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Background: Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited., Methods: We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case-control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium., Results: The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had >20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (<20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population., Conclusions: These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification., Impact: Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts.

Background: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li-Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and postzygotic mosaicism (PZM) is critically needed for risk assessment and management., Methods: Participants in the Li-Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible. Demographics, personal/family cancer history, and clinical laboratory test reports were obtained. DNA from multiple tissues was analyzed using a custom QIAseq assay (ACE panel) that included TP53 and other CH-associated genes; the ACE panel and eyebrow follicles were assessed in a workflow to discern TP53 PV clinical categories., Results: Among 134 participants there was a significant difference for the age at diagnosis (P &lt; 0.001), component cancers (P = 0.007), and clinical testing criteria (P &lt; 0.001), comparing germline with PZM or ACE. ACE panel analysis of DNA from 55 sets of eyebrow follicles (mean 1.4 ug) and 36 formalin-fixed, paraffin imbedded tissues demonstrated low variance (SE, 3%; P = 0.993) for TP53 variant allele fraction, with no significant difference (P = 0.965) between tissue types, and detected CH gene PVs. Of 55 multi-tissue cases, germline status was confirmed for 20, PZM in seven, ACE for 25, and three were indeterminate. Additional CH variants were detected in six ACE and two germline cases., Conclusions: We demonstrated an effective approach and tools for discerning germline TP53 status., Impact: Discernment of PZM and TP53-driven CH increases diagnostic accuracy and enables risk-appropriate care., (©2022 American Association for Cancer Research.)

Background: Weight gain and other anthropometric measures on the risk of ovarian cancer for women with BRCA mutations are not known. We conducted a prospective analysis of weight change since age 18, height, body mass index (BMI) at age 18, and current BMI and the risk of developing ovarian cancer among BRCA1 and BRCA2 mutation carriers., Methods: In this prospective cohort study, height, weight, and weight at age 18 were collected at study enrollment. Weight was updated biennially. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for ovarian cancer., Results: This study followed 4,340 women prospectively. There were 121 incident cases of ovarian cancer. Weight gain of more than 20 kg since age 18 was associated with a 2-fold increased risk of ovarian cancer, compared with women who maintained a stable weight (HR, 2.00; 95% CI, 1.13-3.54; P = 0.02). Current BMI of 26.5 kg/m 2 or greater was associated with an increased risk of ovarian cancer in BRCA1 mutation carriers, compared with those with a BMI less than 20.8 kg/m 2 (Q4 vs. Q1 HR, 2.13; 95% CI, 1.04-4.36; P = 0.04). There were no significant associations between height or BMI at age 18 and risk of ovarian cancer., Conclusions: Adult weight gain is a risk factor for ovarian cancer in women with a BRCA1 or BRCA2 mutation., Impact: These findings emphasize the importance of maintaining a healthy body weight throughout adulthood in women at high risk for ovarian cancer., (©2021 American Association for Cancer Research.)

Background: The success of multisite collaborative research relies on effective data collection, harmonization, and aggregation strategies. Data Coordination Centers (DCC) serve to facilitate the implementation of these strategies. The utility of a DCC can be particularly relevant for research on rare diseases where collaboration from multiple sites to amass large aggregate datasets is essential. However, approaches to building a DCC have been scarcely documented., Methods: The Li-Fraumeni Exploration (LiFE) Consortium's DCC was created using multiple open source packages, including LAM/G Application (Linux, Apache, MySQL, Grails), Extraction-Transformation-Loading (ETL) Pentaho Data Integration Tool, and the Saiku-Mondrian client. This document serves as a resource for building a rare disease DCC for multi-institutional collaborative research., Results: The primary scientific and technological objective to create an online central repository into which data from all participating sites could be deposited, harmonized, aggregated, disseminated, and analyzed was completed. The cohort now include 2,193 participants from six contributing sites, including 1,354 individuals from families with a pathogenic or likely variant in TP53 . Data on cancer diagnoses are also available. Challenges and lessons learned are summarized., Conclusions: The methods leveraged mitigate challenges associated with successfully developing a DCC's technical infrastructure, data harmonization efforts, communications, and software development and applications., Impact: These methods can serve as a framework in establishing other collaborative research efforts. Data from the consortium will serve as a great resource for collaborative research to improve knowledge on, and the ability to care for, individuals and families with Li-Fraumeni syndrome., (©2020 American Association for Cancer Research.)

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes., Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach., Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments., Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers., Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies., (©2014 American Association for Cancer Research.)

Cancer prevention postdoctoral fellowships have existed since the 1970s. The National Cancer Institute facilitated a meeting by a panel of experts in April 2013 to consider four important topics for future directions for cancer prevention postdoctoral training programs: (i) future research needs; (ii) underrepresented disciplines; (iii) curriculum; and (iv) career preparation. Panelists proffered several areas needing more research or emphasis, ranging from computational science to culture. Health care providers, along with persons from nontraditional disciplines in scientific training programs such as engineers and lawyers, were among those recognized as being underrepresented in training programs. Curriculum suggestions were that fellows receive training in topics such as leadership and human relations, in addition to learning the principles of epidemiology, cancer biologic mechanisms, and behavioral science. For career preparation, there was a clear recognition of the diversity of employment options available besides academic positions, and that program leaders should do more to help fellows identify and prepare for different career paths. The major topics and strategies covered at this meeting can help form the basis for cancer prevention training program leaders to consider modifications or new directions, and keep them updated with the changing scientific and employment climate for doctoral degree recipients and postdoctoral fellows.

