Shelly Cummings

Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.

PURPOSE Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer. PATIENTS AND METHODS A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy. RESULTS Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005). CONCLUSION Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.

Male breast cancer in Cowden syndrome patients with germline PTEN mutations.

Cowden syndrome (CS) (OMIM 158350) is a multiple hamartoma syndrome associated with germline mutations in thePTEN tumour suppressor gene. While CS is characterised most commonly by non-cancerous lesions (mucocutaneous trichilemmomas, acral and palmoplantar keratoses, and papillomatous papules), it is also associated with an increased susceptibility to breast cancer (in females) and thyroid cancer, as well as non-cancerous conditions of the breast and thyroid. Here we report two cases of male breast cancer occurring in patients with classical CS phenotypes and germline PTEN mutations. The first subject was diagnosed with CS indicated primarily by mucocutaneous papillomatosis, facial trichilemmomas, and macrocephaly with frontal bossing at the age of 31 years. He developed breast cancer at 41 years and subsequently died of the disease. A PTENmutation, c.802delG, was identified in this subject, yet none of his family members showed evidence of a CS phenotype, suggesting that thisPTEN mutation may be a de novo occurrence. The second subject had a CS phenotype including multiple trichilemmomas and thyroid adenoma, developed male breast cancer at 43 years, and died of the disease at 57 years. He was a carrier of aPTEN mutation c.347-351delACAAT that cosegregated with the CS phenotype in affected family members. These two cases of male breast cancer associated with germlinePTEN mutations and the CS phenotype suggest that CS may be associated with an increased risk of early onset male as well as female breast cancer.

Predictors of Contralateral Prophylactic Mastectomy in Women With a BRCA1 or BRCA2 Mutation: The Hereditary Breast Cancer Clinical Study Group

PURPOSE To evaluate the rate of prophylactic contralateral mastectomy in an international cohort of women with hereditary breast cancer and to evaluate the predictors of uptake of preventive surgery. PATIENTS AND METHODS Women with a BRCA1 or BRCA2 mutation who had been diagnosed with unilateral breast cancer were followed prospectively for a minimum of 1.5 years. Information was collected on prophylactic surgery, tamoxifen use, and the occurrence of contralateral breast cancer. RESULTS Nine hundred twenty-seven women were included in the study; of these, 253 women (27.3%) underwent a contralateral prophylactic mastectomy after the initial diagnosis of breast cancer. There were large differences in uptake of contralateral prophylactic mastectomy by country, ranging from 0% in Norway to 49.3% in the United States. Among women from North America, those who had a prophylactic contralateral mastectomy were significantly younger at breast cancer diagnosis (mean age, 39 years) than were those without preventive surgery (mean age, 43 years). Women who initially underwent breast-conserving surgery were less likely to undergo contralateral prophylactic mastectomy than were women who underwent a mastectomy (12% v 40%; P < 10(-4)). Women who had elected for a prophylactic bilateral oophorectomy were more likely to have had their contralateral breast removed than those with intact ovaries (33% v 18%; P < 10(-4)). CONCLUSION Age, type of initial breast cancer surgery, and prophylactic oophorectomy are all predictive of prophylactic contralateral mastectomy in women with breast cancer and a BRCA mutation. The acceptance of contralateral preventive mastectomy was much higher in North America than in Europe.

Rapid progression of prostate cancer in men with a BRCA2 mutation.

Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P<0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation.

Cancer Genetic Testing and Assisted Reproduction

PURPOSE Because of increasing uptake of cancer genetic testing and the improving survival of young patients with cancer, health care practitioners including oncologists will increasingly be asked about options for assisted reproduction by members of families affected by hereditary cancer syndromes. Among these reproductive options, preimplantation genetic diagnosis (PGD) offers the opportunity to select embryos without familial cancer-predisposing mutations. METHODS A review of the published literature supplemented by a survey of PGD centers in the United States. RESULTS Prenatal diagnosis and/or embryo selection after genetic testing has already been performed in the context of more than a dozen familial cancer syndromes, including the common syndromes of genetic predisposition to colon and breast cancer. CONCLUSION While constituting new reproductive options for families affected by cancer, the medical indications and ethical acceptance of assisted reproductive technologies for adult-onset cancer predisposition syndromes remain to be defined. Continued discussion of the role of PGD in the reproductive setting is needed to inform the responsible use of these technologies to decrease the burden of heritable cancers.

