Nancie Petrucelli

Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2

Abstract: Hereditary breast and ovarian cancer due to mutations in the BRCA1 and BRCA2 genes is the most common cause of hereditary forms of both breast and ovarian cancer. The overall prevalence of BRCA1/2 mutations is estimated to be from 1 in 400 to 1 in 800 with a higher prevalence in the Ashkenazi Jewish population (1 in 40). Estimates of penetrance (cancer risk) vary considerably depending on the context in which they were derived and have been shown to vary within families with the same BRCA1/2 mutation. This suggests there is no exact risk estimate that can be applied to all individuals with a BRCA1/2 mutation. The likelihood of harboring a BRCA1 or BRCA2 mutation is dependent on ones personal and/or family history of cancer and can be estimated using various mutation probability models. For those individuals who have a BRCA1 or BRCA2 mutation, several screening and primary prevention options have been suggested, including prophylactic surgery and chemoprevention. Once a BRCA1 or BRCA2 mutation has been identified in a family, testing of at-risk relatives can identify those family members who also have the familial mutation and thus need increased surveillance and early intervention when a cancer is diagnosed.

Hereditary breast and ovarian cancer syndrome the impact of race on uptake of genetic counseling and testing.

Breast cancer is a significant cause of morbidity and mortality in the United States. Although breast cancer is more common among White American (WA) women, incidence rates are higher among young African American (AA) women. Approximately 5-10% of all breast cancer can be accounted for by germline mutations in the breast cancer (BRCA)1 and BRCA2 genes responsible for hereditary breast and ovarian cancer (HBOC) syndrome. Although genetic counseling (GC) and genetic testing (GT) for HBOC have become widely accepted by the WA population, cancer genetic services are underused among AA. Many investigators have evaluated a wide spectrum of BRCA1 and BRCA2 mutations in the AA and African population with the possible identification of African founder mutations. Barriers to GC and GT include lack of knowledge and/or negative attitudes regarding genetics and genetics research, and concerns regarding the potential for racial discrimination. It is important for future research to focus on ways in which to eliminate barriers to GC and GT to alleviate disparity in the use of genetic services among high-risk AA women.

Clinical Interpretation and Recommendations for Patients with a Variant of Uncertain Significance in BRCA1 or BRCA2: A Survey of Genetic Counseling Practice

The intent of this study was to document current practices in breast cancer genetic counseling and identify areas of variability for patients with a variant of uncertain significance (VUS) in the BRCA1 or BRCA2 gene. Registered members of the National Society of Genetic Counselors (NSGC) Cancer Special Interest Group (SIG) were sent an invitation via electronic mail to participate in an online questionnaire. The questionnaire was divided into three sections: clinical experience, clinical meaning, and risk perceptions and clinical recommendations for clinical situations involving a VUS. Fifty-seven of the eligible members responded. During the pre-test counseling session for a BRCA risk assessment patient, the vast majority of counselors (80.7%) mention VUS as a possible test result. Nearly half, 49.1%, report having given such a result to their patients at least one to four times. However, only 63.2% felt as though their patients understood the meaning of a VUS result. When asked to conclude the implication of a VUS and make medical management recommendations, the responses were varied. Nevertheless, a good proportion of counselors expressed the importance of testing other family members to help clarify the probands risk and aid in medical management issues. Although the recent recommendations by the American College of Medical Genetics suggest standards for the interpretation of sequence variations, they do not provide guidelines for making clinical recommendations based on these variations. The results of this study reveal significant diversity in the personal interpretation of a VUS result, leading to various clinical recommendations, and suggest a need for clinical management recommendations as well.

Prospective analysis of association between statin use and breast cancer risk in the women's health initiative.

Background: Statins are a class of cholesterol-lowering drugs that affect many intracellular pathways that may have implications for chemoprevention against cancer. Epidemiologic data on statins and breast cancer are conflicting. We analyzed updated data from the Womens Health Initiative (WHI) to assess the relationship between statins and breast cancer risk. Methods: The population included 154,587 postmenopausal women ages 50 to 79 years, with 7,430 pathologically confirmed cases of breast cancer identified over an average of 10.8 (SD, 3.3) years. Information on statins was collected at baseline and years one, three, six, and nine. Self- and interviewer-administered questionnaires were used to collect information on risk factors. Cox proportional hazards regression was used to calculate HRs with 95% confidence intervals (CI) to evaluate the relationship between statin use and cancer risk. Statistical tests were two-sided. Results: Statins were used by 11,584 (7.5%) women at baseline. The annualized rate of breast cancer was 0.42% among statin users and 0.42% among nonusers. The multivariable adjusted HR of breast cancer for users versus nonusers was 0.94 (95% CI, 0.83–1.06). In the multivariable-adjusted, time-dependent model, the HR for simvastatin was 0.87 (95% CI, 0.71–1.07). There was no significant trend by overall duration of use (P value for trend 0.68). There was no effect of tumor stage, grade, or hormone receptor status. Conclusion: Overall, statins were not associated with breast cancer risk. Impact: Our study is one of the largest prospective observational studies on this topic, and substantially adds to the literature suggesting no relationship between statins and breast cancer risk. Cancer Epidemiol Biomarkers Prev; 22(10); 1868–76. ©2013 AACR.