Background: BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers., Methods: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made., Results: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2)., Conclusions: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers., Impact: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers., (©2011 AACR.)

Background: Large rearrangements account for 8% to 15% of deleterious BRCA mutations, although none have been characterized previously in individuals of Mexican ancestry., Methods: DNA from 106 Hispanic patients without an identifiable BRCA mutation by exonic sequence analysis was subjected to multiplexed quantitative differential PCR. One case of Native American and African American ancestry was identified via multiplex ligation-dependent probe amplification. Long-range PCR was used to confirm deletion events and to clone and sequence genomic breakpoints. Splicing patterns were derived by sequencing cDNA from reverse transcription-PCR of lymphoblastoid cell line RNA. Haplotype analysis was conducted for recurrent mutations., Results: The same deletion of BRCA1 exons 9 through 12 was identified in five unrelated families. Long-range PCR and sequencing indicated a deletion event of 14.7 kb. A 3-primer PCR assay was designed based on the deletion breakpoints, identified within an AluSp element in intron 8 and an AluSx element in intron 12. Haplotype analysis confirmed common ancestry. Analysis of cDNA showed direct splicing of exons 8 to 13, resulting in a frameshift mutation and predicted truncation of the BRCA1 protein., Conclusions: We identified and characterized a novel large BRCA1 deletion in five unrelated families-four of Mexican ancestry and one of African and Native American ancestry, suggesting the possibility of founder effect of Amerindian or Mestizo origin. This BRCA1 rearrangement was detected in 3.8% (4 of 106) of BRCA sequence-negative Hispanic families. An assay for this mutation should be considered for sequence-negative high-risk Hispanic patients.

Unlabelled: Approximately 12% of the U.S. population is Hispanic, with the majority residing in urban centers such as Los Angeles. The prevalence of BRCA mutations among high-risk Hispanic families is unknown., Methods: One hundred and ten unrelated probands of Hispanic origin, with a personal or family history of breast and/or ovarian cancer, presented for genetic cancer risk assessment, were enrolled in an Institutional Review Board-approved registry and underwent BRCA testing. Haplotype analyses were done if BRCA mutations were observed in two or more unrelated probands., Results: Mean age at diagnosis was 37 years (range = 23-59) for the 89 (81%) probands with invasive breast cancer. Overall, 34 (30.9%) had deleterious mutations (25 in BRCA1, 9 in BRCA2), 25 (22.7%) had one or more unclassified variants, and 51 (46.4%) had negative results. The mean pretest mutation probability using the Couch model, Myriad model, and BRCAPro was 19.6% (range = 4-77%). The combined average mutation probability was 32.8% for carriers, 15.5% for noncarriers, and 12.9% for variant carriers (P < 0.0001). The most common deleterious mutation was 185delAG (4 of 34, 11.8%). The Hispanic 185delAG carrier families share the same haplotype from D17s1320 through BRCA1, as do two reference Ashkenazi Jewish families. Haplotype analyses of additional recurrent BRCA1 mutations [IVS5+1G>A (n=2),S955X (n = 3), R1443X (n = 3), and 2552delC (n = 2)] also suggest founder effects, with four of six mutations seen almost exclusively in families with Latin American/Caribbean or Spanish ancestry., Conclusion: This is the largest study to date of high-risk Hispanic families in the United States. Six recurrent mutations accounted for 47% (16 of 34) of the deleterious mutations in this cohort. The BRCA1185delAG mutation was prevalent (3.6%) in this clinic-based cohort of predominantly Mexican descent, and shared the Ashkenazi Jewish founder haplotype.

Background: Women with breast cancer and a BRCA mutation have a high risk of developing a contralateral breast cancer. It is generally believed that the two cancers represent independent events. However, the extent of concordance between the first and second tumors with respect to hormone receptor expression and other pathologic features is unknown., Purpose: To determine the degree of concordance of estrogen receptor (ER) status, tumor grade, and histology in tumors from women with bilateral breast cancer and a BRCA mutation., Subjects and Methods: Women with a history of bilateral invasive breast cancers were selected from an international registry of women with BRCA1 or BRCA2 mutations. Medical records were reviewed to document the characteristics of each cancer and the treatments received., Results: Data were available for 286 women with bilateral breast cancer and a BRCA mutation (211 BRCA1; 75 BRCA2). The mean interval between first and second tumor was 5.1 years. The two tumors were concordant more often than expected for ER status (P < 0.0001) and for grade (P < 0.0001), but not for histology (P = 0.55). The ER status of the first tumor was highly predictive of the ER status of the second tumor (odds ratio, 8.7; 95% confidence interval, 3.5-21.5; P < 0.0001). Neither age, menopausal status, oophorectomy nor tamoxifen use was predictive of the ER status of the second tumor., Conclusions: There is strong concordance in ER status and tumor grade between independent primary breast tumors in women with a BRCA mutation. The excess concordance may be due to common risk factors, genetic variation, or the existence of a preneoplastic lesion that is common to both tumors.