Cancer Risk In Mutation Carriers Research Articles

Alcohol Consumption, Cigarette Smoking, and Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Results from The BRCA1 and BRCA2 Cohort Consortium.

Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential. Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers and 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers and 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HRP) was 1.36 (95% CI, 0.99-1.87). For BRCA2 mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR = 1.25; 95% CI, 1.01-1.55 and HRP = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk. The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation. This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.

Germline CHEK2 Gene Mutations in Hereditary Breast Cancer Predisposition - Mutation Types and their Biological and Clinical Relevance.

Hereditary mutations in the CHEK2 gene (which encodes CHK2 kinase) contribute to a moderately increased risk of breast cancer (BC) and other cancers. Large variations in the frequency of CHEK2 mutations and the occurrence of variants of unknown clinical significance (VUS) complicate estimation of cancer risk in carriers of germline CHEK2 mutations. We performed mutation analysis of 1,526 high-risk Czech BC patients and 3,360 Czech controls. Functional analysis was performed for identified VUS using a model system based on a human RPE1-CHEK2-KO cell line harboring biallelic inactivation of endogenous CHEK2. The frequency of ten truncating CHEK2 variants differed markedly between BC patients (2.26%) and controls (0.11%; p = 4.1 × 1012). We also found 23 different missense variants in 4.5% patients and in 4.0% of controls. The most common was p.I157T, which was found in patients and controls with the same frequency. Functional analysis identified nine functionally deleterious VUS, another nine functionally neutral VUS, and four intermediate VUS (including p.I157T). We found that carriers of truncating CHEK2 mutations had a high BC risk (OR 8.19; 95% CI 4.11-17.75), and that carriers of functionally deleterious missense variants had a moderate risk (OR 4.06; 95% CI, 1.37-13.39). Carriers of these mutations developed BC at 44.4 and 50.7 years, respectively. Functionally neutral and functionally intermediate missense variants did not increase the BC risk. BC in CHEK2 mutation carriers was frequently ER-positive and of higher grade. Notably, carriers of CHEK2 mutations developed second cancers more frequently than BRCA1/BRCA2/PALB2/p53 or mutation non-carriers. Hereditary CHEK2 mutations contribute to the development of hereditary BC. The associated cancer risk in mutation carriers increases with the number of affected individuals in a family. Annual follow-up with breast ultrasound, mammography, or magnetic resonance imaging is recommended for asymptomatic mutation carriers from the age of 40. Surgical prevention and specific follow-up of other tumors should be considered based on family cancer history. The work was supported by grants from the Czech Health Research Council of the Ministry of Health of the Czech Republic NR 15-28830A, 16-29959A, NV19-03-00279, projects of the PROGRES Q28/LF1, GAUK 762216, SVV2019 / 260367, PRIMUS/17/MED/9, UNCE/MED/016, Progress Q26, LQ1604 NPU II and project AVČR Qualitas. The analysis of a set of unselected controls was made possible by the existence and support of the scientific infrastructure of the National Center for Medical Genomics (LM2015091) and its project aimed at creating a reference database of genetic variants of the Czech Republic (CZ.02.1.01/0.0/0.0/16_013/0001634). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 2. 4. 2019 Accepted: 14. 5. 2019.

Screening and surgical prophylaxis for hereditary cancer syndromes with high risk of endometrial and ovarian cancer.

In the era of advanced cancer genomics, our recognition of hereditary cancer mutations continues to increase. Two of these conditions, which carry an increased risk of female cancers including endometrial, ovarian, breast, are hereditary breast and ovarian cancer syndrome and Lynch syndrome. Risk-reducing surgery, such as mastectomy, salpingo-oophorectomy, and hysterectomy may decrease cancer risk for mutation carriers. Background, indications, techniques, and consequences of these surgical procedures are reviewed.

Abstract 4177: The joint effects of polygenic risk scores and pathogenic variants in cancer predisposition genes on breast cancer risk in the general population: results from the CARRIERS study

