Author: "Houlston, RS" / Publication Year Range: Last 10 years - Searchworks@Jio Institute Digital Library Search Results

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277 results on '"Houlston, RS"'

1. 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

2. 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

3. 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

4. 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

5. Elongin C (ELOC/TCEB1) associated von Hippel-Lindau disease

Author: Andreou, A, Yngvadottir, B, Bassaganyas, L, Clarke, G, Martin, E, Whitworth, J, Cornish, AJ, Genomics England Research Consortium, Houlston, RS, Rich, P, Egan, C, Hodgson, SV, Warren, AY, Snape, K, and Maher, ER
Abstract: BACKGROUND: Around 95% of patients with clinical features diagnostic of Von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the VCB-CR complex which plays a key role in oxygen sensing and degradation of hypoxia inducible factors. To date, only variants in VHL has been shown to cause VHL disease. MATERIALS AND METHODS: We undertook trio analysis by Whole-exome sequencing (WES) in a proband with VHL disease but without a detectable VHL mutation. Molecular studies were also performed on paired DNA extracted from the proband's kidney tumour and blood and bioinformatics analysis of sporadic renal cell carcinoma data set was undertaken. RESULTS: A de novo pathogenic variant in ELOC (NM_005648.4:c.236A > G [p.Tyr79Cys]) gene was identified in the proband. ELOC encodes elongin C, a key component [C] of the VCB-CR complex. The p.Tyr79Cys substitution is a mutational hotspot in sporadic VHL-competent renal cell carcinoma (RCC) and has previously been shown to mimic the effects of pVHL deficiency on hypoxic signalling. Analysis of a RCC from the proband showed similar findings to that in somatically ELOC mutated RCC (expression of hypoxia responsive proteins, no somatic VHL variants and chromosome 8 loss). CONCLUSIONS: These findings are consistent with pathogenic ELOC variants being a novel cause for VHL disease and suggest that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL variant.
Published: 2022

6. 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

7. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author: Chen, H, Majumdar, A, Wang, L, Kar, S, Brown, KM, Feng, H, Turman, C, Dennis, J, Easton, D, Michailidou, K, Simard, J, Breast Cancer Association Consortium (BCAC), Bishop, T, Cheng, IC, Huyghe, JR, Schmit, SL, Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO, O'Mara, TA, Spurdle, AB, Endometrial Cancer Association Consortium (ECAC), Gharahkhani, P, Schumacher, J, Jankowski, J, Gockel, I, Esophageal Cancer GWAS Consortium, Bondy, ML, Houlston, RS, Jenkins, RB, Melin, B, Glioma International Case Control Consortium (GICC), Lesseur, C, Ness, AR, Diergaarde, B, Olshan, AF, Head-Neck Cancer GWAS Consortium, Amos, CI, Christiani, DC, Landi, MT, McKay, JD, International Lung Cancer Consortium (ILCCO), Brossard, M, Iles, MM, Law, MH, MacGregor, S, Melanoma GWAS Consortium, Beesley, J, Jones, MR, Tyrer, J, Winham, SJ, Ovarian Cancer Association Consortium (OCAC), Klein, AP, Petersen, G, Li, D, Wolpin, BM, Pancreatic Cancer Case-Control Consortium (PANC4), Pancreatic Cancer Cohort Consortium (PanScan), Eeles, RA, Haiman, CA, Kote-Jarai, Z, Schumacher, FR, PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS, Brennan, P, Chanock, SJ, Gaborieau, V, Purdue, MP, Renal Cancer GWAS Consortium, Pharoah, P, Hung, RJ, Amundadottir, LT, Kraft, P, Pasaniuc, B, and Lindström, S
Abstract: Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
Published: 2021

8. Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Author: Law, PJ, Timofeeva, M, Fernandez-Rozadilla, C, Broderick, P, Studd, J, Fernandez-Tajes, J, Farrington, S, Svinti, V, Palles, C, Orlando, G, Sud, A, Holroyd, A, Penegar, S, Theodoratou, E, Vaughan-Shaw, P, Campbell, H, Zgaga, L, Hayward, C, Campbell, A, Harris, S, Deary, IJ, Starr, J, Gatcombe, L, Pinna, M, Briggs, S, Martin, L, Jaeger, E, Sharma-Oates, A, East, J, Leedham, S, Arnold, R, Johnstone, E, Wang, H, Kerr, D, Kerr, R, Maughan, T, Kaplan, R, Al-Tassan, N, Palin, K, Hänninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Renkonen-Sinisalo, L, Lepistö, A, Böhm, J, Mecklin, J-P, Buchanan, DD, Win, A-K, Hopper, J, Jenkins, ME, Lindor, NM, Newcomb, PA, Gallinger, S, Duggan, D, Casey, G, Hoffmann, P, Nöthen, MM, Jöckel, K-H, Easton, DF, Pharoah, PDP, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Consortium, Practical, Harkin, A, Allan, K, McQueen, J, Paul, J, Iveson, T, Saunders, M, Butterbach, K, Chang-Claude, J, Hoffmeister, M, Brenner, H, Kirac, I, Matošević, P, Hofer, P, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Tomlinson, I, Houlston, RS, Dunlop, MG, Law, Philip J [0000-0001-9663-4611], Timofeeva, Maria [0000-0002-2503-4253], Fernandez-Rozadilla, Ceres [0000-0001-7330-4804], Broderick, Peter [0000-0002-8348-5829], Studd, James [0000-0002-7157-754X], Farrington, Susan [0000-0001-5955-7389], Svinti, Victoria [0000-0001-9926-0416], Sud, Amit [0000-0002-6133-0164], Hayward, Caroline [0000-0002-9405-9550], Campbell, Archie [0000-0003-0198-5078], Martin, Lynn [0000-0003-3962-389X], East, James [0000-0001-8035-3700], Kaplan, Richard [0000-0002-0189-8348], Al-Tassan, Nada [0000-0001-9076-0334], Palin, Kimmo [0000-0002-4621-6128], Salomaa, Veikko [0000-0001-7563-5324], Buchanan, Daniel D [0000-0003-2225-6675], Win, Aung-Ko [0000-0002-2794-5261], Jenkins, Mark E [0000-0002-8964-6160], Easton, Douglas F [0000-0003-2444-3247], Pharoah, Paul DP [0000-0001-8494-732X], Eeles, Rosalind A [0000-0002-3698-6241], Muir, Kenneth [0000-0001-6429-988X], Pashayan, Nora [0000-0003-0843-2468], Harkin, Andrea [0000-0002-8831-7381], Paul, James [0000-0001-7367-5816], Hofer, Philipp [0000-0003-2550-6019], Brezina, Stefanie [0000-0001-5238-6900], Cheadle, Jeremy P [0000-0001-9453-8458], Tomlinson, Ian [0000-0003-3037-1470], Houlston, Richard S [0000-0002-5268-0242], and Apollo - University of Cambridge Repository
Subjects: Male, Science, Inheritance Patterns, cancer genetics, Datasets as Topic, colorectal cancer, Genome-wide association studies, Polymorphism, Single Nucleotide, Article, White People, Asian People, Risk Factors, Cancer genomics, Humans, Genetic Predisposition to Disease, lcsh:Science, Cancer genetics, neoplasms, cancer genomics, genomiikka, Middle Aged, Colorectal cancer, digestive system diseases, peräsuolisyöpä, syöpägeenit, Genetic Loci, Case-Control Studies, genome-wide association studies, lcsh:Q, syöpätaudit, Female, Colorectal Neoplasms, Genome-Wide Association Study
Abstract: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention., In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.
Published: 2019

