Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families

A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2–4% of such families. The extent to which major genomic rearrangements in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4–88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.     

Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation‐negative familial ovarian cancers

BACKGROUND:

Inherited mutations account for approximately 10% of all epithelial ovarian cancers. Breast cancer (BRCA1 and BRACA2) gene mutations are responsible for up to 85% of inherited breast and/or ovarian cancer. Another condition that has been associated with ovarian cancer is hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which carries a lifetime risk of up to 13% for ovarian cancer. The objective of this study was to determine the incidence of HNPCC‐related gene mutations in patients with familial ovarian cancer who previously tested negative for BRCA1 and BRCA2 gene mutations.

METHODS:

Seventy‐seven probands were identified who had familial ovarian cancer and negative BRCA gene mutation testing. Their pedigrees were analyzed for HNPCC syndrome. DNA samples underwent gene sequencing and Southern blot analysis for mutations in the 3 most common HNPCC‐associated genes: mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) with reflex testing for MSH6 if tests for the first 2 genes were negative.

RESULTS:

None of the probands met Amsterdam criteria for the clinical diagnosis of HNPCC. DNA testing revealed 2 patients (2.6%) with deleterious mutations in the MSH2 gene. An additional 8 patients (10.4%) had substitutions in either the MLH1 gene or the MSH2 gene that were classified as variants of uncertain significance. If Amsterdam criteria were expanded to include ovarian cancer, then 15 of 77 patients (19.5%) would have met these expanded criteria. One deleterious mutation was noted in this group, yielding a mutation incidence of 6.7%. This percentage may be even higher if any of the identified variants of uncertain significance are confirmed to be deleterious.

CONCLUSIONS:

HNPCC should be considered when evaluating patients with suspected hereditary ovarian cancer who have had negative BRCA mutation testing. Cancer 2009. © 2009 American Cancer Society.     

BRCA mutation rate and characteristics of prostate tumor in breast and ovarian cancer families: analysis of 6,591 Italian pedigrees

Objective:As prostate cancer (PrC) shows a BRCA mutation rate as high as 30%, it becomes crucial to find the optimal selection criteria for genetic testing. The primary objective of this study was to evaluate the BRCA mutation rate in families with PrC associated with breast and/or ovarian cancers; secondary aims were to compare the characteristics of families and BRCA-related PrC outcome among BRCA1 and BRCA2 carriers.Methods:Following the Modena criteria for the BRCA test, we evaluated the mutation rate in families with breast and/or ovarian cancer with a Gleason score ≥7 PrCs, by testing breast or ovarian cases and inferring the mutation in the prostate cases. The characteristics of families and BRCA-related PrC outcomes were measured using the chi-square (χ²) test and Kaplan–Meier methods, respectively.Results:Among 6,591 families, 580 (8.8%) with a Gleason score ≥ 7 PrCs were identified, of which 332 (57.2%) met the Modena selection criteria for BRCA testing. Overall, 215 breast or ovarian cancer probands (64.8%) were tested, of which 41 resulted positive for BRCA and one for CHEK2 genes (19.5%). No statistically significant differences were found in BRCA-related PrC prognosis and in the characteristics of families among BRCA1, BRCA2 and non-tested patients. Ten of 23 (44%) mutations in the BRCA2 gene fell in the prostate cancer cluster region (PCCR) at the 3′ terminal of the 7914 codon.Conclusions:It appears the Modena criteria are very useful for BRCA testing selection in families with breast and/or ovarian cancer and PrC. A trend toward a worse prognosis has been found in BRCA2 carriers.     

Earlier age of onset of BRCA mutation-related cancers in subsequent generations

BACKGROUND:

Women who are diagnosed with a deleterious mutation in either breast cancer (BRCA) gene have a high risk of developing breast and ovarian cancers at young ages. In this study, the authors assessed age at diagnosis in 2 generations of families with known mutations to investigate for earlier onset in subsequent generations.