Abstract Background: Understanding the joint effect on breast cancer risk of rare pathogenic variants in cancer predisposition genes and polygenic risk scores (PRS) from common variants can enable a precision approach to breast cancer management. Previous work found that PRS were associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers recruited from cancer genetics clinics (Kuchenbaecker et al. JNCI 2017). The joint effects of pathogenic variants and PRS have not been studied in samples drawn from the general population. There is also no existing study evaluating the effect of PRS in mutation carriers in genes other than BRCA1/2. Here we evaluate the joint effects of PRS and pathogenic mutations in established cancer predisposition genes in a population-based case-control sample. Method: We analyzed 53,199 European-ancestry individuals (20,730 controls and 21,272 cases) drawn from 7 cohorts and 2 population-based case-control studies in the CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium. Targeted sequencing was performed using dual bar-coded QIAseq. Mutation calling was conducted with Haplotype Caller and Vardict. We sequenced 18 breast cancer predisposition genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHECK2, FANCC, MLH1, MSH2, MSH6, NF1, PALB2, PTEN, RAD51C, RAD51D and TP53. The PRS was calculated based on 128 common variants using effect estimates from the largest published breast cancer GWAS. The PRS was standardized to a mean of 0 and standard deviation of 1. Logistic regression was performed to assess the combined effect of identified mutation and common variants (including main and interaction effects for carrier status and PRS). Results: A total of 1,770 pathogenic mutations were observed. About 1% of the study sample had mutations in either BRCA1 (n=209) or BRCA2 gene (n=305), and 2.2% had mutations in other genes (n=1,176). The effect of PRS in BRCA1 carriers was OR= 0.97 (95%CI: 0.62, 1.52); however, this is not statistically significantly different from the PRS in non-carriers [OR=1.23 (95%CI: 1.20, 1.25)] or previous estimates in carriers [OR: 1.14, 95%CI: 1.11-1.17]. The effect of PRS in BRCA2 carriers was OR=1.87 (95%CI: 1.31, 2.78) which was statistically significantly different from that of the non-carriers. Among the mutation carriers in genes other than BRCA, the effect of PRS on breast cancer was OR=1.00 (95%CI: 0.88,1.15). Conclusion: Consistent with previous studies, we did not find evidence that the effect of the PRS among BRCA1 carriers was statistically significantly different than non-carriers. We found some evidence that the PRS effect may be larger among BRCA2 carriers than non-carriers. Our results also suggest that PRS may not have a strong effect on breast cancer risk in mutation carriers of other predisposition genes; further work is needed for verification. Citation Format: Chi Gao, Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Kun Y. Lee, Jenna Lilyquist, Nicholas J. Boddicker, Bruce Eckloff, Raed Samara, Josh Klebba, Paul Auer, Leslie Bernstein, Mia Gaudet, Hoda Anton-Culver, Amy Trentham-Dietz, Julie R. Palmer, Song Yao, Christopher Haiman, Janet E. Olson, Susan Domchek, Jeffrey Weitzel, David Goldgar, Katherine L. Nathanson, Eric C. Polley, Fergus J. Couch, Peter Kraft. The joint effects of polygenic risk scores and pathogenic variants in cancer predisposition genes on breast cancer risk in the general population: results from the CARRIERS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4177.

Quality of Clinician-Reported Cancer History When Ordering Genetic Testing.

Clinical history data reported on test requisition forms (TRFs) for hereditary cancer multigene panel testing (MGPT) are routinely used by genetic testing laboratories. More recently, publications have incorporated TRF-based clinical data into studies exploring yield of testing by phenotype and estimating cancer risks for mutation carriers. We aimed to assess the quality of TRF data for patients undergoing MGPT. Ten percent of patients who underwent hereditary cancer MGPT between January and June 2015 at a clinical laboratory were randomly selected. TRF-reported cancer diagnoses were evaluated for completeness and accuracy for probands and relatives using clinical documents such as pedigrees and chart notes as the comparison standard in cases where these documents were submitted after the time of test order. TRF-reported cancer sites and ages at diagnosis were complete for > 90.0% of proband cancer diagnoses overall, and the completion rate was even higher (> 96.0%) for breast, ovarian, colorectal, and uterine cancers. When reported, these data were accurate on TRFs for > 99.5% of proband cancer sites and > 97.5% of proband ages at diagnosis. Cancer site and age at diagnosis data were also complete on the TRF for the majority of cancers among first- and second-degree relatives. Completeness decreased as relation to the proband became more distant, whereas accuracy remained high across all degrees of relation. Data collected as part of cancer genetic risk assessment is completely and accurately reported on TRFs for the majority of probands and their close relatives and is comparable to information directly obtained from clinic notes, particularly for breast and other cancers commonly associated with hereditary cancer syndromes.