9. Runs of homozygosity and testicular cancer risk

Author: Loveday, C, Sud, A, Litchfield, K, Levy, M, Holroyd, A, Broderick, P, Kote-Jarai, Z, Dunning, AM, Muir, K, Peto, J, Eeles, R, Easton, DF, Dudakia, D, Orr, N, Pashayan, N, Rustin, Gordon, Srihari, Narayanan N, Cole, David, Askill, Colin, Bertelli, Gianfilippo, Barber, James, Gilby, Ed, White, Jeff, Baybrooke, Jeremy, Leahy, Michael, Welch, Richard, Chakraborti, Prabir, Joffe, Johnathan, Brown, Richard, Faust, Guy, Simmonds, Peter, Mazhar, Danish, Stockdale, Andrew, Hrounda, David, Humber, Caroline, Appel, Wiebke, Hong, Anne, Howard, Grahame, Douglas, Fiona, Bloomfield, David, Butt, Mohammad, Kelly, Kay, Mehra, Rakesh, Rogers, Paul, Hatton, Matthew, Hennig, Ivo, McAteer, John, Savage, Philip, Seckl, Michael, Gale, Joanna, Clark, Peter, Woby, Steve, Rathmell, Adrian, Lamont, Alan, Sarwar, Naveed, Stuart, Nick, Chowdhury, Simon, Beesley, Sharon, Winkler, Mathius, Hamid, Abdel, Pathak, Sanjeev, Madhavan, Krishnaswamy, Highley, Martin, Money-Kryle, Julian, Brock, Cathryn, Sreenivasan, Thiagarajan, Henderson, Brian E, Haiman, Christopher A, Schumacher, Fredrick R, Al Olama, Ali Amin, Benlloch, Sara, Berndt, Sonja I, Conti, David V, Wiklund, Fredrik, Chanock, Stephen, Gapster, Susan, Stevens, Victoria L, Tangen, Catherine M, Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Schleutker, Johanna, Albanes, Demetrius, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Geraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Maehle, Lovise, Neal, David E, Hamdy, Freddie C, Donovan, Jenny L, Travis, Ruth C, Hamilton, Robert J, Ingles, Sue Ann, Rosenstein, Barry S, Lu, Yong-Jie, Giles, Graham G, Kibel, Adam S, Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L, Park, Jong Y, Stanford, Janet L, Cybulski, Cezary, Nordestgaard, Borge G, Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M, Teixeira, Manuel R, Neuhausen, Susan L, De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F, Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A, Dominguez, Manuela Gago, Roobol, Monique J, Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albrigh, Lisa, Pandha, Hardev, Thibodeau, Stephen N, Reid, A, Huddart, RA, Houlston, RS, Turnbull, C, and Urology
Subjects: Oncology, Male, Endocrinology, Diabetes and Metabolism, LOCI, Genome-wide association study, Runs of Homozygosity, SUSCEPTIBILITY, VARIANTS, 0302 clinical medicine, Endocrinology, testicular germ cell tumour, Risk Factors, Genotype, genetics, Andrology, 030219 obstetrics & reproductive medicine, Genome, Homozygote, Neoplasms, Germ Cell and Embryonal, Disease gene identification, homozygosity mapping, Life Sciences & Biomedicine, RECENT POSITIVE SELECTION, medicine.medical_specialty, Urology, Biology, BREAST, Polymorphism, Single Nucleotide, 03 medical and health sciences, Endocrinology & Metabolism, Testicular Neoplasms, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Genetic predisposition, cancer, Humans, Allele, GENOME-WIDE ASSOCIATION, SEX DETERMINATION, runs of homozygosity, Science & Technology, IDENTIFICATION, Cancer, recessive, medicine.disease, GERM-CELL TUMOR, CONSANGUINITY, Reproductive Medicine, Relative risk, genome-wide association studies, Genome-Wide Association Study
Abstract: BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p
Published: 2019

10. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Author: Lin WY, Fordham SE, Hungate E, Sunter NJ, Elstob C, Xu Y, Park C, Quante A, Strauch K, Gieger C, Skol A, Rahman T, Sucheston-Campbell L, Wang J, Hahn T, Clay-Gilmour AI, Jones GL, Marr HJ, Jackson GH, Menne T, Collin M, Ivey A, Hills RK, Burnett AK, Russell NH, Fitzgibbon J, Larson RA, Le Beau MM, Stock W, Heidenreich O, Alharbi A, Allsup DJ, Houlston RS, Norden J, Dickinson AM, Douglas E, Lendrem C, Daly AK, Palm L, Piechocki K, Jeffries S, Bornhäuser M, Röllig C, Altmann H, Ruhnke L, Kunadt D, Wagenführ L, Cordell HJ, Darlay R, Andersen MK, Fontana MC, Martinelli G, Marconi G, Sanz MA, Cervera J, Gómez-Seguí I, Cluzeau T, Moreilhon C, Raynaud S, Sill H, Voso MT, Lo-Coco F, Dombret H, Cheok M, Preudhomme C, Gale RE, Linch D, Gaal-Wesinger J, Masszi A, Nowak D, Hofmann WK, Gilkes A, Porkka K, Milosevic Feenstra JD, Kralovics R, Grimwade D, Meggendorfer M, Haferlach T, Krizsán S, Bödör C, Stölzel F, Onel K, and Allan JM
Subjects: RISK, HLA, OLDER PATIENTS, AML, hemic and lymphatic diseases, HUMAN-LEUKOCYTE ANTIGEN, HIF-1-ALPHA, IMMUNE ESCAPE, CLONAL EVOLUTION, CANCER, GENE-MUTATIONS
Abstract: Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10 -8 ; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10 -10 ; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).
Published: 2021

11. Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: a Mendelian randomisation analysis

Author: Culliford, R, Cornish, AJ, Law, PJ, Farrington, SM, Palin, K, Jenkins, MA, Casey, G, Hoffmeister, M, Brenner, H, Chang-Claude, J, Kirac, I, Maughan, T, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Dunlop, MG, Houlston, RS, Culliford, R, Cornish, AJ, Law, PJ, Farrington, SM, Palin, K, Jenkins, MA, Casey, G, Hoffmeister, M, Brenner, H, Chang-Claude, J, Kirac, I, Maughan, T, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Dunlop, MG, and Houlston, RS
Abstract: BACKGROUND: Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). METHODS: We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. RESULTS: No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown. CONCLUSIONS: Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.
Published: 2021

12. Cross-cancer GWAS meta-analysis of more than 370,000 cases and 530,000 controls identifies multiple novel cancer risk regions

Author: Lindstrom, S, Kar, S, Wang, L, Turman, C, MacDonald, J, Bammler, T, BCAC, OCAC, PRACTICAL, Huyghe, J, Schmit, S, O'Mara, TA, Thompson, DJ, Gharahkhani, P, MacGregor, S, Brennan, P, Houlston, RS, Melin, BS, Amos, CI, McKay, J, Iles, MM, Law, MH, Klein, A, Amundadottir, L, Pasaniuc, B, Pharoah, P, Hung, RJ, and Kraft, P
Published: 2020

13. Cross-cancer cross-tissue Transcriptome-wide Association Study (TWAS) of 11 cancers identifies 56 novel genes

Author: Feng, H, Majumdar, A, Pasaniuc, B, Chen, H, Lindstrom, S, Huyghe, J, Schmit, SL, O'Mara, TA, Thompson, DJ, MacGregor, S, Brennan, P, Mckay, J, Houlston, RS, Melin, BS, Amos, C, Cus, AE, Iles, MM, Kar, S, Pharoah, P, Hung, RJ, Kraft, P, BCAC, and OCAC
Published: 2020

14. Modifiable pathways for colorectal cancer: a mendelian randomisation analysis

Author: Cornish, AJ, Law, PJ, Timofeeva, M, Palin, K, Farrington, SM, Palles, C, Jenkins, MA, Casey, G, Brenner, H, Chang-Claude, J, Hoffmeister, M, Kirac, I, Maughan, T, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Tomlinson, I, Dunlop, MG, Houlston, RS, Cornish, AJ, Law, PJ, Timofeeva, M, Palin, K, Farrington, SM, Palles, C, Jenkins, MA, Casey, G, Brenner, H, Chang-Claude, J, Hoffmeister, M, Kirac, I, Maughan, T, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Tomlinson, I, Dunlop, MG, and Houlston, RS
Abstract: BACKGROUND: Epidemiological studies have linked lifestyle, cardiometabolic, reproductive, developmental, and inflammatory factors to the risk of colorectal cancer. However, which specific factors affect risk and the strength of these effects are unknown. We aimed to examine the relationship between potentially modifiable risk factors and colorectal cancer. METHODS: We used a random-effects model to examine the relationship between 39 potentially modifiable risk factors and colorectal cancer in 26 397 patients with colorectal cancer and 41 481 controls (ie, people without colorectal cancer). These population data came from a genome-wide association study of people of European ancestry, which was amended to exclude UK BioBank data. In the model, we used genetic variants as instruments via two-sample mendelian randomisation to limit bias from confounding and reverse causation. We calculated odds ratios per genetically predicted SD unit increase in each putative risk factor (ORSD) for colorectal cancer risk. We did mendelian randomisation Egger regressions to identify evidence of potential violations of mendelian randomisation assumptions. A Bonferroni-corrected threshold of p=1·3 × 10-3 was considered significant, and p values less than 0·05 were considered to be suggestive of an association. FINDINGS: No putative risk factors were significantly associated with colorectal cancer risk after correction for multiple testing. However, suggestive associations with increased risk were noted for genetically predicted body fat percentage (ORSD 1·14 [95% CI 1·03-1·25]; p=0·0086), body-mass index (1·09 [1·01-1·17]; p=0·023), waist circumference (1·13 [1·02-1·26]; p=0·018), basal metabolic rate (1·10 [1·03-1·18]; p=0·0079), and concentrations of LDL cholesterol (1·14 [1·04-1·25]; p=0·0056), total cholesterol (1·09 [1·01-1·18]; p=0·025), circulating serum iron (1·17 [1·00-1·36]; p=0·049), and serum vitamin B12 (1·21 [1·04-1·42]; p=0·016), although potential pleiotropy among geneti
Published: 2020