METHODS:

Of the 132 BRCA‐positive women with breast cancer who participated in a high‐risk protocol at The University of Texas MD Anderson Cancer Center (Gen 2), 106 women could be paired with a family member in the previous generation (Gen 1) who was diagnosed with a BRCA‐related cancer (either breast cancer or ovarian cancer). Age at diagnosis, location of the mutation, and year of birth were recorded. A previously published parametric anticipation model was applied in these genetically predisposed families.

RESULTS:

The median age of cancer diagnosis was 42 years (range, 28‐55 years) in Gen 2 and 48 years (range, 30‐72 years) in Gen 1 (P < .001). In the parametric model, the estimated change in the expected age at onset for the entire cohort was 7.9 years (P < .0001). Statistically significant earlier ages at diagnosis also were observed within subgroups of BRCA1 and BRCA2 mutations, maternal inheritance, paternal inheritance, breast cancer only, and breast cancer‐identified and ovarian cancer‐identified families.

CONCLUSIONS:

Breast and ovarian cancers in BRCA mutation carriers appeared to be diagnosed at an earlier age in later generations. The authors concluded that patients who are younger at the onset of BRCA‐related cancers should continue to be tracked to offer appropriate screening modalities at appropriate ages. Cancer 2011. © 2011 American Cancer Society.     

The association between smoking and cancer incidence in BRCA1 and BRCA2 mutation carriers

Tobacco smoke is an established carcinogen, but the association between tobacco smoking and cancer risk in BRCA mutation carriers is not clear. The aim of this study was to evaluate prospectively the association between tobacco smoking and cancer incidence in a cohort of BRCA1 and BRCA2 mutation carriers. The study population consisted of unaffected BRCA mutation carriers. Information on lifestyle including smoking histories, reproductive factors, and past medical histories was obtained through questionnaires. Incident cancers were updated biennially via follow‐up questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using time‐dependent Cox regression models. There were 700 incident cancers diagnosed over 26,711 person‐years of follow‐up. The most frequent cancers seen in BRCA mutation carriers were breast (n = 428; 61%) and ovarian (n = 109; 15%) cancer. Compared to nonsmokers, (ever) smoking was associated with a modest increased risk of all cancers combined (HR = 1.17; 95%CI 1.01–1.37). Women in the highest group of total pack‐years (4.3–9.8) had an increased risk of developing any cancer (HR = 1.27; 95%CI 1.04–1.56), breast cancer (HR = 1.33, 95%CI 1.02–1.75), and ovarian cancer (HR = 1.68; 95%CI 1.06–2.67) compared to never smokers. The associations between tobacco smoking and cancer did not differ by BRCA mutation type or by age at diagnosis. This prospective study suggests that tobacco smoking is associated with a modest increase in the risks of breast and ovarian cancer among women with BRCA1 or BRCA2 mutation.     

Hereditary ovarian cancer in Ashkenazi Jews

Ovarian cancer is the fourth leading cause of cancer deaths among American women. While women in both the Ashkenazi and non-Ashkenazi populations have an estimated 1.7% lifetime risk of acquiring malignancy, the proportion of hereditary ovarian cancer is much higher in the Ashkenazim. Most of this increased proportion of hereditary ovarian cancer risk is accounted for by inherited mutations in the BRCA1 and BRCA2 genes. In the Ashkenazi Jewish population, 29 to 41% of ovarian cancer is believed to be secondary to inheriting one of three founder mutations in BRCA1 and BRCA2, while only 10% of ovarian cancer is attributed to mutations of these genes in non-Ashkenazim. In the US population in general, it is estimated that between 1 out of 345 and 1 out of 1000 individuals carries a BRCA mutation, compared with approximately 1 in 40 individuals of Ashkenazi Jewish descent. The ovarian cancer risk up to age 70 associated with BRCA mutation carriers has been reported to be as high as 66% for BRCA1 and 27% for BRCA2mutation carriers. Ovarian cancer in Ashkenazi kindreds has served as a model for the study of the histopathology of inherited ovarian cancers as well as for the study of risk reduction and screening among all women at inherited risk of ovarian cancer.     

