton, DF
Abstract: BACKGROUND: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
Published: 2022

31. Cancer Prevention with Resistant Starch in Lynch Syndrome Patients in the CAPP2-Randomized Placebo Controlled Trial: Planned 10-Year Follow-up

Author: Mathers, JC, Elliott, F, Macrae, F, Mecklin, J-P, Moslein, G, McRonald, FE, Bertario, L, Evans, DG, Gerdes, A-M, Ho, JWC, Lindblom, A, Morrison, PJ, Rashbass, J, Ramesar, RS, Seppala, TT, Thomas, HJW, Sheth, HJ, Pylvanainen, K, Reed, L, Borthwick, GM, Bishop, DT, Burn, J, Mathers, JC, Elliott, F, Macrae, F, Mecklin, J-P, Moslein, G, McRonald, FE, Bertario, L, Evans, DG, Gerdes, A-M, Ho, JWC, Lindblom, A, Morrison, PJ, Rashbass, J, Ramesar, RS, Seppala, TT, Thomas, HJW, Sheth, HJ, Pylvanainen, K, Reed, L, Borthwick, GM, Bishop, DT, and Burn, J
Abstract: The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33-0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non-colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32-0.84; P = 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non-colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62-1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non-colorectal cancer cancers for patients with LS. PREVENTION RELEVANCE: Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic
Published: 2022

32. Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies

Author: Jung, AY, Ahearn, TU, Behrens, S, Middha, P, Bolla, MK, Wang, Q, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Becher, H, Brenner, H, Canzian, F, Carey, LA, Consortium, C, Czene, K, Eliassen, AH, Eriksson, M, Evans, DG, Figueroa, JD, Fritschi, L, Gabrielson, M, Giles, GG, Guenel, P, Hadjisavvas, A, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Huesing, A, Kaaks, R, Kosma, V-M, Koutros, S, Kraft, P, Lacey, J, Le Marchand, L, Lissowska, J, Loizidou, MA, Mannermaa, A, Maurer, T, Murphy, RA, Olshan, AF, Olsson, H, Patel, A, Perou, CM, Rennert, G, Shibli, R, Shu, X-O, Southey, MC, Stone, J, Tamimi, RM, Teras, LR, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Wolk, A, Wu, AH, Yang, XR, Zheng, W, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Chatterjee, N, Schmidt, MK, Garcia-Closas, M, Chang-Claude, J, Jung, AY, Ahearn, TU, Behrens, S, Middha, P, Bolla, MK, Wang, Q, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Becher, H, Brenner, H, Canzian, F, Carey, LA, Consortium, C, Czene, K, Eliassen, AH, Eriksson, M, Evans, DG, Figueroa, JD, Fritschi, L, Gabrielson, M, Giles, GG, Guenel, P, Hadjisavvas, A, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Huesing, A, Kaaks, R, Kosma, V-M, Koutros, S, Kraft, P, Lacey, J, Le Marchand, L, Lissowska, J, Loizidou, MA, Mannermaa, A, Maurer, T, Murphy, RA, Olshan, AF, Olsson, H, Patel, A, Perou, CM, Rennert, G, Shibli, R, Shu, X-O, Southey, MC, Stone, J, Tamimi, RM, Teras, LR, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Wolk, A, Wu, AH, Yang, XR, Zheng, W, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Chatterjee, N, Schmidt, MK, Garcia-Closas, M, and Chang-Claude, J
Abstract: BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all
Published: 2022

33. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Author: Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Lynch, BM, Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, and Lynch, BM
Abstract: OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer r
Published: 2022

34. Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

Author: Loveday, C, Garrett, A, Law, P, Hanks, S, Poyastro-Pearson, E, Adlard, JW, Barwell, J, Berg, J, Brady, AF, Brewer, C, Chapman, C, Cook, J, Davidson, R, Donaldson, A, Douglas, F, Greenhalgh, L, Henderson, A, Izatt, L, Kumar, A, Lalloo, F, Miedzybrodzka, Z, Morrison, PJ, Paterson, J, Porteous, M, Rogers, MT, Walker, L, Breast and Ovarian Cancer Susceptibility Collaboration, Eccles, D, Evans, DG, Snape, K, Hanson, H, Houlston, RS, Turnbull, C, Loveday, C, Garrett, A, Law, P, Hanks, S, Poyastro-Pearson, E, Adlard, JW, Barwell, J, Berg, J, Brady, AF, Brewer, C, Chapman, C, Cook, J, Davidson, R, Donaldson, A, Douglas, F, Greenhalgh, L, Henderson, A, Izatt, L, Kumar, A, Lalloo, F, Miedzybrodzka, Z, Morrison, PJ, Paterson, J, Porteous, M, Rogers, MT, Walker, L, Breast and Ovarian Cancer Susceptibility Collaboration, Eccles, D, Evans, DG, Snape, K, Hanson, H, Houlston, RS, and Turnbull, C
Abstract: BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of
Published: 2022

35. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Author: Hendricks, Laj, Hoogerbrugge, N, Venselaar, H, Aretz, S, Spier, I, Legius, E, Brems, H, de Putter, R, Claes, Kbm, Evans, Dg, Woodward, Er, Genuardi, Maurizio, Brugnoletti, F, van Ierland, Y, Dijke, K, Tham, E, Tesi, B, Schuurs-Hoeijmakers, Jhm, Branchaud, M, Salvador, H, Jahn, A, Schnaiter, S, Anastasiadou, Vc, Brunet, J, Oliveira, C, Roht, L, Blatnik, A, Irmejs, A, Mensenkamp, Ar, Vos, Jr, Genuardi M (ORCID:0000-0002-7410-8351), Hendricks, Laj, Hoogerbrugge, N, Venselaar, H, Aretz, S, Spier, I, Legius, E, Brems, H, de Putter, R, Claes, Kbm, Evans, Dg, Woodward, Er, Genuardi, Maurizio, Brugnoletti, F, van Ierland, Y, Dijke, K, Tham, E, Tesi, B, Schuurs-Hoeijmakers, Jhm, Branchaud, M, Salvador, H, Jahn, A, Schnaiter, S, Anastasiadou, Vc, Brunet, J, Oliveira, C, Roht, L, Blatnik, A, Irmejs, A, Mensenkamp, Ar, Vos, Jr, and Genuardi M (ORCID:0000-0002-7410-8351)
Abstract: Background: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age. Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2. Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants. Keywords: Genetic association studies; Genetic variation; Human genetics; Medical oncology; Phenotype.
Published: 2022

36. European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender

Author: Seppälä, TT, Latchford, A, Negoi, I, Soares, AS, Jimenez-Rodriguez, R, Sánchez-Guillén, L, Evans, DG, Ryan, N, Crosbie, EJ, Dominguez-Valentin, M, Burn, J, Kloor, M, von Knebel Doeberitz, M, van Duijnhoven, JB, Quirke, P, Sampson, JR, Møller, P, Möslein, G, and the European Hereditary Tumour Group (EHTG) and European Society
Abstract: Background Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene‐ and gender‐specific guidelines has been acknowledged. Methods The European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) developed a multidisciplinary working group consisting of surgeons, clinical and molecular geneticists, pathologists, epidemiologists, gastroenterologists, and patient representation to conduct a graded evidence review. The previous Mallorca guideline format was used to revise the clinical guidance. Consensus for the guidance statements was acquired by three Delphi voting rounds. Results Recommendations for clinical and molecular identification of Lynch syndrome, surgical and endoscopic management of Lynch syndrome‐associated colorectal cancer, and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum. Manchester consensus guidelines for gynaecological management were endorsed. Executive and layperson summaries were provided. Conclusion The recommendations from the EHTG and ESCP for identification of patients with Lynch syndrome, colorectal surveillance, surgical management of colorectal cancer, lifestyle and chemoprevention in Lynch syndrome that reached a consensus (at least 80 per cent) are presented.
Published: 2021

37. Characterising the loss-of-function impact of 5 ' untranslated region variants in 15,708 individuals (vol 11, 2523, 2020)

Author: Whiffin, N, Karczewski, KJ, Zhang, X, Chothani, S, Smith, MJ, Evans, DG, Roberts, AM, Quaife, NM, Schafer, S, Rackham, O, Alfoeldi, J, O'Donnell-Luria, AH, Francioli, LC, Armean, IM, Aguilar Salinas, CA, Cook, SA, Barton, PJR, MacArthur, DG, and Ware, JS
Subjects: Multidisciplinary Sciences, Science & Technology, Genome Aggregation Database Consortium, Science & Technology - Other Topics, Genome Aggregation Database Production Team
Published: 2021

38. Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Author: Park, HA, Neumeyer, S, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baten, A, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Brucker, SY, Burwinkel, B, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Børresen-Dale, A-L, Grenaker Alnæs, GI, Sahlberg, KK, Ottestad, L, Kåresen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebråten, O, Naume, B, Fosså, A, Kiserud, CE, Reinertsen, KV, Helland, Å, Riis, M, Geisler, J, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dörk, T, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grip, M, Guénel, P, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Han, S, Harkness, EF, Hart, SN, He, W, Heemskerk-Gerritsen, BAM, Hopper, JL, Hunter, DJ, Clarke, C, Marsh, D, Scott, R, Baxter, R, Yip, D, Carpenter, J, Davis, A, Pathmanathan, N, Simpson, P, Graham, D, Sachchithananthan, M, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Bennett, I, Bogwitz, M, Botes, L, Brennan, M, Brown, M, Buckley, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Chauhan, D, Chauhan, M, Christian, A, Cohen, P, Colley, A, Crook, A, Cui, J, Cummings, M, Dawson, S-J, DeFazio, A, Delatycki, M, Dickson, R, Dixon, J, Edkins, T, Edwards, S, Farshid, G, Fellows, A, Fenton, G, Field, M, Flanagan, J, Fong, P, Forrest, L, Fox, S, French, J, Friedlander, M, Gaff, C, Gattas, M, George, P, Greening, S, Harris, M, Hart, S, Hayward, N, Hopper, J, Hoskins, C, Hunt, C, James, P, Jenkins, M, Kidd, A, Kirk, J, Koehler, J, Kollias, J, Lakhani, S, Lawrence, M, Lindeman, G, Lipton, L, Lobb, L, Mann, G, McLachlan, SA, Meiser, B, Milne, R, Nightingale, S, O’Connell, S, O’Sullivan, S, Ortega, DG, Pachter, N, Patterson, B, Pearn, A, Phillips, K, Pieper, E, Rickard, E, Robinson, B, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Sexton, A, Shelling, A, Southey, M, Spurdle, A, Taylor, J, Taylor, R, Thorne, H, Trainer, A, Tucker, K, Visvader, J, Walker, L, Williams, R, Winship, I, Young, MA, Jager, A, Jakubowska, A, John, EM, Jung, A, Kaaks, R, Kapoor, PM, Keeman, R, Khusnutdinova, E, Kitahara, CM, Koppert, LB, Koutros, S, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lo, W-Y, Lubiński, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Muranen, TA, Nevanlinna, H, Newman, WG, Nordestgaard, BG, Offit, K, Olshan, AF, Olsson, H, Park-Simon, T-W, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Radice, P, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schoemaker, MJ, Schwentner, L, Shah, M, Shu, X-O, Simard, J, Smeets, A, Southey, MC, Spinelli, JJ, Stevens, V, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, van Veen, EM, Vijai, J, Wang, S, Wendt, C, Winqvist, R, Wolk, A, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Zheng, W, Kraft, P, Chang-Claude, J, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Park, Hanla A. [0000-0001-8055-3729], Dennis, Joe [0000-0003-4591-1214], Augustinsson, Annelie [0000-0003-3415-0536], Brenner, Hermann [0000-0002-6129-1572], Canzian, Federico [0000-0002-4261-4583], Cox, Angela [0000-0002-5138-1099], Devilee, Peter [0000-0002-8023-2009], Fasching, Peter A. [0000-0003-4885-8471], Harkness, Elaine F. [0000-0001-6625-7739], Hart, Steven N. [0000-0001-7714-2734], Heemskerk-Gerritsen, Bernadette A. M. [0000-0002-9724-6693], Jakubowska, Anna [0000-0002-5650-0501], Kapoor, Pooja Middha [0000-0001-5503-8215], Kurian, Allison W. [0000-0002-6175-9470], Newman, William G. [0000-0002-6382-4678], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Sawyer, Elinor J. [0000-0001-8285-4111], Scott, Christopher [0000-0003-1340-0647], Smeets, Ann [0000-0002-5091-6602], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Pharoah, Paul D. P. [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Medicin och hälsovetenskap, Cancer Research, Genotyping Techniques, Breast Neoplasms, Case-Control Studies, Cigarette Smoking, Female, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, ALCOHOL, Medical and Health Sciences, 0302 clinical medicine, Breast cancer, Pleiotropy, Epidemiology, Medicine, TOBACCO, Breast Neoplasms/epidemiology, Cigarette Smoking/adverse effects, WOMEN, ASSOCIATION, Single Nucleotide, 3. Good health, Substance abuse, 692/699/67/1347, 030220 oncology & carcinogenesis, Life Sciences & Biomedicine, 692/499, medicine.medical_specialty, 3122 Cancers, Single-nucleotide polymorphism, Article, 03 medical and health sciences, Internal medicine, ddc:610, Polymorphism, Genetic association, Science & Technology, business.industry, Cancer, medicine.disease, 030104 developmental biology, Clinical research, Risk factors, TISSUE, INFERENCE, CIGARETTE-SMOKING, business
Abstract: Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P = 0.11 × 10–2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
Published: 2021