Abstract SY32-01: Knowledge management and decision support for commonly tested susceptibility mutations

Abstract Challenges: Germline testing for inherited genetic susceptibility to cancer has become cheaper and widely used. Multigene panels now routinely test 25 to 123 genes. Health care providers, including clinicians and genetic counselors, must interpret results, assess the risk of various cancers, and advise on clinical management strategies. Aside from a small number of well-known genes, clinicians lack simple and reliable tools to personalize prevention decisions for individuals who test positive. Evidence on the types of cancer associated with susceptibility genes, and on the magnitude of increased risks associated with a mutation, is emerging at a fast rate. However, a large number of combinations of cancer type and gene variant needs to be considered. No comprehensive databases exist, information is dispersed over a vast number of published studies, the quality of the studies is uneven, and the data presented are seldom directly applicable to precision prevention decisions, which require absolute risk estimates. Thus, when assessing cancer risks for mutation carriers, clinical practice can take little advantage of the impressive scientific advancements in this field. Approaches: This presentation describes ongoing work to develop tools that could facilitate the translation into clinical practice of research results that would otherwise be difficult to access, systematize, interpret, and convert into actionable knowledge. The long-term goal should be to develop a clinical decision-support system that allows a clinician to enter important factors about a patient with a mutation and immediately receive patient-specific absolute risk estimates. The foundation for the clinical decision-support system needs to be laid by systematically collecting and curating studies on gene cancer associations and, ideally, developing a public access knowledge base for researchers and health care providers. These steps need computational tools for efficient implementations of this plan and for sustainable long-term updating of the knowledge base and decision-support system. The ask2me.org project and the data science behind it are attempting to achieve some of these steps. This project will be used as an illustration throughout. Impact: Progress in this area will have a direct clinical impact by providing patient-specific absolute risk estimates. These risk estimates will, in turn, lead to more carefully personalized prevention and management for individuals undergoing susceptibility testing, and will help us optimize screening and behavioral interventions to reduce risk. Citation Format: Giovanni Parmigiani, Danielle Braun, Kevin S. Hughes. Knowledge management and decision support for commonly tested susceptibility mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY32-01.

Risk of uterine cancer for BRCA1 and BRCA2 mutation carriers

BackgroundWhether BRCA1 and BRCA2 mutation carriers have a clinically relevant elevated risk of uterine cancer has implications for risk-reducing surgery. AimThis multicentre, prospective cohort study assessed uterine cancer risk for mutation carriers compared with the general population. MethodsEligible mutation carriers were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) cohort study, had a uterus present and no history of uterine cancer at cohort entry. Epidemiological, lifestyle and clinical data were collected at cohort entry and updated three-yearly. Cancer events were verified using pathology reports. Follow-up was censored at death or last contact. Relative risk of uterine cancer was estimated using the standardised incidence ratio (SIR), with the expected number of cases determined using population-based data for Australia. ResultsOf 1,111 mutation carriers in kConFab, 283 were excluded due to prior hysterectomy (N = 278), prior uterine cancer (N = 2) or being non-residents (N = 3). After a median follow-up of 9.0 years, five incident uterine cancers were reported in the 828 eligible women (419 had prior breast cancer and 160 had prior tamoxifen use), compared to 2.04 expected (SIR = 2.45; 95% confidence interval [CI]: 0.80–5.72; P = 0.11). In 438 BRCA1 mutation carriers and 390 BRCA2 mutation carriers, three and two incident cases of uterine cancer were reported, respectively, compared to 1.04 expected (SIR = 2.87; 95% CI: 0.59–8.43; P = 0.18) and 0.99 expected (SIR = 2.01; 95% CI: 0.24–7.30; P = 0.52), respectively. All cases were endometrioid subtype, International Federation of Gynaecology and Obstetrics stage I–II disease. No serous uterine cancers were reported. ConclusionsOur findings are consistent with those from most other reports and do not support routine risk-reducing hysterectomy for BRCA1 and BRCA2 mutation carriers.

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

BRCA1/BRCA2 founder mutations and cancer risks: impact in the western Danish population.

Mutations in the BRCA1 and BRCA2 genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We used a western Danish clinic-based cohort of 299 BRCA families to study the female cancer risk in mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In BRCA1, the cumulative cancer risk at age 70 was 35% for breast cancer and 29% for ovarian cancer. In BRCA2, the cumulative risk was 44% for breast cancer and 15% for ovarian cancer. We identified 47 distinct BRCA1 mutations and 48 distinct mutations in BRCA2. Among these, 8 founder mutations [BRCA1 c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and BRCA2 c.6373delA, c.7008-1G>A, c.7617+1G>A and c.8474delC] were found to account for 23% of the BRCA1 mutations and for 32% of the BRCA2 mutations. The BRCA1 mutation c.3319G>T was, compared to other BRCA1 mutations, associated with a higher risk for ovarian cancer. In conclusion, founder mutations in BRCA1 and BRCA2 contribute to up to one-third of the families in western Denmark and among these the BRCA1 c.3319G>T mutation is potentially linked to an increased risk of ovarian cancer.