Familial Clustering of Breast and Prostate Cancer and Risk of Postmenopausal Breast Cancer in the Women's Health Initiative Study

Evidence suggests that the risk of breast and prostate cancer is increased among those with a family history of the same disease and particularly among first‐degree relatives. However, less is known about the relationship between breast and prostate cancer within families and particularly among minority populations.

Reanalysis of BRCA1/2 negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability

While up to 25% of ovarian cancer (OVCA) cases are thought to be due to inherited factors, the majority of genetic risk remains unexplained. To address this gap, we sought to identify previously undescribed OVCA risk variants through the whole exome sequencing (WES) and candidate gene analysis of 48 women with ovarian cancer and selected for high risk of genetic inheritance, yet negative for any known pathogenic variants in either BRCA1 or BRCA2. In silico SNP analysis was employed to identify suspect variants followed by validation using Sanger DNA sequencing. We identified five pathogenic variants in our sample, four of which are in two genes featured on current multi-gene panels; (RAD51D, ATM). In addition, we found a pathogenic FANCM variant (R1931*) which has been recently implicated in familial breast cancer risk. Numerous rare and predicted to be damaging variants of unknown significance were detected in genes on current commercial testing panels, most prominently in ATM (n = 6) and PALB2 (n = 5). The BRCA2 variant p.K3326*, resulting in a 93 amino acid truncation, was overrepresented in our sample (odds ratio = 4.95, p = 0.01) and coexisted in the germline of these women with other deleterious variants, suggesting a possible role as a modifier of genetic penetrance. Furthermore, we detected loss of function variants in non-panel genes involved in OVCA relevant pathways; DNA repair and cell cycle control, including CHEK1, TP53I3, REC8, HMMR, RAD52, RAD1, POLK, POLQ, and MCM4. In summary, our study implicates novel risk loci as well as highlights the clinical utility for retesting BRCA1/2 negative OVCA patients by genomic sequencing and analysis of genes in relevant pathways.

Variants in the Signaling Protein TSAd are Associated with Susceptibility to Ovarian Cancer in BRCA1/2 Negative High Risk Families

A substantial fraction of familial ovarian cancer cases cannot be attributed to specific genetic factors. The discovery of additional susceptibility genes will permit a more accurate assessment of hereditary cancer risk and allow for monitoring of predisposed women in order to intervene at the earliest possible stage. We focused on a population with elevated familial breast and ovarian cancer risk. In this study, we identified a SNP rs926103 whose minor allele is associated with predisposition to ovarian but not breast cancer in a Caucasian high-risk population without BRCA1/BRCA2 mutations. We have found that the allelic variation of rs926103, which alters amino acid 52 of the encoded protein SH2D2A/TSAd, results in differences in the activity of this protein involved in multiple signal transduction pathways, including regulation of immune response, tumor vascularization, cell growth, and differentiation. Our observation provides a novel candidate genetic biomarker of elevated ovarian cancer risk in members of high-risk families without BRCA1/2 mutations, as well as a potential therapeutic target, TSAd.

Cell-free DNA results lead to unexpected diagnosis

Maternal cell‐free DNA (cfDNA) results that are discordant with the diagnostic fetal karyotype should prompt further investigation. If deeper analysis of the cfDNA results demonstrates a “saw‐tooth” pattern characteristic of genome‐wide imbalance, maternal malignancy is suggested. Identifying the maternal malignancy can, however, be difficult.

Variable expressivity of Familial Medullary Thyroid Carcinoma (FMTC) due to a RET V804M (GTGG|[rarr]|ATG) mutation in two families: Reluctance of gene carriers to accept prophylactic thyroidectomy

Multiple endocrine neoplasia type 2 (MEN 2) and familial medullary thyroid carcinoma (FMTC) are autosomal dominantly inherited cancer syndromes that predispose to the development of C-cell hyperplasia and MTC. MEN 2A and FMTC are caused by multiple mutations in exons 10, 11, 13, 14 and 15 of the RET proto-oncogene. Associations between phenotype and specific germline RET mutations in exons 10, 11 and 13 have been established. We have studied 2 large FMTC families with a mutation in codon 804 in exon 14 (GTG→ATG; Val804Met) in which some individuals over age 70 had no overt clinical evidence of medullary thyroid carcinoma despite carrying or transmitting this mutation, In addition, some affected individuals with metastatic disease have had a relatively benign course, suggesting that this mutation causes a less aggressive form of MTC. Because of the presence of active MTC, including metastasis, in younger individuals within these families, we have continued to advocate thyroid surgery on the basis of mutation analysis. However, the apparent absence of disease in older individuals caused some of the younger individuals also known to be gene carriers to be reluctant to accept the recommended prophylactic thyroidectomy. Thus, counseling issues remain difficult in families with FMTC for specific mutations, even in a genetic disease usually considered to have a high penetrance, often with expression at much younger ages. These families emphasize the importance of molecular genetic testing in individuals or families with a history of FMTC, since identifying the specific RET mutation significantly influences the decision-making process for the affected individuals.