39. European guidelines from theEHTGandESCPfor Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender

Author: Seppälä TT, Latchford A, Negoi I, Sampaio Soares A, Jimenez-Rodriguez R, Sánchez-Guillén L, Evans DG, Ryan N, Crosbie EJ, Dominguez-Valentin M, Burn J, Kloor M, Knebel Doeberitz MV, Duijnhoven FJBV, Quirke P, Sampson JR, Møller P, Möslein G, and European Hereditary Tumour Group (EHTG) and European Society of Coloproctology
Abstract: Background Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene- and gender-specific guidelines has been acknowledged. Methods The European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) developed a multidisciplinary working group consisting of surgeons, clinical and molecular geneticists, pathologists, epidemiologists, gastroenterologists, and patient representation to conduct a graded evidence review. The previous Mallorca guideline format was used to revise the clinical guidance. Consensus for the guidance statements was acquired by three Delphi voting rounds. Results Recommendations for clinical and molecular identification of Lynch syndrome, surgical and endoscopic management of Lynch syndrome-associated colorectal cancer, and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum. Manchester consensus guidelines for gynaecological management were endorsed. Executive and layperson summaries were provided. Conclusion The recommendations from the EHTG and ESCP for identification of patients with Lynch syndrome, colorectal surveillance, surgical management of colorectal cancer, lifestyle and chemoprevention in Lynch syndrome that reached a consensus (at least 80 per cent) are presented.
Published: 2021

40. Survival from breast cancer in women with a BRCA2 mutation by treatment

Author: Evans, DG, Phillips, K-A, Milne, RL, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, SA, Evans, DG, Phillips, K-A, Milne, RL, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, and Narod, SA
Abstract: BACKGROUND: The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateral oophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation. METHODS: We identified 664 women with stage I-III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features. RESULTS: The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR = 1.23 (95% CI, 0.62-2.45, p = 0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR = 0.45; 95% CI, 0.28-0.72, p = 0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65-1.53: p = 0.56). CONCLUSIONS: For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.
Published: 2021

41. Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium

Author: Morra, A, Jung, AY, Behrens, S, Keeman, R, Ahearn, TU, Anton-Culver, H, Arndt, V, Augustinsson, A, Auvinen, PK, Freeman, LEB, Becher, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Brenner, H, Briceno, I, Brucker, SY, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Egan, KM, Evans, DG, Fasching, PA, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Grip, M, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Han, SN, Hart, SN, Hartman, M, Heyworth, JS, Hoppe, R, Hopper, JL, Hunter, DJ, Ito, H, Jager, A, Jakimovska, M, Jakubowska, A, Janni, W, Kaaks, R, Kang, D, Kapoor, PM, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Mariapun, S, Matsuo, K, Mavroudis, D, Milne, RL, Muranen, TA, Newman, WG, Noh, D-Y, Nordestgaard, BG, Obi, N, Olshan, AF, Olsson, H, Park-Simon, T-W, Petridis, C, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rashid, MU, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schwentner, L, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Tamimi, RM, Tapper, W, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Wang, SS, Williams, JA, Winqvist, R, Wolk, A, Wu, AH, Yoo, K-Y, Yu, J-C, Zheng, W, Ziogas, A, Yang, XR, Eliassen, AH, Holmes, MD, Garcia-Closas, M, Teo, SH, Schmidt, MK, Chang-Claude, J, Morra, A, Jung, AY, Behrens, S, Keeman, R, Ahearn, TU, Anton-Culver, H, Arndt, V, Augustinsson, A, Auvinen, PK, Freeman, LEB, Becher, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Brenner, H, Briceno, I, Brucker, SY, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Egan, KM, Evans, DG, Fasching, PA, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Grip, M, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Han, SN, Hart, SN, Hartman, M, Heyworth, JS, Hoppe, R, Hopper, JL, Hunter, DJ, Ito, H, Jager, A, Jakimovska, M, Jakubowska, A, Janni, W, Kaaks, R, Kang, D, Kapoor, PM, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Mariapun, S, Matsuo, K, Mavroudis, D, Milne, RL, Muranen, TA, Newman, WG, Noh, D-Y, Nordestgaard, BG, Obi, N, Olshan, AF, Olsson, H, Park-Simon, T-W, Petridis, C, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rashid, MU, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schwentner, L, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Tamimi, RM, Tapper, W, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Wang, SS, Williams, JA, Winqvist, R, Wolk, A, Wu, AH, Yoo, K-Y, Yu, J-C, Zheng, W, Ziogas, A, Yang, XR, Eliassen, AH, Holmes, MD, Garcia-Closas, M, Teo, SH, Schmidt, MK, and Chang-Claude, J
Abstract: BACKGROUND: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. METHODS: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. RESULTS: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (P adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking. CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
Published: 2021

42. Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study

Author: Schrijver, LH, Antoniou, AC, Olsson, H, Mooij, TM, Roos-Blom, M-J, Azarang, L, Adlard, J, Ahmed, M, Barrowdale, D, Davidson, R, Donaldson, A, Eeles, R, Evans, DG, Frost, D, Henderson, A, Izatt, L, Ong, K-R, Bonadona, V, Coupier, I, Faivre, L, Fricker, J-P, Gesta, P, van Engelen, K, Jager, A, Menko, FH, Mourits, MJE, Singer, CF, Tan, YY, Foretova, L, Navratilova, M, Schmutzler, RK, Ellberg, C, Gerdes, A-M, Caldes, T, Simard, J, Olah, E, Jakubowska, A, Rantala, J, Osorio, A, Hopper, JL, Phillips, K-A, Milne, RL, Terry, MB, Nogues, C, Engel, C, Kast, K, Goldgar, DE, van Leeuwen, FE, Easton, DF, Andrieu, N, Rookus, MA, Schrijver, LH, Antoniou, AC, Olsson, H, Mooij, TM, Roos-Blom, M-J, Azarang, L, Adlard, J, Ahmed, M, Barrowdale, D, Davidson, R, Donaldson, A, Eeles, R, Evans, DG, Frost, D, Henderson, A, Izatt, L, Ong, K-R, Bonadona, V, Coupier, I, Faivre, L, Fricker, J-P, Gesta, P, van Engelen, K, Jager, A, Menko, FH, Mourits, MJE, Singer, CF, Tan, YY, Foretova, L, Navratilova, M, Schmutzler, RK, Ellberg, C, Gerdes, A-M, Caldes, T, Simard, J, Olah, E, Jakubowska, A, Rantala, J, Osorio, A, Hopper, JL, Phillips, K-A, Milne, RL, Terry, MB, Nogues, C, Engel, C, Kast, K, Goldgar, DE, van Leeuwen, FE, Easton, DF, Andrieu, N, and Rookus, MA
Abstract: BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a
Published: 2021

43. The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Author: Lakeman, IMM, van den Broek, AJ, Vos, JAM, Barnes, DR, Adlard, J, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Balmana, J, Barrowdale, D, Benitez, J, Borg, A, Caldes, T, Caligo, MA, Chung, WK, Claes, KBM, Collee, JM, Couch, FJ, Daly, MB, Dennis, J, Dhawan, M, Domchek, SM, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Godwin, AK, Goldgar, DE, Hahnen, E, Hake, CR, Hamann, U, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, PA, Janavicius, R, Jensen, UB, Jiao, Y, John, EM, Joseph, V, Karlan, BY, Kets, CM, Konstantopoulou, I, Kwong, A, Legrand, C, Leslie, G, Lesueur, F, Loud, JT, Lubinski, J, Manoukian, S, McGuffog, L, Miller, A, Gomes, DM, Montagna, M, Mouret-Fourme, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Olah, E, Olopade, OI, Park, SK, Parsons, MT, Peterlongo, P, Piedmonte, M, Radice, P, Rantala, J, Rennert, G, Risch, HA, Schmutzler, RK, Sharma, P, Simard, J, Singer, CF, Stadler, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Teule, A, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tung, N, van Rensburg, EJ, Vega, A, Wappenschmidt, B, Devilee, P, van Asperen, CJ, Bernstein, JL, Offit, K, Easton, DF, Rookus, MA, Chenevix-Trench, G, Antoniou, AC, Robson, M, Schmidt, MK, Lakeman, IMM, van den Broek, AJ, Vos, JAM, Barnes, DR, Adlard, J, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Balmana, J, Barrowdale, D, Benitez, J, Borg, A, Caldes, T, Caligo, MA, Chung, WK, Claes, KBM, Collee, JM, Couch, FJ, Daly, MB, Dennis, J, Dhawan, M, Domchek, SM, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Godwin, AK, Goldgar, DE, Hahnen, E, Hake, CR, Hamann, U, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, PA, Janavicius, R, Jensen, UB, Jiao, Y, John, EM, Joseph, V, Karlan, BY, Kets, CM, Konstantopoulou, I, Kwong, A, Legrand, C, Leslie, G, Lesueur, F, Loud, JT, Lubinski, J, Manoukian, S, McGuffog, L, Miller, A, Gomes, DM, Montagna, M, Mouret-Fourme, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Olah, E, Olopade, OI, Park, SK, Parsons, MT, Peterlongo, P, Piedmonte, M, Radice, P, Rantala, J, Rennert, G, Risch, HA, Schmutzler, RK, Sharma, P, Simard, J, Singer, CF, Stadler, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Teule, A, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tung, N, van Rensburg, EJ, Vega, A, Wappenschmidt, B, Devilee, P, van Asperen, CJ, Bernstein, JL, Offit, K, Easton, DF, Rookus, MA, Chenevix-Trench, G, Antoniou, AC, Robson, M, and Schmidt, MK
Abstract: PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
Published: 2021

44. Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk

Author: Kapoor, PM, Mavaddat, N, Choudhury, PP, Wilcox, AN, Lindstrom, S, Behrens, S, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Jung, A, Abu-Ful, Z, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Freeman, LEB, Becher, H, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bojesen, SE, Brauch, H, Brenner, H, Bruening, T, Cai, Q, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chanock, SJ, Chatterjee, N, Chenevix-Trench, G, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dai, JY, Earp, HS, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Gaudet, MM, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hatse, S, Heyworth, J, Holleczek, B, Hoover, RN, Hopper, JL, Howell, A, Hunter, DJ, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Linet, M, Lissowska, J, Llaneza, A, MacInnis, RJ, Martinez, ME, Maurer, T, McLean, C, Neuhausen, SL, Newman, WG, Norman, A, O'Brien, KM, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Perou, CM, Pita, G, Polley, EC, Prentice, RL, Rennert, G, Rennert, HS, Ruddy, KJ, Sandler, DP, Saunders, C, Schoemaker, MJ, Schoettker, B, Schumacher, F, Scott, C, Scott, RJ, Shu, X-O, Smeets, A, Southey, MC, Spinelli, JJ, Stone, J, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Troester, MA, Vachon, CM, van Veen, EM, Wang, X, Weinberg, CR, Weltens, C, Willett, W, Winham, SJ, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Schmidt, MK, Kraft, P, Easton, DF, Milne, RL, Garcia-Closas, M, Chang-Claude, J, Kapoor, PM, Mavaddat, N, Choudhury, PP, Wilcox, AN, Lindstrom, S, Behrens, S, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Jung, A, Abu-Ful, Z, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Freeman, LEB, Becher, H, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bojesen, SE, Brauch, H, Brenner, H, Bruening, T, Cai, Q, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chanock, SJ, Chatterjee, N, Chenevix-Trench, G, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dai, JY, Earp, HS, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Gaudet, MM, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hatse, S, Heyworth, J, Holleczek, B, Hoover, RN, Hopper, JL, Howell, A, Hunter, DJ, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Linet, M, Lissowska, J, Llaneza, A, MacInnis, RJ, Martinez, ME, Maurer, T, McLean, C, Neuhausen, SL, Newman, WG, Norman, A, O'Brien, KM, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Perou, CM, Pita, G, Polley, EC, Prentice, RL, Rennert, G, Rennert, HS, Ruddy, KJ, Sandler, DP, Saunders, C, Schoemaker, MJ, Schoettker, B, Schumacher, F, Scott, C, Scott, RJ, Shu, X-O, Smeets, A, Southey, MC, Spinelli, JJ, Stone, J, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Troester, MA, Vachon, CM, van Veen, EM, Wang, X, Weinberg, CR, Weltens, C, Willett, W, Winham, SJ, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Schmidt, MK, Kraft, P, Easton, DF, Milne, RL, Garcia-Closas, M, and Chang-Claude, J
Abstract: We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
Published: 2021

45. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Morra, A, Escala-Garcia, M, Beesley, J, Keeman, R, Canisius, S, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Augustinsson, A, Freeman, LEB, Becher, H, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brenner, H, Bruening, T, Buys, SS, Caan, B, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Cheng, T-YD, Clarke, CL, Colonna, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Dork, T, Dossus, L, Dunning, AM, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, Gago-Dominguez, M, Garcia-Saenz, JA, Giles, GG, Grip, M, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Hartikainen, JM, Hartmann, A, He, W, Hooning, MJ, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, Janni, W, John, EM, Jung, AY, Kaaks, R, Keupers, M, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Linet, M, Luben, RN, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, Michailidou, K, Milne, RL, Mulligan, AM, Muranen, TA, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Olshan, AF, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peissel, B, Peterlongo, P, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Presneau, N, Rack, B, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Lubinski, J, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teras, LR, Terry, MB, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Hurson, AN, Winqvist, R, Wolk, A, Ziogas, A, Brauch, H, Garcia-Closas, M, Pharoah, PDP, Easton, DF, Chenevix-Trench, G, Schmidt, MK, Morra, A, Escala-Garcia, M, Beesley, J, Keeman, R, Canisius, S, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Augustinsson, A, Freeman, LEB, Becher, H, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brenner, H, Bruening, T, Buys, SS, Caan, B, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Cheng, T-YD, Clarke, CL, Colonna, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Dork, T, Dossus, L, Dunning, AM, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, Gago-Dominguez, M, Garcia-Saenz, JA, Giles, GG, Grip, M, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Hartikainen, JM, Hartmann, A, He, W, Hooning, MJ, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, Janni, W, John, EM, Jung, AY, Kaaks, R, Keupers, M, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Linet, M, Luben, RN, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, Michailidou, K, Milne, RL, Mulligan, AM, Muranen, TA, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Olshan, AF, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peissel, B, Peterlongo, P, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Presneau, N, Rack, B, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Lubinski, J, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teras, LR, Terry, MB, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Hurson, AN, Winqvist, R, Wolk, A, Ziogas, A, Brauch, H, Garcia-Closas, M, Pharoah, PDP, Easton, DF, Chenevix-Trench, G, and Schmidt, MK
Abstract: BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast
Published: 2021

46. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author: Johnson, N, Maguire, S, Morra, A, Kapoor, PM, Tomczyk, K, Jones, ME, Schoemaker, MJ, Gilham, C, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baynes, C, Freeman, LEB, Beckmann, MW, Benitez, J, Bermisheva, M, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Burwinkel, B, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Doerk, T, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, Hooning, MJ, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, John, EM, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lambrechts, D, Le Marchand, L, Linet, M, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mavroudis, D, Mayes, R, Meindl, A, Milne, RL, Neuhausen, SL, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Obi, N, Olshan, AF, Olson, JE, Olsson, H, Orban, E, Park-Simon, T-W, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Rennert, HS, Ruddy, KJ, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Scott, C, Shu, X-O, Simard, J, Smichkoska, S, Sohn, C, Southey, MC, Spinelli, JJ, Stone, J, Tamimi, RM, Taylor, JA, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, van Veen, EM, Wang, SS, Weinberg, CR, Wendt, C, Wildiers, H, Winqvist, R, Wolk, A, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Howie, AF, Peto, J, dos-Santos-Silva, I, Swerdlow, AJ, Chang-Claude, J, Schmidt, MK, Orr, N, Fletcher, O, Johnson, N, Maguire, S, Morra, A, Kapoor, PM, Tomczyk, K, Jones, ME, Schoemaker, MJ, Gilham, C, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baynes, C, Freeman, LEB, Beckmann, MW, Benitez, J, Bermisheva, M, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Burwinkel, B, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Doerk, T, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, Hooning, MJ, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, John, EM, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lambrechts, D, Le Marchand, L, Linet, M, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mavroudis, D, Mayes, R, Meindl, A, Milne, RL, Neuhausen, SL, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Obi, N, Olshan, AF, Olson, JE, Olsson, H, Orban, E, Park-Simon, T-W, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Rennert, HS, Ruddy, KJ, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Scott, C, Shu, X-O, Simard, J, Smichkoska, S, Sohn, C, Southey, MC, Spinelli, JJ, Stone, J, Tamimi, RM, Taylor, JA, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, van Veen, EM, Wang, SS, Weinberg, CR, Wendt, C, Wildiers, H, Winqvist, R, Wolk, A, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Howie, AF, Peto, J, dos-Santos-Silva, I, Swerdlow, AJ, Chang-Claude, J, Schmidt, MK, Orr, N, and Fletcher, O
Abstract: BACKGROUND: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. METHODS: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. RESULTS: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8). CONCLUSIONS: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
Published: 2021

47. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers (vol 12, 1078, 2021)

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Published: 2021

48. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants

Author: Fortuno, C, Lee, K, Olivier, M, Pesaran, T, Mai, PL, de Andrade, KC, Attardi, LD, Crowley, S, Evans, DG, Feng, B-J, Foreman, AKM, Frone, MN, Huether, R, James, PA, McGoldrick, K, Mester, J, Seifert, BA, Slavin, TP, Witkowski, L, Zhang, L, Plon, SE, Spurdle, AB, Savage, SA, Fortuno, C, Lee, K, Olivier, M, Pesaran, T, Mai, PL, de Andrade, KC, Attardi, LD, Crowley, S, Evans, DG, Feng, B-J, Foreman, AKM, Frone, MN, Huether, R, James, PA, McGoldrick, K, Mester, J, Seifert, BA, Slavin, TP, Witkowski, L, Zhang, L, Plon, SE, Spurdle, AB, and Savage, SA
Abstract: Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data among experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.
Published: 2021