Prevalence of BRCA1 and BRCA2 mutations among clinic-based African American families with breast cancer

Abstract. To define the prevalence and relative contributions of BRCA1 and BRCA2 mutations among African American families with breast cancer, we analyzed 28 DNA samples from patients identified through two oncology clinics. The entire coding regions of BRCA1 and BRCA2 were screened by protein truncation test, heteroduplex analysis, or single-stranded conformation polymorphism followed by DNA sequencing of variant bands. Deleterious protein-truncating BRCA1 and BRCA2 mutations were identified in five patients or 18% of the entire cohort. Only 8% (1 of 13) of women with a family history of breast cancer, but no ovarian cancer, had mutations. The mutation rates were higher for women from families with a history of breast cancer and at least one ovarian cancer (three of six, 50%). One woman with a family history of undocumented cancers was also found to carry a deleterious mutation in BRCA2. The spectrum of mutations was unique in that one novel BRCA1 mutation (1625del5) and three novel BRCA2 mutations (1536del4, 6696delTC, and 7795delCT) were identified. No recurrent mutations were identified in this cohort, although one BRCA2 (2816insA) mutation had been previously reported. In addition, two BRCA1 and four BRCA2 missense mutations of unknown significance were identified, one of which was novel. Taken together with our previous report on recurrent mutations seen in unrelated families, we conclude that African Americans have a unique mutation spectrum in BRCA1 and BRCA2 genes, but recurrent mutations are likely to be more widely dispersed and therefore not readily identifiable in this population.

NSGC Practice Guideline: Risk Assessment and Genetic Counseling for Hereditary Breast and Ovarian Cancer

PurposeThe purpose of this document is to present a current and comprehensive set of practice recommendations for effective genetic cancer risk assessment, counseling and testing for hereditary breast and ovarian cancer. The intended audience is genetic counselors and other health professionals who care for individuals with, or at increased risk of, hereditary breast and/or ovarian cancer.

How Often Do BRCA Mutation Carriers Tell Their Young Children of the Family's Risk for Cancer? A Study of Parental Disclosure of BRCA Mutations to Minors and Young Adults

PURPOSE Predictive genetic testing for adult-onset diseases is generally discouraged until the age at which interventions are believed to be helpful. Yet, many BRCA mutation carriers discuss their results with their children. This study describes the prevalence and experiences of parental communication of BRCA results to children under the age of 25 years old. PATIENTS AND METHODS Forty-two BRCA mutation carriers completed semistructured telephone interviews assessing self-reported disclosure to offspring and parent experiences with disclosure. Qualitative responses were coded for themes. chi(2) tests and logistic regression analyses with robust variance estimates were used to evaluate parent and child characteristics associated with disclosure. RESULTS Fifty-five percent of parents reported discussing hereditary risk of cancer with at least one child. By parent report, 49% of the 86 offspring learned of their parents genetic test results or the hereditary cancer risk. Offspring age was strongly associated with disclosure (P = .001), and the majority of adolescent and adult children learned of the familial mutation or the hereditary risk of cancer. Parents reported that some offspring did not appear to understand the significance of the information shared, and that some offspring had initial negative reactions to disclosure. Physician (14%) and genetic counselor (21%) involvement in parent decisions to disclose were low. CONCLUSION Children of BRCA mutation carriers learn of their parents genetic test results many years before preventive interventions are indicated. Further research is needed to examine how young individuals understand this information and its psychosocial impact and influence on subsequent lifestyle and health behaviors.

Uptake and timing of bilateral prophylactic salpingo-oophorectomy among BRCA1 and BRCA2 mutation carriers

Purpose: To evaluate prophylactic salpingo-oophorectomy uptake and timing among BRCA1/2 mutation carriers in a cancer risk assessment program.Methods: Clinical records of female BRCA1/2 mutation carriers who received cancer genetic counseling between 1996 and 2003 were reviewed to determine the completion and the timing of prophylactic salpingo-oophorectomy. Logistic regression models evaluated associations between subject characteristics and surgery. Survival analysis methods were used to estimate the distribution of time to surgery.Results: Among 88 women, 70% underwent prophylactic salpingo-oophorectomy. Prophylactic salpingo-oophorectomy was associated with older age, white race, having children, and a family history of ovarian cancer. Many women waited more than 12 months to undergo surgery and some delayed by several years. Younger age and not having children were associated with delays to surgery.Conclusion: Prophylactic salpingo-ooporectomy is an acceptable risk reduction measure for many BRCA1/2 mutation carriers. Some women make this decision many years after genetic testing. Continued discussion of the risks and benefits of risk reduction options may facilitate the uptake of recommended risk reduction interventions among BRCA mutation carriers.

Learning of your parent's BRCA mutation during adolescence or early adulthood: a study of offspring experiences

Objective: To examine the experience, comprehension and perceptions of learning of a parents BRCA mutation during adolescence and early adulthood, and explore the impact on offsprings physical and psychosocial well‐being.