BRCA1 and BRCA2 Mutations in Breast and Ovarian Cancer Syndrome: Reflection on the Creighton University Historical Series of High Risk Families

Over the last four decades, Henry Lynch has collected pedigrees and samples from high risk breast and/or ovarian cancer families, generating a unique resource for the study of breast cancer susceptibility. These families have made a major contribution to increasing our knowledge in the cancer genetic susceptibility field, allowing the discovery of a genetic association between breast and ovarian cancer predisposition, contributing to the mapping of the BRCA1 and BRCA2 genes, advancing the idea of the existence of other breast cancer susceptibility genes, allowing the evaluation of BRCA-associated cancer risks and psychosocial aspects of BRCA testing and so on. Ten years after the cloning of BRCA1 and BRCA2, we report the current status of these families and compare the observed BRCA1/2 mutation detection rate with the estimations obtained by linkage analysis of the Breast Cancer Linkage Consortium families.     

Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

The role of the lifetime number of ovulatory cycles has not been evaluated in the context of BRCA‐associated ovarian cancer. Thus, we conducted a matched case–control study to evaluate the relationship between the cumulative number of ovulatory cycles (and contributing components) and risk of developing ovarian cancer in BRCA mutation carriers (1,329 cases and 5,267 controls). Information regarding reproductive and hormonal factors was collected from a routinely administered questionnaire. Conditional logistic regression was used to evaluate all associations. We observed a 45% reduction in the risk of developing ovarian cancer among women in the lowest vs. highest quartile of ovulatory cycles (OR = 0.55; 95% CI 0.41–0.75, p = 0.0001). Breastfeeding for more than 12 months was associated with a 38% (95% CI 0.48–0.79) and 50% (95% CI 0.29–0.84) reduction in risk among BRCA1 and BRCA2 mutation carriers, respectively. For oral contraceptive use, maximum benefit was seen with five or more years of use among BRCA1 mutation carriers (OR = 0.50; 95% CI 0.40–0.63) and three or more years for BRCA2 mutation carriers (OR = 0.42; 95% CI 0.22–0.83). Increasing parity was associated with a significant inverse trend among BRCA1 (OR = 0.87; 95% CI 0.79–0.96; p‐trend = 0.005) but not BRCA2 mutation carriers (OR 0.98; 95% CI 0.81–1.19; p‐trend = 0.85). A later age at menopause was associated with an increased risk in women with a BRCA1 mutation (OR trend = 1.18; 95% CI 1.03–1.35; p = 0.02). These findings support an important role of breastfeeding and oral contraceptive use for the primary prevention of ovarian cancer among women carrying BRCA mutations.     

Association of gBRCA1/2 mutation locations with ovarian cancer risk in Japanese patients from the CHARLOTTE study

Whether germline (g) breast cancer susceptibility gene (BRCA) mutations are located within or outside the ovarian cancer cluster region (OCCR) (1380‐4062 bp for gBRCA1, and between 3249‐5681 bp and 6645‐7471 bp for gBRCA2) may influence risk variations for ovarian cancers. This ad hoc analysis of the CHARLOTTE epidemiological study in Japan assessed the distribution of gBRCA1/2 mutations in patients with newly diagnosed ovarian cancer, and investigated an association between gBRCA1/2 mutation locations and ovarian cancer risk. Differences in patient background and clinical characteristics in subgroups stratified by gBRCA1/2 mutation locations were also evaluated. We analyzed the data of 93 patients (14.7%) from the CHARLOTTE study who were positive for gBRCA1/2 mutations. After excluding 16 cases with L63X founder mutation, 28 (65.1%) of gBRCA1 mutations were within the OCCR. Of 30 gBRCA2 mutations, 15 (50.0%) were within the OCCR. Of 27 patients (one patient excluded for unknown family history) with gBRCA1 mutations located in the OCCR, 11 (40.7%) had a family history of ovarian cancer; the proportion of patients with a family history of ovarian cancer and gBRCA1 mutations outside the OCCR was lower (13.3%). Sixty percent of patients with gBRCA1 mutations outside the OCCR had a family history of breast cancer; the proportion of patients with a family history of breast cancer and gBRCA1 mutations within the OCCR was relatively lower (33.3%). Understanding the mutation locations may contribute to more accurate risk assessments of susceptible individuals and early detection of ovarian cancer among gBRCA mutation carriers.     

PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside

Individuals with breast and ovarian cancer susceptibility gene 1 (BRCA1) or BRCA2 germline mutations have a significantly increased lifetime risk for breast and ovarian cancers. BRCA‐mutant cancer cells have abnormal homologous recombination (HR) repair of DNA. In these tumors, the base excision repair (BER) pathway is important for cell survival. The poly(adenosine diphosphate‐ribose) polymerase (PARP) enzymes play a key role in BER, and PARP inhibitors are effective in causing cell death in BRCA‐mutant cells while sparing normal cells—a concept called synthetic lethality. PARP inhibitors are the first cancer therapeutics designed to exploit synthetic lethality. Recent clinical trials in BRCA‐mutant, metastatic breast cancer demonstrated improved outcomes with single‐agent PARP inhibitors (olaparib and talazoparib) over chemotherapy. However, resistance to PARP inhibitors remains a challenge. Primarily due to myelosuppression, the combination of PARP inhibitors with chemotherapy has been difficult. Novel combinations with chemotherapy, immunotherapy, and other targeted therapies are being pursued. In this review, the authors discuss current knowledge of PARP inhibitors in BRCA‐mutant breast cancer and potential future directions for these agents. Cancer 2018;124:2498‐506 . © 2018 American Cancer Society.     

BRCA1 and BRCA2: Chemosensitivity, Treatment Outcomes and Prognosis

BRCA1 and BRCA2 are important breast and ovarian cancer susceptibility genes, and mutations in these two genes confer lifetime risks of breast cancer of up to 80% and ovarian cancer risks of up to 40%. Clinico-pathological studies have identified features that are specific to BRCA1-related breast cancer, but this has been more difficult for BRCA2-related breast cancer. Ovarian cancers due to BRCA1 or BRCA2 mutations cannot usually be distinguished from their non-hereditary counterparts on morphological grounds, but micro-array data suggest that differences do exist. Prognostic studies have shown that breast cancer in a BRCA1 mutation carrier is likely to have a similar, or worse, outcome than that occurring in a BRCA2- or non-carrier of the same age. By contrast, most studies indicate that women developing a BRCA1/2-related ovarian cancer have an improved survival compared with non-carriers, particularly if they receive platinum-based therapy. In support of this, in vitro chemo-sensitivity studies have found that human cells lacking BRCA1 may be particularly sensitive to cisplatinum and to other drugs that cause double-strand breaks in DNA. Nevertheless, in breast cancer, little is known regarding clinically important differences in response to chemotherapy between BRCA1/2 mutation carriers and non-carriers, and between different chemotherapeutic regimens within existing series of BRCA1/2 mutation carriers. There are no published prospective studies. It is hoped that, in the near future, randomised controlled trials will be started with the aim of answering these important clinical questions.     

Poly(ADP-Ribose) Inhibition: Exploring a New Approach to Breast Cancer Prevention in <Emphasis Type="Italic">BRCA1/2</Emphasis> Mutation Carriers

Carriers of deleterious BRCA1 and BRCA2 mutations face an elevated risk of developing breast cancer. This risk warrants consideration of prevention interventions. Currently, the only proven prevention intervention for BRCA mutation carriers is risk-reducing surgery. Inhibitors of poly(ADP-ribose) polymerase (PARP) are a new class of drugs that appear to be effective in treating BRCA mutation–associated cancers and triple-negative breast cancers. PARP inhibitors may offer a new approach to breast cancer prevention in BRCA mutation carriers. This article reviews current breast cancer prevention interventions for BRCA mutation carriers and discusses the rationale for investigating new chemoprevention agents in this population. The mechanism of action of PARP inhibitors and the rationale for studying them in BRCA mutation carriers is reviewed. Published clinical trials regarding PARP inhibitors and ongoing research regarding PARP inhibitors and breast cancer prevention are reviewed.     

Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis

Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost‐effective screening strategy.     