15. Subclonal TP53 copy number is associated with prognosis in multiple myeloma

Author: Shah, V, Johnson, DC, Sherborne, AL, Ellis, S, Aldridge, FM, Howard-Reeves, J, Begum, F, Price, A, Kendall, J, Chiecchio, L, Savola, S, Jenner, MW, Drayson, MT, Owen, RG, Gregory, WM, Morgan, GJ, Davies, FE, Houlston, RS, Cook, G, Cairns, DA, Jackson, G, and Kaiser, MF
Subjects: Male, Survival Rate, Lymphoid Neoplasia, Gene Dosage, Humans, Female, Tumor Suppressor Protein p53, Multiple Myeloma, Disease-Free Survival, Gene Deletion, Genomic Instability
Abstract: Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal TP53 deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; P = .01). Clonal, but not subclonal, TP53 deletions were associated with clinical markers of advanced disease, specifically lower platelet counts (P < .001) and increased lactate dehydrogenase (P < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) (P = .002) or del(1p) (P = .006). Biallelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies.
Published: 2018

16. Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Author: Went, M, Sud, A, Försti, A, Halvarsson, BM, Weinhold, N, Kimber, S, van Duin, M, Thorleifsson, G, Holroyd, A, Johnson, DC, Li, N, Orlando, G, Law, PJ, Ali, M, Chen, B, Mitchell, JS, Gudbjartsson, DF, Kuiper, R, Stephens, OW, Bertsch, U, Broderick, P, Campo, C, Bandapalli, OR, Einsele, H, Gregory, WA, Gullberg, U, Hillengass, J, Hoffmann, P, Jackson, GH, Jöckel, KH, Johnsson, E, Kristinsson, SY, Mellqvist, UH, Nahi, H, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, ZS, Muir, K, Pashayan, N, Nickel, J, Nöthen, MM, Rafnar, T, Ross, FM, da Silva Filho, MI, Thomsen, H, Turesson, I, Vangsted, A, Andersen, NF, Waage, A, Walker, BA, Wihlborg, AK, Broyl, A, Davies, FE, Thorsteinsdottir, U, Langer, C, Hansson, M, Goldschmidt, H, Kaiser, M, Sonneveld, P, Stefansson, K, Morgan, GJ, Hemminki, K, Nilsson, B, Houlston, RS, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Olama, AAA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, The PRACTICAL Consortium, and Claessens, Frank
Subjects: Male, Quality Control, Risk, Chromatin Immunoprecipitation, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Bayes Theorem, Polymorphism, Single Nucleotide, Chromatin, Gene Expression Regulation, Humans, Female, Genetic Predisposition to Disease, Multiple Myeloma, Promoter Regions, Genetic, Genome-Wide Association Study
Abstract: © 2018, The Author(s). Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM. ispartof: Nature Communications vol:9 issue:1 ispartof: location:England status: published
Published: 2018

17. Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia

Author: Vijayakrishnan, J, Studd, J, Broderick, P, Kinnersley, B, Holroyd, A, Law, PJ, Kumar, R, Allan, JM, Harrison, CJ, Moorman, AV, Vora, A, Roman, E, Rachakonda, S, Kinsey, SE, Sheridan, E, Thompson, PD, Irving, JA, Koehler, R, Hoffmann, P, Nöthen, MM, Heilmann-Heimbach, S, Jöckel, KH, Easton, DF, Pharaoh, PDP, Dunning, AM, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Greaves, M, Zimmerman, M, Bartram, CR, Schrappe, M, Stanulla, M, Hemminki, K, Houlston, RS, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Olama, AAA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, YJ, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, The PRACTICAL Consortium, and Claessens, Frank
Subjects: Male, Oncogene Proteins, Fusion, Glycosyltransferases, Prognosis, Polymorphism, Single Nucleotide, HLA Antigens, Risk Factors, Child, Preschool, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Core Binding Factor Alpha 2 Subunit, Humans, Female, Genetic Predisposition to Disease, Child, Genome-Wide Association Study
Abstract: © 2018 The Author(s). Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology. ispartof: Nature Communications vol:9 issue:1 ispartof: location:England status: published
Published: 2018

18. Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia (vol 9, 1340, 2018)

Author: Vijayakrishnan, J, Studd, J, Broderick, P, Kinnersley, B, Holroyd, A, Law, PJ, Kumar, R, Allan, JM, Harrison, CJ, Moorman, AV, Vora, A, Roman, E, Rachakonda, S, Kinsey, SE, Sheridan, E, Thompson, PD, Irving, JA, Koehler, R, Hoffmann, P, Noethen, MM, Heilmann-Heimbach, S, Joeckel, K-H, Easton, DF, Pharaoh, PDP, Dunning, AM, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Greaves, M, Zimmerman, M, Bartram, CR, Schrappe, M, Stanulla, M, Hemminki, K, Houlston, RS, Vijayakrishnan, J, Studd, J, Broderick, P, Kinnersley, B, Holroyd, A, Law, PJ, Kumar, R, Allan, JM, Harrison, CJ, Moorman, AV, Vora, A, Roman, E, Rachakonda, S, Kinsey, SE, Sheridan, E, Thompson, PD, Irving, JA, Koehler, R, Hoffmann, P, Noethen, MM, Heilmann-Heimbach, S, Joeckel, K-H, Easton, DF, Pharaoh, PDP, Dunning, AM, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Greaves, M, Zimmerman, M, Bartram, CR, Schrappe, M, Stanulla, M, Hemminki, K, and Houlston, RS
Abstract: The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
Published: 2019

19. Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma (vol 9, 3707, 2018)

Author: Went, M, Sud, A, Foersti, A, Halvarsson, B-M, Weinhold, N, Kimber, S, van Duin, M, Thorleifsson, G, Holroyd, A, Johnson, DC, Li, N, Orlando, G, Law, PJ, Ali, M, Chen, B, Mitchell, JS, Gudbjartsson, DF, Kuiper, R, Stephens, OW, Bertsch, U, Broderick, P, Campo, C, Bandapalli, OR, Einsele, H, Gregory, WA, Gullberg, U, Hillengass, J, Hoffmann, P, Jackson, GH, Joeckel, K-H, Johnsson, E, Kristinsson, SY, Mellqvist, U-H, Nahi, H, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Grindedal, EM, Neal, DE, Hamdy, FC, Donovan, JL, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Khaw, K-T, Cannon-Albright, L, Pandha, H, Thibodeau, SN, Nickel, J, Noethen, MM, Rafnar, T, Ross, FM, Filho, MIDS, Thomsen, H, Turesson, I, Vangsted, A, Andersen, NF, Waage, A, Walker, BA, Wihlborg, A-K, Broyl, A, Davies, FE, Thorsteinsdottir, U, Langer, C, Hansson, M, Goldschmidt, H, Kaiser, M, Sonneveld, P, Stefansson, K, Morgan, GJ, Hemminki, K, Nilsson, B, Houlston, RS, Went, M, Sud, A, Foersti, A, Halvarsson, B-M, Weinhold, N, Kimber, S, van Duin, M, Thorleifsson, G, Holroyd, A, Johnson, DC, Li, N, Orlando, G, Law, PJ, Ali, M, Chen, B, Mitchell, JS, Gudbjartsson, DF, Kuiper, R, Stephens, OW, Bertsch, U, Broderick, P, Campo, C, Bandapalli, OR, Einsele, H, Gregory, WA, Gullberg, U, Hillengass, J, Hoffmann, P, Jackson, GH, Joeckel, K-H, Johnsson, E, Kristinsson, SY, Mellqvist, U-H, Nahi, H, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Grindedal, EM, Neal, DE, Hamdy, FC, Donovan, JL, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Khaw, K-T, Cannon-Albright, L, Pandha, H, Thibodeau, SN, Nickel, J, Noethen, MM, Rafnar, T, Ross, FM, Filho, MIDS, Thomsen, H, Turesson, I, Vangsted, A, Andersen, NF, Waage, A, Walker, BA, Wihlborg, A-K, Broyl, A, Davies, FE, Thorsteinsdottir, U, Langer, C, Hansson, M, Goldschmidt, H, Kaiser, M, Sonneveld, P, Stefansson, K, Morgan, GJ, Hemminki, K, Nilsson, B, and Houlston, RS
Abstract: The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
Published: 2019

20. Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility (vol 8, 1892, 2017)

Author: Sud, A, Thomsen, H, Law, PJ, Foersti, A, Filho, MIDS, Holroyd, A, Broderick, P, Orlando, G, Lenive, O, Wright, L, Cooke, R, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Eeles, R, Kote-Jarai, Z, Muir, K, Pashayan, N, Hoffmann, P, Noethen, MM, Joeckel, K-H, von Strandmann, EP, Lightfoot, T, Kane, E, Roman, E, Lake, A, Montgomery, D, Jarrett, RF, Swerdlow, AJ, Engert, A, Orr, N, Hemminki, K, Houlston, RS, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Sud, A, Thomsen, H, Law, PJ, Foersti, A, Filho, MIDS, Holroyd, A, Broderick, P, Orlando, G, Lenive, O, Wright, L, Cooke, R, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Eeles, R, Kote-Jarai, Z, Muir, K, Pashayan, N, Hoffmann, P, Noethen, MM, Joeckel, K-H, von Strandmann, EP, Lightfoot, T, Kane, E, Roman, E, Lake, A, Montgomery, D, Jarrett, RF, Swerdlow, AJ, Engert, A, Orr, N, Hemminki, K, Houlston, RS, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, and Menegaux, F
Abstract: The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.
Published: 2019

21. Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes

Author: Went, M, Kinnersley, B, Sud, A, Johnson, DC, Weinhold, N, Forsti, A, van Duin, Mark, Orlando, G, Mitchell, JS, Kuiper, Ronella, Walker, BA, Gregory, WM, Hoffmann, P, Jackson, GH, Nothen, MM, da Silva, MI, Thomsen, H, Broijl, A., Davies, FE, Thorsteinsdottir, U, Hansson, M, Kaiser, M, Sonneveld, Pieter, Goldschmidt, H, Stefansson, K, Hemminki, K, Nilsson, B, Morgan, GJ, Houlston, RS, Went, M, Kinnersley, B, Sud, A, Johnson, DC, Weinhold, N, Forsti, A, van Duin, Mark, Orlando, G, Mitchell, JS, Kuiper, Ronella, Walker, BA, Gregory, WM, Hoffmann, P, Jackson, GH, Nothen, MM, da Silva, MI, Thomsen, H, Broijl, A., Davies, FE, Thorsteinsdottir, U, Hansson, M, Kaiser, M, Sonneveld, Pieter, Goldschmidt, H, Stefansson, K, Hemminki, K, Nilsson, B, Morgan, GJ, and Houlston, RS
Published: 2019

22. Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

Author: Sud, A, Thomsen, H, Law, PJ, Försti, A, da Silva Filho, MI, Holroyd, A, Broderick, P, Orlando, G, Lenive, O, Wright, L, Cooke, R, Easton, D, Pharaoh, P, Dunning, A, Peto, J, Canzian, F, Eeles, R, Kote-Jarai, S, Muir, K, Pashayan, N, the PRACTICAL consortium, Hoffman, P, Nöthen, MM, Jöckel, K-H, von Strandmann, EP, Lightfoot, T, Kane, E, Roman, E, Lake, A, Montgomery, D, Jarrett, RF, Swerdlow, AJ, Engert, A, Orr, N, Hemminki, K, Houlston, RS, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository
Subjects: Humans, Genetic Predisposition to Disease, Hodgkin Disease, Polymorphism, Single Nucleotide, Alleles, HLA-DP beta-Chains, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract: Several susceptibility loci for classical Hodgkin lymphoma (cHL) have been reported, however much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies (GWAS), a new GWAS, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all cHL at 6q22.33 (rs9482849, P=1.52 × 10-8) and for nodular sclerosis HL (NSHL) at 3q28 (rs4459895, P=9.43 × 10-17), 6q23.3 (rs6928977, P=4.62 × 10-55 11), 10p14 (rs3781093, P=9.49 × 10-13), 13q34 (rs112998813, P=4.58 × 10-8) and 16p13.13 (rs34972832, P=2.12 × 10-8). Additionally, independent loci within the HLA region are observed for NSHL (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity HL (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.
Published: 2017

23. Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21.

Author: Ostrom, QT, Kinnersley, B, Wrensch, MR, Eckel-Passow, JE, Armstrong, G, Rice, T, Chen, Y, Wiencke, JK, McCoy, LS, Hansen, HM, Amos, CI, Bernstein, JL, Claus, EB, Il'yasova, D, Johansen, C, Lachance, DH, Lai, RK, Merrell, RT, Olson, SH, Sadetzki, S, Schildkraut, JM, Shete, S, Rubin, JB, Lathia, JD, Berens, ME, Andersson, U, Rajaraman, P, Chanock, SJ, Linet, MS, Wang, Z, Yeager, M, GliomaScan consortium, Houlston, RS, Jenkins, RB, Melin, B, Bondy, ML, Barnholtz-Sloan, JS, Ostrom, QT, Kinnersley, B, Wrensch, MR, Eckel-Passow, JE, Armstrong, G, Rice, T, Chen, Y, Wiencke, JK, McCoy, LS, Hansen, HM, Amos, CI, Bernstein, JL, Claus, EB, Il'yasova, D, Johansen, C, Lachance, DH, Lai, RK, Merrell, RT, Olson, SH, Sadetzki, S, Schildkraut, JM, Shete, S, Rubin, JB, Lathia, JD, Berens, ME, Andersson, U, Rajaraman, P, Chanock, SJ, Linet, MS, Wang, Z, Yeager, M, GliomaScan consortium, Houlston, RS, Jenkins, RB, Melin, B, Bondy, ML, and Barnholtz-Sloan, JS
Abstract: Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.
Published: 2018

24. Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci

Author: Tanskanen, T, van den Berg, L, Valimaki, N, Aavikko, M, Ness-Jensen, E, Hveem, K, Wettergren, Y, Lindskog, EB, Tonisson, N, Metspalu, A, Silander, K, Orlando, G, Law, PJ, Tuupanen, S, Gylfe, AE, Hanninen, UA, Cajuso, T, Kondelin, J, Sarin, A-P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, MA, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, FR, Casey, G, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Houlston, RS, Palin, K, Aaltonen, LA, Tanskanen, T, van den Berg, L, Valimaki, N, Aavikko, M, Ness-Jensen, E, Hveem, K, Wettergren, Y, Lindskog, EB, Tonisson, N, Metspalu, A, Silander, K, Orlando, G, Law, PJ, Tuupanen, S, Gylfe, AE, Hanninen, UA, Cajuso, T, Kondelin, J, Sarin, A-P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, MA, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, FR, Casey, G, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Houlston, RS, Palin, K, and Aaltonen, LA
Abstract: Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.
Published: 2018

25. Neutral tumor evolution in myeloma is associated with poor prognosis

Author: Johnson, DC, Lenive, O, Mitchell, J, Jackson, G, Owen, R, Drayson, M, Cook, G, Jones, JR, Pawlyn, C, Davies, FE, Walker, BA, Wardell, C, Gregory, WM, Cairns, D, Morgan, GJ, Houlston, RS, and Kaiser, MF
Abstract: Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcome we analysed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase III trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory therapy (IMiD). By analysing mutant allele frequency distributions in tumors we found that 17-20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in non-intensively treated patients, consistent with reduced therapeutic efficacy of micro-environment modulating IMiD drugs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcome and personalising therapy.
Published: 2017

26. Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

Author: Zuber, V, Bettella, F, Witoelar, A, Andreassen, OA, Mills, IG, Urbanucci, A, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Weischer, M, Travis, RC, Neal, D, Pharoah, P, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Chenevix-Trench, G, Humphreys, M, Hung, RJ, Han, Y, Brennan, P, Bickeböller, H, Rosenberger, A, Houlston, RS, Caporaso, N, Landi, MT, Heinrich, J, Risch, A, Wu, X, Ye, Y, Christiani, DC, Amos, CI, Easton, DF, Michailidou, K, Bolla, MK, Wang, Q, Berchuck, A, Antoniou, A, McGuffog, L, Couch, F, Offit, K, Dennis, J, Dunning, AM, Lee, A, Dicks, E, Luccarini, C, Benitez, J, Gonzalez-Neira, A, Simard, J, Tessier, DC, Bacot, F, Vincent, D, LaBoissière, S, Zuber, Verena [0000-0001-9827-1877], Pharoah, Paul [0000-0001-8494-732X], Khaw, Kay-Tee [0000-0002-8802-2903], Easton, Douglas [0000-0003-2444-3247], Wang, Jean [0000-0002-9139-0627], Antoniou, Antonis [0000-0001-9223-3116], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Lee, Andrew [0000-0003-0677-0252], Dicks, Ed [0000-0002-0617-0401], and Apollo - University of Cambridge Repository
Subjects: risk loci, schizophrenia, breast cancer risk, super-enhancer, genome-wide association studies, BRD4, chromatin, functional annotation, prostate cancer risk, SNPs
Abstract: $\textbf{Background:}$ Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. $\textbf{Results:}$ Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. $\textbf{Conclusions:}$ This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.
Published: 2017
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27. Genome-wide association study identifies multiple risk loci for renal cell carcinoma