49. Uptake of hysterectomy and bilateral salpingooophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

Author: Seppala, TT, Dominguez-Valentin, M, Crosbie, EJ, Engel, C, Aretz, S, Macrae, F, Winship, I, Capella, G, Thomas, H, Hovig, E, Nielsen, M, Sijmons, RH, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Mints, M, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Green, K, Lalloo, F, Hill, J, Schmiegel, W, Vangala, D, Perne, C, Strauss, H-G, Tecklenburg, J, Holinski-Feder, E, Steinke-Lange, V, Mecklin, J-P, Plazzer, J-P, Pineda, M, Navarro, M, Vida, JB, Kariv, R, Rosner, G, Pinero, TA, Pavicic, W, Kalfayan, P, Ten Broeke, SW, Jenkins, MA, Sunde, L, Bernstein, I, Burn, J, Greenblatt, M, Cappel, WHDVTN, Della Valle, A, Lopez-Koestner, F, Alvarez, K, Buettner, R, Goergens, H, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Redler, S, Weitz, J, Pylvaenaeinen, K, Renkonen-Sinisalo, L, Lepisto, A, Hopper, JL, Win, AK, Lindor, NM, Gallinger, S, Marchand, LL, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Wadt, KAW, Mourits, MJE, Ketabi, Z, Denton, OG, Rodland, EA, Vasen, H, Neffa, F, Esperon, P, Tjandra, D, Moeslein, G, Rokkones, E, Sampson, JR, Evans, DG, Moller, P, Seppala, TT, Dominguez-Valentin, M, Crosbie, EJ, Engel, C, Aretz, S, Macrae, F, Winship, I, Capella, G, Thomas, H, Hovig, E, Nielsen, M, Sijmons, RH, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Mints, M, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Green, K, Lalloo, F, Hill, J, Schmiegel, W, Vangala, D, Perne, C, Strauss, H-G, Tecklenburg, J, Holinski-Feder, E, Steinke-Lange, V, Mecklin, J-P, Plazzer, J-P, Pineda, M, Navarro, M, Vida, JB, Kariv, R, Rosner, G, Pinero, TA, Pavicic, W, Kalfayan, P, Ten Broeke, SW, Jenkins, MA, Sunde, L, Bernstein, I, Burn, J, Greenblatt, M, Cappel, WHDVTN, Della Valle, A, Lopez-Koestner, F, Alvarez, K, Buettner, R, Goergens, H, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Redler, S, Weitz, J, Pylvaenaeinen, K, Renkonen-Sinisalo, L, Lepisto, A, Hopper, JL, Win, AK, Lindor, NM, Gallinger, S, Marchand, LL, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Wadt, KAW, Mourits, MJE, Ketabi, Z, Denton, OG, Rodland, EA, Vasen, H, Neffa, F, Esperon, P, Tjandra, D, Moeslein, G, Rokkones, E, Sampson, JR, Evans, DG, and Moller, P
Abstract: PURPOSE: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants. METHODS: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years. RESULTS: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery. CONCLUSION: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.
Published: 2021

50. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study

Author: Bancroft, EK, Page, EC, Brook, MN, Thomas, S, Taylor, N, Pope, J, McHugh, J, Jones, A-B, Karlsson, Q, Merson, S, Ong, KR, Hoffman, J, Huber, C, Maehle, L, Grindedal, EM, Stormorken, A, Evans, DG, Rothwell, J, Lalloo, F, Brady, AF, Bartlett, M, Snape, K, Hanson, H, James, P, McKinley, J, Mascarenhas, L, Syngal, S, Ukaegbu, C, Side, L, Thomas, T, Barwell, J, Teixeira, MR, Izatt, L, Suri, M, Macrae, FA, Poplawski, N, Chen-Shtoyerman, R, Ahmed, M, Musgrave, H, Nicolai, N, Greenhalgh, L, Brewer, C, Pachter, N, Spigelman, AD, Azzabi, A, Helfand, BT, Halliday, D, Buys, S, Cajal, TRY, Donaldson, A, Cooney, KA, Harris, M, McGrath, J, Davidson, R, Taylor, A, Cooke, P, Myhill, K, Hogben, M, Aaronson, NK, Ardern-Jones, A, Bangma, CH, Castro, E, Dearnaley, D, Dias, A, Dudderidge, T, Eccles, DM, Green, K, Eyfjord, J, Falconer, A, Foster, CS, Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lilja, H, Lindeman, GJ, Lubinski, J, Axcrona, K, Mikropoulos, C, Mitra, A, Moynihan, C, Raghallaigh, HN, Rennert, G, Collier, R, Offman, J, Kote-Jarai, Z, Eeles, RA, Bancroft, EK, Page, EC, Brook, MN, Thomas, S, Taylor, N, Pope, J, McHugh, J, Jones, A-B, Karlsson, Q, Merson, S, Ong, KR, Hoffman, J, Huber, C, Maehle, L, Grindedal, EM, Stormorken, A, Evans, DG, Rothwell, J, Lalloo, F, Brady, AF, Bartlett, M, Snape, K, Hanson, H, James, P, McKinley, J, Mascarenhas, L, Syngal, S, Ukaegbu, C, Side, L, Thomas, T, Barwell, J, Teixeira, MR, Izatt, L, Suri, M, Macrae, FA, Poplawski, N, Chen-Shtoyerman, R, Ahmed, M, Musgrave, H, Nicolai, N, Greenhalgh, L, Brewer, C, Pachter, N, Spigelman, AD, Azzabi, A, Helfand, BT, Halliday, D, Buys, S, Cajal, TRY, Donaldson, A, Cooney, KA, Harris, M, McGrath, J, Davidson, R, Taylor, A, Cooke, P, Myhill, K, Hogben, M, Aaronson, NK, Ardern-Jones, A, Bangma, CH, Castro, E, Dearnaley, D, Dias, A, Dudderidge, T, Eccles, DM, Green, K, Eyfjord, J, Falconer, A, Foster, CS, Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lilja, H, Lindeman, GJ, Lubinski, J, Axcrona, K, Mikropoulos, C, Mitra, A, Moynihan, C, Raghallaigh, HN, Rennert, G, Collier, R, Offman, J, Kote-Jarai, Z, and Eeles, RA
Abstract: BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This s
Published: 2021

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