Risk of metachronous breast cancer after BRCA mutation–associated ovarian cancer

BACKGROUND:

This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes (BRCA‐OC).

METHODS:

The Memorial Sloan‐Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA‐OC who participated in genetic testing and follow‐up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA‐OC. Overall survival (OS) and BC‐free survival (BCFS) were determined by the Kaplan‐Meier method; patients were censored at the time of last follow‐up.

RESULTS:

A total of 164 patients had BRCA‐OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01‐55 years]). Median follow‐up from OC for those not developing BC was 5.8 years (0.25‐55.6 years). There were 46 deaths, but none were due to BC. The 5‐ and 10‐year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5‐ and 10‐year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA‐OC. In this pseudo‐incident subset, 5‐ and 10‐ year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5‐ and 10‐year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively.

CONCLUSIONS:

OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA‐OC. Cancer 2013. © 2012 American Cancer Society.     

Japanese nationwide observational multicenter study of tumor BRCA1/2 variant testing in advanced ovarian cancer

The association between germline BRCA1 and BRCA2 pathogenic variants (mutations: gBRCAm) and ovarian cancer risk is well established. Germline testing alone cannot detect somatic BRCA1/2 pathogenic variants (sBRCAm), which is calculated based on the proportion of tumor BRCAm (tBRCAm) from tumor samples and gBRCAm. Homologous recombination deficiency (HRD) results mainly from genetic/epigenetic alterations in homologous recombination repair-related genes and can be evaluated by genomic instability status. In Japan, the prevalence of tBRCAm, sBRCAm, and HRD remains unclear. This multicenter, cross-sectional, observational study, CHaRacterIzing the croSs-secTional approach to invEstigate the prevaLence of tissue BRCA1/2 mutations in newLy diagnosEd advanced ovarian cancer patients (CHRISTELLE), evaluated the prevalence of tBRCAm, sBRCAm, and HRD in tumor specimens from newly diagnosed patients with ovarian cancer who underwent gBRCA testing. Of the 205 patients analyzed, 26.8% had a tBRCAm, including tBRCA1m (17.6%) and tBRCA2m (9.3%). The overall prevalence of tBRCAm, gBRCAm, sBRCAm, and HRD-positive status was 26.8%, 21.5%, 6.3%, and 60.0%, respectively. The calculated sBRCAm/tBRCAm ratio was 23.6% (13/55), and the prevalence of gBRCA variant of uncertain significance was 3.9%. These results suggest gBRCA testing alone cannot clearly identify the best course of treatment, highlighting the importance of sBRCA testing in Japan. The present results also suggest that testing for tBRCA and HRD should be encouraged in advanced ovarian cancer patients to drive precision medicine.     

Combined annotation‐dependent depletion score for BRCA1/2 variants in patients with breast and/or ovarian cancer

Utility of combined annotation‐dependent depletion (CADD) score was recently reported to rank pathogenicity as C‐scores ranging 1‐99 for both confirmed deleterious mutation. Using C‐scores for BRCA1/2 variants, we tried to constitute the classification system for variant of uncertain significance (VUS), which had been a major problem of genetic testing for hereditary breast and/or ovarian cancer. We analyzed BRCA1/2 genes for 283 patients with breast and/or ovarian cancer. The deleterious mutation and missesne mutations, minor variant, and wild type of BRCA1 and ‐2 were 5, 27, 251 and 15, 85, 183, respectively. Meanwhile, the variants with C‐score ≥10 were involved in 19/283 (6.7%) in BRCA1 and 34/283 (12%) in BRCA2. All deleterious mutations were included in this group. Frequency of personal history and family history of ovarian cancer were significantly high, and frequency of serous adenocarcinoma of ovary and triple negative breast cancer was relatively high in the group with deleterious mutations. Similar findings were seen in patients with variants of C‐score ≥10. According to the C‐score and population frequency, we could define VUS for 11 patients out of 283 patients (3.9 CADD is useful to classify the variant of BRCA1/2 and selecting the patient who needs further segregation studies.     