Author: Scelo, G, Purdue, MP, Brown, KM, Johansson, M, Wang, Z, Eckel-Passow, JE, Ye, Y, Hoffman, JN, Choi, J, Foll, M, Gaborieau, V, Machiela, MJ, Colli, LM, Li, P, Sampson, JN, Abedi-Ardekani, B, Besse, C, Blanche, H, Boland, A, Burdette, L, Charbrier, A, Durand, G, Le Calvez-Kelm, F, Prokhortchouk, E, Robinot, N, Skyrabin, KG, Wozniak, MB, Yeager, M, Basta-Jovanovich, G, Dzamic, Z, Foretova, L, Holcatova, I, Janout, V, Mates, D, Mukeriya, A, Rascu, S, Zaridze, D, Bencko, V, Cybulski, C, Fabianova, E, Jinga, V, Lissowska, J, Lubinski, J, Navratilova, M, Rudnai, P, Szeszenia-Dabrowska, N, Benhamou, S, Cancel-Tassin, G, Cussenot, O, Baglietto, L, Boeing, H, Khaw, K-T, Weiderpass, E, Ljungberg, B, Sitaram, RT, Bruinsma, F, Jordan, SJ, Severi, G, Winship, I, Hveem, K, Vatten, LJ, Fletcher, T, Koppova, K, Larsson, SC, Wolk, A, Banks, RE, Selby, PJ, Easton, DF, Pharoah, P, Andreotti, G, Beane Freeman, LE, Koutros, S, Albanes, D, Mannisto, S, Weinstein, S, Clark, PE, Edwards, TL, Lipworth, L, Gapstur, SM, Stevens, VL, Carol, H, Freedman, ML, Pomerantz, MM, Cho, E, Kraft, P, Preston, MA, Wilson, KM, Gaziano, JM, Sesso, HD, Black, A, Freedman, ND, Huang, WY, Anema, JG, Kahnoski, RJ, Lane, BR, Noyes, SL, Petillo, D, Teh, BT, Peters, U, White, E, Anderson, GL, Johnson, L, Luo, J, Buring, J, Lee, I-M, Chow, W-H, Moore, LE, Wood, C, Eisen, T, Henrion, M, Larkin, J, Barman, P, Leibovich, BC, Choueiri, TK, Lathrop, GM, Rothman, N, Deleuze, J-F, McKay, JD, Parker, AS, Wu, X, Houlston, RS, Brennan, P, and Chanock, SJ
Abstract: Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10−10), 3p22.1 (rs67311347, P=2.5 × 10−8), 3q26.2 (rs10936602, P=8.8 × 10−9), 8p21.3 (rs2241261, P=5.8 × 10−9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10−8), 11q22.3 (rs74911261, P=2.1 × 10−10) and 14q24.2 (rs4903064, P=2.2 × 10−24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
Published: 2017

28. Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1,905 trial patients

Author: Shah, V, Sherborne, AL, Walker, BA, Johnson, DC, Boyle, EM, Ellis, S, Begum, DB, Proszek, PZ, Jones, JR, Pawlyn, C, Savola, S, Jenner, MW, Drayson, MT, Owen, RG, Houlston, RS, Cairns, DA, Gregory, WM, Cook, G, Davies, F, Jackson, GH, Morgan, GJ, and Kaiser, MF
Abstract: Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10−7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10−14) and 1.68 (P=2.18 × 10−14), respectively. Patients with ‘double-hit’ defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10−27) for all patients and 3.19 (P=1.23 × 10−18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10−15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P
Published: 2017

29. Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

Author: Rodriguez-Broadbent, H, Law, PJ, Sud, A, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Ripatti, S, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, Houlston, RS, Rodriguez-Broadbent, H, Law, PJ, Sud, A, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Ripatti, S, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, and Houlston, RS
Abstract: While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 × 10-4 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.
Published: 2017

30. Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs.

Author: Zhou, F, Wang, Y, Liu, H, Ready, N, Han, Y, Hung, RJ, Brhane, Y, McLaughlin, J, Brennan, P, Bickeböller, H, Rosenberger, A, Houlston, RS, Caporaso, N, Landi, MT, Brüske, I, Risch, A, Ye, Y, Wu, X, Christiani, DC, Goodman, G, Chen, C, Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team, Amos, CI, Wei, Q, Zhou, F, Wang, Y, Liu, H, Ready, N, Han, Y, Hung, RJ, Brhane, Y, McLaughlin, J, Brennan, P, Bickeböller, H, Rosenberger, A, Houlston, RS, Caporaso, N, Landi, MT, Brüske, I, Risch, A, Ye, Y, Wu, X, Christiani, DC, Goodman, G, Chen, C, Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team, Amos, CI, and Wei, Q
Published: 2017

31. Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis

Author: May-Wilson, S, Sud, A, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Fisher, D, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, Houlston, RS, May-Wilson, S, Sud, A, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Fisher, D, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, and Houlston, RS
Abstract: BACKGROUND: While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk. METHODS: We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels. RESULTS: Risk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65-0.92, P = 3.9 × 10-3; ORPOA = 0.36, 95% CI: 0.15-0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93-0.98, P = 3.7 × 10-4; ORAA = 1.05, 95% CI: 1.02-1.07, P = 1.7 × 10-4). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01-1.35, P = 0.041). CONCLUSION: Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk.
Published: 2017

32. Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia

Author: Gu, F, Zhang, H, Hyland, PL, Berndt, S, Gapstur, SM, Wheeler, W, Amos, CI, Bezieau, S, Bickeboller, H, Brenner, H, Brennan, P, Chang-Claude, J, Conti, DV, Doherty, JA, Gruber, SB, Harrison, TA, Hayes, RB, Hoffmeister, M, Houlston, RS, Hung, RJ, Jenkins, MA, Kraft, P, Lawrenson, K, Mckay, J, Markt, S, Mucci, L, Phelan, CM, Qu, C, Risch, A, Rossing, MA, Wichmann, H-E, Shi, J, Schernhammer, E, Yu, K, Landi, MT, Caporaso, NE, Gu, F, Zhang, H, Hyland, PL, Berndt, S, Gapstur, SM, Wheeler, W, Amos, CI, Bezieau, S, Bickeboller, H, Brenner, H, Brennan, P, Chang-Claude, J, Conti, DV, Doherty, JA, Gruber, SB, Harrison, TA, Hayes, RB, Hoffmeister, M, Houlston, RS, Hung, RJ, Jenkins, MA, Kraft, P, Lawrenson, K, Mckay, J, Markt, S, Mucci, L, Phelan, CM, Qu, C, Risch, A, Rossing, MA, Wichmann, H-E, Shi, J, Schernhammer, E, Yu, K, Landi, MT, and Caporaso, NE
Abstract: Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway < 0.00625). The two most significant genes were NPAS2 (pgene = 0.0062) and AANAT (pgene = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway = 0.021); this association was not confirmed in GECCO (ppathway = 0.76) or the combined data (ppathway = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.
Published: 2017

33. Apparent Mendelian inheritance of breast and colorectal cancer: chance, genetic heterogeneity or a new gene?

Author: Lipton, L, Thomas, HJ, Eeles, RA, Houlston, RS, Longmuir, M, Davison, R, Hodgson, SV, Murday, VA, Norbury, CG, Taylor, C, and Tomlinson, IP
Subjects: skin and connective tissue diseases
Abstract: It is not uncommon for cancer geneticists to be referred families with apparently Mendelian co-inheritance of breast and bowel cancer. Such families present a particular problem as regards the intensity of their screening for these diseases and the utility of genetic testing. Many 'breast-colon' cancer families probably result from chance clustering of two common cancers. Other 'breast-colon' cancer families may result from known cancer syndromes, such as hereditary breast-ovarian cancer or hereditary non-polyposis colon cancer, either by conferring a high risk of one cancer type and a slightly increased risk of the other, or through a predisposition to one of the two cancers and chance occurrence of the other. Anecdotally, however, many geneticists wonder about the existence of a distinct 'breast-colon cancer syndrome', since some families present good a priori evidence of genetic disease and yet cannot readily be accounted for by known genes or chance. The identification of unknown 'breast-colon cancer' genes is likely to be difficult, relying primarily on candidate gene analysis, including loci separately implicated in breast or colorectal cancer, or in other multiple cancer syndromes. Studies such as those on APC I1307K and CHEK2 1100delC may suggest the way forward for the identification of 'breast-colon cancer' genes.
Published: 2016