Familial Pancreatic Cancer: To Screen or not to Screen?

Familial Pancreatic Cancer: To Screen or not to Screen?

Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2.

In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.

Lymphocyte Telomere Length Is Long in BRCA1 and BRCA2 Mutation Carriers Regardless of Cancer-Affected Status

Telomere length has been linked to risk of common diseases, including cancer, and has previously been proposed as a biomarker for cancer risk. Germline BRCA1 and BRCA2 mutations predispose to breast, ovarian, and other cancer types. We investigated telomere length in BRCA mutation carriers and their non-carrier relatives and further examined whether telomere length is a modifier of cancer risk in mutation carriers. We measured mean telomere length in DNA extracted from whole blood using high-throughput quantitative PCR. Participants were from the EMBRACE study in United Kingdom and Eire (n = 4,822) and comprised BRCA1 (n = 1,628) and BRCA2 (n = 1,506) mutation carriers and their non-carrier relatives (n = 1,688). We find no significant evidence that mean telomere length is associated with breast or ovarian cancer risk in BRCA mutation carriers. However, we find mutation carriers to have longer mean telomere length than their non-carrier relatives (all carriers vs. non-carriers, Ptrend = 0.0018), particularly in families with BRCA2 mutations (BRCA2 mutation carriers vs. all non-carriers, Ptrend = 0.0016). Our findings lend little support to the hypothesis that short mean telomere length predisposes to cancer. Conversely, our main and unexpected finding is that BRCA mutation carriers (regardless of cancer status) have longer telomeres than their non-mutation carrier, non-cancer-affected relatives. The longer telomere length in BRCA2 mutation carriers is consistent with its role in DNA damage response. Overall, it seems that increased telomere length may be a consequence of these mutations, but is not itself directly related to the increased cancer risk in carriers. The finding that mutation carriers have longer mean telomere lengths than their non-carrier relatives is unexpected but biologically plausible and could open up new lines of research into the functions of the BRCA proteins. To our knowledge, this is the largest study of telomere length in BRCA mutation carriers and their relatives. The null cancer-risk association supports recent large prospective studies of breast and ovarian cancer and indicates that mean telomere length would not be a useful biomarker in these cancers. Cancer Epidemiol Biomarkers Prev; 23(6); 1018-24. ©2014 AACR.

Local approaches to hereditary breast cancer

The diagnostic and local treatment modalities of hereditary breast cancer (HBC) are evolving based on emerging evidence from new imaging, radiotherapy and surgical studies. The optimal selection of diagnostic and therapeutic strategies for the individual HBC patient remains an area of active research in this relatively new patient population. In this context, some rational pathways of intervention are currently available to both reduce cancer risk in mutation carriers without a cancer diagnosis, as well as to reduce the risk of recurrence or new cancers among the carriers already diagnosed with a malignancy. It is encouraging to notice to what degree certain interventions have successfully reduced both the risk of malignancy and the anxiety associated with this genetic diagnosis. This updated report aims at summarizing the most recent findings, while it identifies the areas of uncertainty that remain, and continue to present difficult challenges, particularly among younger HBC patients.

Cancer risk in Lynch Syndrome

Lynch Syndrome, or hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by inactivating mutations in DNA mismatch repair genes. It accounts for 2-4% of all incident colorectal cancers. Mutation carriers are at risk of early onset colorectal cancer, endometrial cancer, and a spectrum of other tumours. Accurate estimation of cancer risk for mutation carriers is essential for counselling, and establishing appropriate screening guidelines. This study reviews the current data on cancer risk, and emerging risk reduction strategies.