Oral contraceptives and breast cancer risk in BRCA1 and BRCA2 mutation carriers

Estrogen and progestin in oral contraceptives may be carcinogenic to the breast, and their use has been associated with a modest increase in the risk of breast cancer in the general female population. Women who carry deleterious mutations in breast cancer susceptibility genes, BRCA1 and BRCA2, have a significantly higher risk of breast and ovarian cancer. The literature on the role of oral contraceptives in carriers is sparse and the results are inconclusive. Findings from some case-control studies and the International BRCA1/2 Carrier Cohort Study suggest that oral contraceptive use may be associated with an increased risk of breast cancer in BRCA1 and BRCA2 carriers. Understanding the potential effects of oral contraceptive use among carriers has important implications for preventive strategies and clinical management. Both the possible protective effect for ovarian cancer risk and the increased potential risk of breast cancer must be considered.     

The identification of pathogenic variants in BRCA1/2 negative,high risk,hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants

NGS-based multiple gene panel resequencing in combination with a high resolution CGH-array was used to identify genetic risk factors for hereditary breast and/or ovarian cancer in 237 high risk patients who were previously tested negative for pathogenic BRCA1/2 variants. All patients were screened for pathogenic variants in 94 different cancer predisposing genes. We identified 32 pathogenic variants in 14 different genes (ATM, BLM, BRCA1, CDH1, CHEK2, FANCG, FANCM, FH, HRAS, PALB2, PMS2, PTEN, RAD51C and NBN) in 30 patients (12.7%). Two pathogenic BRCA1 variants that were previously undetected due to less comprehensive and sensitive methods were found. Five pathogenic variants are novel, three of which occur in genes yet unrelated to hereditary breast and/or ovarian cancer (FANCG, FH and HRAS). In our cohort we discovered a remarkably high frequency of truncating variants in FANCM (2.1%), which has recently been suggested as a susceptibility gene for hereditary breast cancer. Two patients of our cohort carried two different pathogenic variants each and 10 other patients in whom a pathogenic variant was confirmed also harbored a variant of unknown significance in a breast and ovarian cancer susceptibility gene. We were able to identify pathogenic variants predisposing for tumor formation in 12.3% of BRCA1/2 negative breast and/or ovarian cancer patients.     

Lifestyle Characteristics in Women Carriers of BRCA Mutations: Results From an Italian Trial Cohort

BackgroundWomen with deleterious mutations in BRCA1/2 have a high lifetime penetrance of developing breast cancer and/or ovarian cancer. Genetic and/or environmental factors may influence BRCA penetrance, and identifying modifiable exposures might be valuable for prevention.Patients and MethodsWe implemented a multicenter prospective 2-arm (1:1) randomized controlled trial to investigate whether a Mediterranean dietary intervention with moderate protein restriction would reduce potential modulators of BRCA penetrance such as insulin-like growth factor 1 (IGF-1), body weight, and metabolic risk factors. We studied the baseline characteristics of women with BRCA-positive disease who joined the trial cohort, focusing on the relationships between selected lifestyle exposures, metabolic/anthropometric parameters, and BRCA-related cancer.ResultsA total of 502 women (304 with a previous diagnosis of breast cancer and/or ovarian cancer and 198 unaffected) with deleterious BRCA mutations, with or without a previous cancer, aged 18 to 70 years and without metastases were included. Late age at menarche and pregnancy were negatively associated with BRCA-related cancer, especially in women with BRCA1-positive disease. Higher fat mass and the presence of 4 or 5 metabolic risk factors were significantly associated with BRCA-related cancer (hazard ratio, 1.87, 95% confidence interval, 1.21-2.88; and hazard ratio, 1.87, 95% confidence interval, 1.11-3.19, respectively), with greater effect in BRCA2-positive women.ConclusionsOur findings confirm previous observations about reproductive factors in women with BRCA disease and suggest a potential impact of metabolic factors in BRCA-related cancer. The prospective follow-up of the trial cohort will enable us to study the environmental modulators of BRCA penetrance and their impact in relation to the history of BRCA-related cancer. [ClinicalTrials.gov NCT03066856]