34. Evidence for a colorectal cancer susceptibility locus on chromosome 3q21-q24 from a high-density SNP genome-wide linkage scan (vol 15, pg 2903, 2006)

Author: Kemp, Z, Carvajal-Carmona, L, Spain, S, Barclay, E, Gorman, M, Martin, L, Jaeger, E, Brooks, N, Bishop, DT, Thomas, H, Tomlinson, I, Papaemmanuil, E, Webb, E, Sellick, GS, Wood, W, Evans, G, Lucassen, A, Maher, ER, Houlston, RS, and Identificat, CTG
Published: 2016

35. Localisation of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43

Author: Alam, A, Bevan, S, Churchman, M, Barclay, E, Barker, K, Jaeger, EEM, Leigh, IM, Houlston, RS, and Tomlinson, IPM
Published: 2016

36. Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma

Author: Johnson, DC, Weinhold, N, Mitchell, JS, Chen, B, Kaiser, M, Begum, DB, Hillengass, J, Bertsch, U, Gregory, WA, Cairns, D, Jackson, GH, Försti, A, Nickel, J, Hoffmann, P, Nöethen, MM, Stephens, OW, Barlogie, B, Davis, FE, Hemminki, K, Goldschmidt, H, Houlston, RS, and Morgan, GJ
Abstract: Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to identify genetic markers associated with MM overall survival (MM-OS), we conduct a meta-analysis of four patient series of European ancestry, totalling 3,256 patients with 1,200 MM-associated deaths. Each series is genotyped for ∼600,000 single nucleotide polymorphisms across the genome; genotypes for six million common variants are imputed using 1000 Genomes Project and UK10K as the reference. The association between genotype and OS is assessed by Cox proportional hazards model adjusting for age, sex, International staging system and treatment. We identify a locus at 6q25.1 marked by rs12374648 associated with MM-OS (hazard ratio=1.34, 95% confidence interval=1.22-1.48, P=4.69 × 10 -9). Our findings have potential clinical implications since they demonstrate that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors.
Published: 2016

37. Identification of four new susceptibility loci for testicular germ cell tumour

Author: Litchfield, K, Holroyd, A, Lloyd, A, Broderick, P, Nsengimana, J, Eeles, R, Easton, DF, Dudakia, D, UKTCC, Bishop, DT, Reid, A, Huddart, RA, Grotmol, T, Wiklund, F, Shipley, J, Houlston, RS, and Turnbull, C
Abstract: Genome wide association studies (GWAS) have identified multiple risk loci for testicular germ cell tumour (TGCT), revealing a polygenic model of disease susceptibility strongly influenced by common variation. To identify further SNPs associated with TGCT we conducted a multistage GWAS with combined dataset of >25,000 individuals (6,059 cases and 19,094 controls). We identified new risk loci for TGCT at 3q23 (rs11705932, TFDP2, P = 1.5 x 10-9), 11q14.1 (rs7107174, GAB2, P = 9.7 x 10-11), 16p13.13 (rs4561483, GSPT1, P = 1.6 x 10-8) and 16q24.2 (rs55637647, ZFPM1, P = 3.4 x 10-9). We additionally present detailed functional analysis of these loci, identifying a strong relationship between rs4561483 risk genotype and increased GSPT1 expression in TGCT patient samples. These findings provide additional support for a polygenic model of TGCT risk and further insight into the biologic basis of disease development.
Published: 2015

38. Genome-wide association study identifies multiple susceptibility loci for glioma

Author: Kinnersley, B, Labussière, M, Holroyd, A, Di Stefano, A-L, Broderick, P, Vijayakrishnan, J, Mokhtari, K, Delattre, J-Y, Gousias, K, Schramm, J, Schoemaker, MJ, Fleming, SJ, Herms, S, Heilmann, S, Schreiber, S, Wichmann, H-E, Nöthen, MM, Swerdlow, A, Lathrop, M, Simon, M, Bondy, M, Sanson, M, and Houlston, RS
Abstract: Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10−9) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10−8), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10−11), 12q21.2 (rs12230172, P=7.53 × 10−11) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10−9). Our findings provide further insights into the genetic basis of the different glioma subtypes.
Published: 2015

39. Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

Author: Orlando, G, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, S, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Aaltonen, LA, Houlston, RS, Orlando, G, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, S, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Aaltonen, LA, and Houlston, RS
Abstract: To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10-8, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2 = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.
Published: 2016

40. Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer

Author: Jarvis, D, Mitchell, JS, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Aaltonen, LA, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Houlston, RS, Jarvis, D, Mitchell, JS, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Aaltonen, LA, Cheadle, JP, Dunlop, MG, Tomlinson, IP, and Houlston, RS
Abstract: BACKGROUND: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC. METHODS: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls. RESULTS: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P=0.033), 1.59 (95% CI: 1.08-2.34, P=0.019) and 1.07 (95% CI: 1.03-1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89-1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P=7.7 × 10(-4)) and 1.40 (95% CI: 1.14-1.72, P=1.2 × 10(-3)), respectively. CONCLUSIONS: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.
Published: 2016

41. Correspondence: SEMA4A variation and risk of colorectal cancer

Author: Kinnersley, B, Chubb, D, Dobbins, S E, Frampton, M, Buch, S, Timofeeva, MN, Castellvi-Bel, S, Farrington, SM, Forsti, A, Hampe, J, Hemminki, K, Hofstra, Robert, Northwood, E, Palles, C, Pinheiro, M, Ruiz-Ponte, C, Schafmayer, C, Teixeira, MR, Westers, H, van Wezel, T, Bishop, DT, Tomlinson, I, Dunlop, MG, Houlston, RS, Kinnersley, B, Chubb, D, Dobbins, S E, Frampton, M, Buch, S, Timofeeva, MN, Castellvi-Bel, S, Farrington, SM, Forsti, A, Hampe, J, Hemminki, K, Hofstra, Robert, Northwood, E, Palles, C, Pinheiro, M, Ruiz-Ponte, C, Schafmayer, C, Teixeira, MR, Westers, H, van Wezel, T, Bishop, DT, Tomlinson, I, Dunlop, MG, and Houlston, RS
Published: 2016

42. A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer

Author: Al-Tassan, NA, Whiffin, N, Hosking, FJ, Palles, C, Farrington, SM, Dobbins, SE, Harris, R, Gorman, M, Tenesa, A, Meyer, BF, Wakil, SM, Kinnersley, B, Campbell, H, Martin, L, Smith, CG, Idziaszczyk, S, Barclay, E, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchannan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Dunlop, MG, Tomlinson, IP, Cheadle, JP, Houlston, RS, Al-Tassan, NA, Whiffin, N, Hosking, FJ, Palles, C, Farrington, SM, Dobbins, SE, Harris, R, Gorman, M, Tenesa, A, Meyer, BF, Wakil, SM, Kinnersley, B, Campbell, H, Martin, L, Smith, CG, Idziaszczyk, S, Barclay, E, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchannan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Dunlop, MG, Tomlinson, IP, Cheadle, JP, and Houlston, RS
Abstract: Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10(-8), odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.
Published: 2015

43. A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer (vol 5, 10442, 2015)

Author: Al-Tassan, NA, Whiffin, N, Hosking, FJ, Palles, C, Farrington, SM, Dobbins, SE, Harris, R, Gorman, M, Tenesa, A, Meyer, BF, Wakil, SM, Kinnersley, B, Campbell, H, Martin, L, Smith, CG, Idziaszczyk, S, Barclay, E, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Dunlop, MG, Tomlinson, IP, Cheadle, JP, Houlston, RS, Al-Tassan, NA, Whiffin, N, Hosking, FJ, Palles, C, Farrington, SM, Dobbins, SE, Harris, R, Gorman, M, Tenesa, A, Meyer, BF, Wakil, SM, Kinnersley, B, Campbell, H, Martin, L, Smith, CG, Idziaszczyk, S, Barclay, E, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Dunlop, MG, Tomlinson, IP, Cheadle, JP, and Houlston, RS
Published: 2015

44. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study

Author: Zhang, C, Doherty, JA, Burgess, S, Hung, RJ, Lindstroem, S, Kraft, P, Gong, J, Amos, CI, Sellers, TA, Monteiro, ANA, Chenevix-Trench, G, Bickeboeller, H, Risch, A, Brennan, P, Mckay, JD, Houlston, RS, Landi, MT, Timofeeva, MN, Wang, Y, Heinrich, J, Kote-Jarai, Z, Eeles, RA, Muir, K, Wiklund, F, Gronberg, H, Berndt, SI, Chanock, SJ, Schumacher, F, Haiman, CA, Henderson, BE, Al Olama, AA, Andrulis, IL, Hopper, JL, Chang-Claude, J, John, EM, Malone, KE, Gammon, MD, Ursin, G, Whittemore, AS, Hunter, DJ, Gruber, SB, Knight, JA, Hou, L, Le Marchand, L, Newcomb, PA, Hudson, TJ, Chan, AT, Li, L, Woods, MO, Ahsan, H, Pierce, BL, Zhang, C, Doherty, JA, Burgess, S, Hung, RJ, Lindstroem, S, Kraft, P, Gong, J, Amos, CI, Sellers, TA, Monteiro, ANA, Chenevix-Trench, G, Bickeboeller, H, Risch, A, Brennan, P, Mckay, JD, Houlston, RS, Landi, MT, Timofeeva, MN, Wang, Y, Heinrich, J, Kote-Jarai, Z, Eeles, RA, Muir, K, Wiklund, F, Gronberg, H, Berndt, SI, Chanock, SJ, Schumacher, F, Haiman, CA, Henderson, BE, Al Olama, AA, Andrulis, IL, Hopper, JL, Chang-Claude, J, John, EM, Malone, KE, Gammon, MD, Ursin, G, Whittemore, AS, Hunter, DJ, Gruber, SB, Knight, JA, Hou, L, Le Marchand, L, Newcomb, PA, Hudson, TJ, Chan, AT, Li, L, Woods, MO, Ahsan, H, and Pierce, BL
Abstract: Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.
Published: 2015

45. Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer

Author: Timofeeva, MN, Ben Kinnersley, Farrington, SM, Whiffin, N, Palles, C, Svinti, V, Lloyd, A, Gorman, M, Ooi, LY, Hosking, F, Barclay, E, Zgaga, L, Dobbins, S, Martin, L, Theodoratou, E, Broderick, P, Tenesa, A, Smillie, C, Grimes, G, Hayward, C, Campbell, A (Archie), Porteous, D, Deary, IJ, Harris, SE, Northwood, EL, Barrett, JH, Smith, G, de Wolf, R, Forman, D, Morreau, H, Ruano, D, Tops, C, van Wijnen, J (Juul), Schrumpf, M, Boot, A (Arnoud), Vasen, HFA, Hes, FJ, van Wezel, T, Franke, A, Lieb, W, Schafmayer, C, Hampe, J, Buch, S, Propping, P, Hemminki, K, Forsti, A, Westers, H, Hofstra, R, Pinheiro, M, Pinto, C, Teixeira, M, Ruiz-Ponte, C, Fernandez-Rozadilla, C, Carracedo, A, Castells, A, Castellvi-Bel, S, Campbell, H, Bishop, DT, Tomlinson, IPM, Dunlop, MG, Houlston, RS, Timofeeva, MN, Ben Kinnersley, Farrington, SM, Whiffin, N, Palles, C, Svinti, V, Lloyd, A, Gorman, M, Ooi, LY, Hosking, F, Barclay, E, Zgaga, L, Dobbins, S, Martin, L, Theodoratou, E, Broderick, P, Tenesa, A, Smillie, C, Grimes, G, Hayward, C, Campbell, A (Archie), Porteous, D, Deary, IJ, Harris, SE, Northwood, EL, Barrett, JH, Smith, G, de Wolf, R, Forman, D, Morreau, H, Ruano, D, Tops, C, van Wijnen, J (Juul), Schrumpf, M, Boot, A (Arnoud), Vasen, HFA, Hes, FJ, van Wezel, T, Franke, A, Lieb, W, Schafmayer, C, Hampe, J, Buch, S, Propping, P, Hemminki, K, Forsti, A, Westers, H, Hofstra, R, Pinheiro, M, Pinto, C, Teixeira, M, Ruiz-Ponte, C, Fernandez-Rozadilla, C, Carracedo, A, Castells, A, Castellvi-Bel, S, Campbell, H, Bishop, DT, Tomlinson, IPM, Dunlop, MG, and Houlston, RS
Abstract: Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 x 10(-7)), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 x 10(-7)); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 x 10(-7) and OR = 1.09, P = 7.4 x 10(-8)); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 x 10(-9)), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P < 2.90 x 10(-6)). We found an excess of rare, damaging variants in base-excision (P = 2.4 x 10(-4)) and DNA mismatch repair genes (P = 6.1 x 10(-4)) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC.
Published: 2015

46. Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis

Author: Freitag, DF, Butterworth, AS, Willeit, P, Howson, JMM, Burgess, S, Kaptoge, S, Young, R, Ho, WK, Wood, AM, Sweeting, M, Spackman, S, Staley, JR, Ramond, A, Harshfield, E, Nielsen, SF, Grande, P, Lange, LA, Bown, MJ, Jones, GT, Scott, RA, Bevan, S, Porcu, E, Thorleifsson, G, Zeng, LY, Kessler, T, Nikpay, M, Do, R, Zhang, WH, Hopewell, JC, Kleber, M, Delgado, GE, Nelson, CP, Goel, A, Bis, JC, Dehghan, Abbas, Ligthart, Symen, Smith, AV, Qu, LM, van 't Hof, FNG, de Bakker, PIW, Baas, AF, van Rij, A, Tromp, G, Kuivaniemi, H, Ritchie, MD, Verma, SS, Crawford, DC, Malinowski, J, de Andrade, M, Kullo, IJ, Peissig, PL, McCarty, CA, Bottinger, EP, Gottesman, O, Crosslin, DR, Carrell, DS, Rasmussen-Torvik, LJ, Pacheco, JA, Huang, J, Timpson, NJ, Kettunen, J, Ala-Korpela, M, Mitchell, GF, Parsa, A, Wilkinson, IB, Gorski, M, Li, Yunlei, Franceschini, N, Keller, MF, Ganesh, SK, Langefeld, CD, Bruijn, L, Brown, MA, Evans, DM, Baltic, S, Ferreira, MA, Baurecht, H, Weidinger, S, Franke, A, Lubitz, SA, Muller-Nurasyid, M, Felix, Janine, Smith, NL, Sudman, M, Thompson, SD, Zeggini, E, Panoutsopoulou, K, Nalls, MA, Singleton, A, Polychronakos, C, Bradfield, JP, Hakonarson, H, Easton, DF, Thompson, D, Tomlinson, IP, Dunlop, M, Hemminki, K, Morgan, G, Eisen, T, Goldschmidt, H, Allan, JM, Henrion, M, Whiffin, N, Wang, YF, Chubb, D, Houlston, RS, Iles, MM, Bishop, DT, Law, MH, Hayward, NK, Luo, Y, Nejentsev, S, Barbalic, M, Crossman, D, Sanna, S, Soranzo, N, Markus, HS, Wareham, NJ, Rader, DJ, O Reilly, M, Assimes, T, Harris, TB, Hofman, Bert, Franco Duran, OH, Gudnason, V, Tracy, R, Psaty, BM, Farrall, M, Watkins, H, Hall, AS, Samani, NJ, Marz, W, Clarke, R, Collins, R, Kooner, JS, Chambers, JC, Kathiresan, S, McPherson, R, Erdmann, J, Kastrati, A, Schunkert, H, Stefansson, K, Thorsteinsdottir, U, Walston, JD, Tybjaerg-Hansen, A, Alam, DS, Majumder, AA, Di Angelantonio, E, Chowdhury, R, Nordestgaard, BG, Saleheen, D, Thompson, SG, Danesh, J, Freitag, DF, Butterworth, AS, Willeit, P, Howson, JMM, Burgess, S, Kaptoge, S, Young, R, Ho, WK, Wood, AM, Sweeting, M, Spackman, S, Staley, JR, Ramond, A, Harshfield, E, Nielsen, SF, Grande, P, Lange, LA, Bown, MJ, Jones, GT, Scott, RA, Bevan, S, Porcu, E, Thorleifsson, G, Zeng, LY, Kessler, T, Nikpay, M, Do, R, Zhang, WH, Hopewell, JC, Kleber, M, Delgado, GE, Nelson, CP, Goel, A, Bis, JC, Dehghan, Abbas, Ligthart, Symen, Smith, AV, Qu, LM, van 't Hof, FNG, de Bakker, PIW, Baas, AF, van Rij, A, Tromp, G, Kuivaniemi, H, Ritchie, MD, Verma, SS, Crawford, DC, Malinowski, J, de Andrade, M, Kullo, IJ, Peissig, PL, McCarty, CA, Bottinger, EP, Gottesman, O, Crosslin, DR, Carrell, DS, Rasmussen-Torvik, LJ, Pacheco, JA, Huang, J, Timpson, NJ, Kettunen, J, Ala-Korpela, M, Mitchell, GF, Parsa, A, Wilkinson, IB, Gorski, M, Li, Yunlei, Franceschini, N, Keller, MF, Ganesh, SK, Langefeld, CD, Bruijn, L, Brown, MA, Evans, DM, Baltic, S, Ferreira, MA, Baurecht, H, Weidinger, S, Franke, A, Lubitz, SA, Muller-Nurasyid, M, Felix, Janine, Smith, NL, Sudman, M, Thompson, SD, Zeggini, E, Panoutsopoulou, K, Nalls, MA, Singleton, A, Polychronakos, C, Bradfield, JP, Hakonarson, H, Easton, DF, Thompson, D, Tomlinson, IP, Dunlop, M, Hemminki, K, Morgan, G, Eisen, T, Goldschmidt, H, Allan, JM, Henrion, M, Whiffin, N, Wang, YF, Chubb, D, Houlston, RS, Iles, MM, Bishop, DT, Law, MH, Hayward, NK, Luo, Y, Nejentsev, S, Barbalic, M, Crossman, D, Sanna, S, Soranzo, N, Markus, HS, Wareham, NJ, Rader, DJ, O Reilly, M, Assimes, T, Harris, TB, Hofman, Bert, Franco Duran, OH, Gudnason, V, Tracy, R, Psaty, BM, Farrall, M, Watkins, H, Hall, AS, Samani, NJ, Marz, W, Clarke, R, Collins, R, Kooner, JS, Chambers, JC, Kathiresan, S, McPherson, R, Erdmann, J, Kastrati, A, Schunkert, H, Stefansson, K, Thorsteinsdottir, U, Walston, JD, Tybjaerg-Hansen, A, Alam, DS, Majumder, AA, Di Angelantonio, E, Chowdhury, R, Nordestgaard, BG, Saleheen, D, Thompson, SG, and Danesh, J
Abstract: Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who ca
Published: 2015