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

Lynch syndrome (LS) is an inherited cancer-predisposing disorder caused by germline mutations in the mismatch repair (MMR) genes. The high variability in individual cancer risk observed among LS patients suggests the existence of modifying factors. Identifying genetic modifiers of risk could help implement personalized surveillance programs based on predicted cancer risks. Here we evaluate the role of the telomerase (hTERT) rs2075786 SNP as a cancer-risk modifier in LS, studying 255 and 675 MMR gene mutation carriers from Spain and the Netherlands, respectively. The study of the Spanish sample revealed that the minor allele (A) confers increased cancer risk at an early age. The analysis of the Dutch sample confirmed the association of the A allele, especially in homozygosity, with increased cancer risk in mutation carriers under the age of 45 (relative riskLSca<45_AA=2.90; 95% confidence interval=1.02-8.26). Rs2075786 is associated with colorectal cancer (CRC) risk neither in the general population nor in non-Lynch CRC families. In silico studies predicted that the SNP causes the disruption of a transcription binding site for a retinoid receptor, retinoid X receptor alpha, probably causing early telomerase activation and therefore accelerated carcinogenesis. Notably, cancer-affected LS patients with the AA genotype have shorter telomeres than those with GG. In conclusion, MMR gene mutation carriers with hTERT rs2075786 are at high risk to develop a LS-related tumor at an early age. Cancer-preventive measures and stricter cancer surveillance at early ages might help prevent or early detect cancer in these mutation carriers.

Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers

Pathogenic mutations in the tumour suppressor genes BRCA1 and BRCA2 confer increased risks for breast and ovarian cancer and account for approximately 15% of the excess familial risk of breast cancer amongst first-degree relatives of patients with breast cancer. There is considerable evidence indicating that these risks vary by other genetic and environmental factors clustering in families. In the past few years, based on the availability of genome-wide association data and samples from large collaborative studies, several common alleles have been found to modify breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. These common alleles explain a small proportion of the genetic variability in breast or ovarian cancer risk for mutation carriers, suggesting more modifiers remain to be identified. We review the so far identified genetic modifiers of breast and ovarian cancer risk and consider the implications for risk prediction. BRCA1 and BRCA2 mutation carriers could be some of the first to benefit from clinical applications of common variants identified through genome-wide association studies. However, to be able to provide more individualized risk estimates, it will be important to understand how the associations vary with different tumour characteristics and their interactions with other genetic and environmental modifiers.

Cancer risk in Jewish BRCA1 and BRCA2 mutation carriers: Effects of oral contraceptive use and parental origin of mutation

BRCA1 and BRCA2 germline mutations substantially increase breast and ovarian cancer risk, yet penetrance is incomplete. The effects of oral contraceptives (OC) on breast cancer risk in mutation carriers are unclear, and the putative effect of parental origin of mutation on cancer risk has not been reported. Data on OC use and parental origin of the mutation were obtained at counseling from 888 BRCA1 (n=638) or BRCA2 (n=250) Jewish Israeli mutation carriers who were counseled and genotyped in a single medical center. Overall, 403 (45.4%) of participants had breast cancer (age at diagnosis 49.65±12.2years), 112 (12.6%) ovarian cancer (age at diagnosis 56.8±10.8years) and the rest (n=373-42%) were asymptomatic carriers (age at counseling 40.7±10.6years). Of study participants, 472 (53.15%) ever used OC, and 298 used OC for at least 5years. In 129 the mutation originated on the paternal side as judged by direct testing or obligate carriership and in 460 the mutation was maternally inherited. Multivariate logistic regression analysis, and stratifying for birth year, age at menarche, breast feeding, and number of births, showed that ever use of OC (Hazards Ratio-HR=1.84 95% CI 1.465-2.314, P=0.001) and paternal compared with maternal origin of mutation (OR=1.55 95% CI 1.14-2.12, P=0.006) were significantly associated with breast cancer and an earlier age at breast cancer diagnosis. The authors conclude that OC use and paternal origin of mutation affect breast cancer penetrance in Jewish BRCA1 and BRCA2 mutation carriers.

Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2

Background:Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2.Methods:Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers.Results:An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3–34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2.Conclusions and inteNo evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.

Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers

Germline mutations in BRCA1 and BRCA2 confer high risks of female breast and ovarian cancer. However, there is strong evidence that these risks are modified by other factors, including familial or genetic factors. Genome-wide association studies have identified several breast cancer genetic susceptibility variants in the general population that are also associated with breast cancer risk for mutation carriers. The patterns of association for these variants vary between BRCA1 and BRCA2 mutation carriers and this variation appears to be driven by their differential associations with breast cancer subtypes defined by estrogen receptor status. We review the latest evidence regarding genetic modifiers of cancer risk for female BRCA1 and BRCA2 mutation carriers emerging from candidate gene studies, variants found in genome-wide association studies (GWAS) to be associated with cancer risk in the general population and GWAS specifically in mutation carriers. We also discuss the implications of these findings for cancer risk prediction in these women. BRCA1 and BRCA2 mutation carriers could potentially be among the first groups of individuals for whom clinically applicable risk profiling could be developed using the common breast cancer susceptibility variants identified through GWAS.

Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.