47. Origins and impact of extrachromosomal DNA.

Author: Bailey C, Pich O, Thol K, Watkins TBK, Luebeck J, Rowan A, Stavrou G, Weiser NE, Dameracharla B, Bentham R, Lu WT, Kittel J, Yang SYC, Howitt BE, Sharma N, Litovchenko M, Salgado R, Hung KL, Cornish AJ, Moore DA, Houlston RS, Bafna V, Chang HY, Nik-Zainal S, Kanu N, McGranahan N, Flanagan AM, Mischel PS, Jamal-Hanjani M, and Swanton C
Subjects: Female, Humans, Male, Enhancer Elements, Genetic genetics, Gene Amplification, Mutation, Organ Specificity, Promoter Regions, Genetic genetics, RNA, Long Noncoding genetics, DNA genetics, Neoplasms genetics, Neoplasms immunology, Neoplasms pathology, Oncogenes genetics
Abstract: Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer 1,2 . Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.1% of tumour samples contain ecDNA. We reveal a pattern highly indicative of tissue-context-based selection for ecDNAs, linking their genomic content to their tissue of origin. We show that not only is ecDNA a mechanism for amplification of driver oncogenes, but it also a mechanism that frequently amplifies immunomodulatory and inflammatory genes, such as those that modulate lymphocyte-mediated immunity and immune effector processes. Moreover, ecDNAs carrying immunomodulatory genes are associated with reduced tumour T cell infiltration. We identify ecDNAs bearing only enhancers, promoters and lncRNA elements, suggesting the combinatorial power of interactions between ecDNAs in trans. We also identify intrinsic and environmental mutational processes linked to ecDNA, including those linked to its formation, such as tobacco exposure, and progression, such as homologous recombination repair deficiency. Clinically, ecDNA detection was associated with tumour stage, more prevalent after targeted therapy and cytotoxic treatments, and associated with metastases and shorter overall survival. These results shed light on why ecDNA is a substantial clinical problem that can cooperatively drive tumour growth signals, alter transcriptional landscapes and suppress the immune system., (© 2024. The Author(s).)
Published: 2024
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48. Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project.

Author: Ní Leathlobhair M, Frangou A, Kinnersley B, Cornish AJ, Chubb D, Lakatos E, Arumugam P, Gruber AJ, Law P, Tapinos A, Jakobsdottir GM, Peneva I, Sahli A, Smyth EM, Ball RY, Sylva R, Benes K, Stark D, Young RJ, Lee ATJ, Wolverson V, Houlston RS, Sosinsky A, Protheroe A, Murray MJ, Wedge DC, and Verrill C
Subjects: Humans, Male, Adult, Seminoma genetics, Seminoma pathology, Genomics methods, Whole Genome Sequencing, Genome, Human, Mutation, Testicular Neoplasms genetics, Testicular Neoplasms pathology, Neoplasms, Germ Cell and Embryonal genetics, Neoplasms, Germ Cell and Embryonal pathology, DNA Copy Number Variations genetics
Abstract: Testicular germ cell tumours (TGCT), which comprise seminoma and non-seminoma subtypes, are the most common cancers in young men. In this study, we present a comprehensive whole genome sequencing analysis of adult TGCTs. Leveraging samples from participants recruited via the UK National Health Service and data from the Genomics England 100,000 Genomes Project, our results provide an extended description of genomic elements underlying TGCT pathogenesis. This catalogue offers a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genome features, including mutational signatures and analysis of extrachromosomal DNA amplification. This study establishes correlations between genomic alterations and histological diversification, revealing divergent evolutionary trajectories among TGCT subtypes. By reconstructing the chronological order of driver events, we identify a subgroup of adult TGCTs undergoing relatively late whole genome duplication. Additionally, we present evidence that human leukocyte antigen loss is a more prevalent mechanism of immune disruption in seminomas. Collectively, our findings provide valuable insights into the developmental and immune modulatory processes implicated in TGCT pathogenesis and progression., (© 2024. The Author(s).)
Published: 2024
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49. Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk.

Author: Law PJ, Studd J, Smith J, Vijayakrishnan J, Harris BT, Mandelia M, Mills C, Dunlop MG, and Houlston RS
Subjects: Humans, Risk Factors, Epigenesis, Genetic, Colorectal Neoplasms genetics, Genome-Wide Association Study, Genetic Predisposition to Disease, Quantitative Trait Loci, Polymorphism, Single Nucleotide
Abstract: Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer-gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment., (© 2024. The Author(s).)
Published: 2024
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50. The genomic landscape of 2,023 colorectal cancers.

Author: Cornish AJ, Gruber AJ, Kinnersley B, Chubb D, Frangou A, Caravagna G, Noyvert B, Lakatos E, Wood HM, Thorn S, Culliford R, Arnedo-Pac C, Househam J, Cross W, Sud A, Law P, Leathlobhair MN, Hawari A, Woolley C, Sherwood K, Feeley N, Gül G, Fernandez-Tajes J, Zapata L, Alexandrov LB, Murugaesu N, Sosinsky A, Mitchell J, Lopez-Bigas N, Quirke P, Church DN, Tomlinson IPM, Sottoriva A, Graham TA, Wedge DC, and Houlston RS
Subjects: Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Young Adult, Chromosomal Instability genetics, Diet adverse effects, DNA Copy Number Variations genetics, HLA Antigens genetics, Microsatellite Instability, Prognosis, Smoking adverse effects, United Kingdom epidemiology, Whole Genome Sequencing, Colorectal Neoplasms classification, Colorectal Neoplasms genetics, Colorectal Neoplasms immunology, Genetic Predisposition to Disease genetics, Genome, Human genetics, Genomics, Mutation
Abstract: Colorectal carcinoma (CRC) is a common cause of mortality 1 , but a comprehensive description of its genomic landscape is lacking 2-9 . Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia coli pks+ colibactin in rectal cancers 10 and the importance of the SBS93 signature 11-13 , which suggests that diet or smoking is a risk factor. Immune-escape driver mutations 14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care., (© 2024. The Author(s).)
Published: 2024
Full Text: View/download PDF

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