Talia Donenberg

Characterization of a Recurrent Germ Line Mutation of the E-Cadherin Gene: Implications for Genetic Testing and Clinical Management

Purpose: To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals. Experimental Design: We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing. Results: We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers. Conclusions: In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.

A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas

The Bahamas is a group of islands in the Caribbean with a high incidence of early onset breast cancer. In isolated populations, the identification of founder mutations in cancer predisposing genes may facilitate genetic testing and counseling. To date, six distinct BRCA1 mutations have been found in patients from cancer families from the Bahamas. The frequencies of these mutant alleles have not been measured in a large series of unselected breast cancer patients from Bahamas. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history of cancer. All patients were screened for six mutations in the BRCA1 gene that have previously been reported in cancer patients from the Bahamas. A mutation was identified in 49 of the 214 breast cancer patients (23%). The mutation frequency was particularly high in women diagnosed before age 50 (33%) in women with a first-degree relative with breast or ovarian cancer (41%) and in women with bilateral breast cancer (58%). Approximately 23% of unselected cases of breast cancer in the Bahamian population are attributable to a founder mutation in the BRCA1 gene—this is the highest reported mutation prevalence for any country studied to date. Genetic testing for these mutations is advisable for all women diagnosed with breast cancer in the Bahamas.

The spectrum of BRCA1 and BRCA2 mutations in breast cancer patients in the Bahamas

We sought to identify the full range of founder mutations in BRCA1 and BRCA2 in the Bahamas and to estimate the proportion of all BRCA1 and BRCA2 mutations that are accounted for by founder mutations. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history. A founder mutation had previously been identified in 49 patients. We conducted full sequencing of the BRCA1 and BRCA2 genes and multiplex ligation‐dependent probe amplification (MLPA) for 156 patients. A novel founder mutation in BRCA2 (exon 17 818delA) was seen in four different patients and five other unique mutations in BRCA1 and BRCA2, including a large deletion (exons 8–9) in BRCA1. In total, a mutation was seen in 58 of the 214 patients (27%); 92% of carriers carried one of the seven founder mutations. Approximately 27% of unselected cases of breast cancer in the Bahamian population are attributable to a mutation in BRCA1 or BRCA2, a prevalence which far exceeds that of any other country. The majority of women who carry a mutation in the Bahamas, carry one of the seven founder mutations, making it possible to offer genetic testing to all women at risk for breast cancer in the Bahamas.

BRCA1 Circos: a visualisation resource for functional analysis of missense variants

Background Inactivating germline mutations in the tumour suppressor gene BRCA1 are associated with a significantly increased risk of developing breast and ovarian cancer. A large number (>1500) of unique BRCA1 variants have been identified in the population and can be classified as pathogenic, non-pathogenic or as variants of unknown significance (VUS). Many VUS are rare missense variants leading to single amino acid changes. Their impact on protein function cannot be directly inferred from sequence information, precluding assessment of their pathogenicity. Thus, functional assays are critical to assess the impact of these VUS on protein activity. BRCA1 is a multifunctional protein and different assays have been used to assess the impact of variants on different biochemical activities and biological processes. Methods and results To facilitate VUS analysis, we have developed a visualisation resource that compiles and displays functional data on all documented BRCA1 missense variants. BRCA1 Circos is a web-based visualisation tool based on the freely available Circos software package. The BRCA1 Circos web tool (http://research.nhgri.nih.gov/bic/circos/) aggregates data from all published BRCA1 missense variants for functional studies, harmonises their results and presents various functionalities to search and interpret individual-level functional information for each BRCA1 missense variant. Conclusions This research visualisation tool will serve as a quick one-stop publically available reference for all the BRCA1 missense variants that have been functionally assessed. It will facilitate meta-analysis of functional data and improve assessment of pathogenicity of VUS.

Treatment of infertility does not increase the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation

OBJECTIVE To evaluate the relationship between use of fertility medication (i.e., selective estrogen receptor [ER] modulator, gonadotropin, or other) or infertility treatment (i.e., IVF or IUI) and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation. DESIGN A matched case-control study of 941 pairs of BRCA1 or BRCA2 mutation carriers with and without a diagnosis of ovarian cancer. SETTING Genetic clinics. PATIENT(S) Detailed information regarding treatment of infertility was collected from a routinely administered questionnaire. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals associated with fertility treatment. RESULT(S) There was no significant relationship between the use of any fertility medication or IVF treatment (odds ratio, 0.66; 95% confidence interval 0.18-2.33) and the subsequent risk of ovarian cancer. CONCLUSION(S) Our findings suggest that treatment for infertility does not significantly increase the risk of ovarian cancer among women with a BRCA mutation.

Prevalence of founder mutations in the BRCA1 and BRCA2 genes among unaffected women from the Bahamas

Population‐based testing for BRCA1/2 mutations detects a high proportion of carriers not identified by cancer family history‐based testing. We sought to determine whether population‐based testing is an effective approach to genetic testing in the Bahamas, where 23% of women with breast cancer carry one of seven founder mutations in the BRCA1 or BRCA2 gene. We determined the prevalence of founder BRCA mutations in 1847 Bahamian women without a personal history of breast or ovarian cancer, unselected for age or family history. We found that 2.8% (20/705) of unaffected women with a family history of breast/ovarian cancer and 0.09% (1/1089) of unaffected women without a family history carry a BRCA mutation. A total of 38% of unaffected women with a known mutation in the family were found to carry the familial mutation. We previously suggested that all Bahamian women with breast or ovarian cancer be offered genetic testing. These current data suggest that additionally all unaffected Bahamian women with a family history of breast/ovarian cancer should be offered genetic testing for the founder BRCA mutations.

Strategies for recruitment of relatives of BRCA mutation carriers to a genetic testing program in the Bahamas

The prevalence of BRCA1 and BRCA2 mutations among unselected breast cancer patients in the Bahamas is 23%. It is beneficial to advise relatives of mutation carriers that they are candidates for genetic testing. Women who test positive are then eligible for preventive interventions, such as oophorectomy. It is not clear how often relatives of women with a mutation in the Bahamas wish to undergo genetic testing for the family mutation. Furthermore, it is not clear how best to communicate this sensitive information to relatives in order to maximize patient compliance. We offered genetic testing to 202 first‐degree relatives of 58 mutation carriers. Of 159 women who were contacted by the proband or other family member, only 14 made an appointment for genetic testing (9%). In contrast, among 32 relatives who were contacted directly by the genetic counselor, 27 came for an appointment (84%). This study suggests that for recruitment of relatives in the Bahamas, direct contact by counselor is preferable to using the proband as an intermediary.

Short report: Follow-up of Bahamian women with a BRCA1 or BRCA2 mutation

We sought to determine to what extent the knowledge of carrying a BRCA1 or BRCA2 mutation influences the uptake of preventive surgeries in Bahamian women, including bilateral salpingo‐oophorectomy and bilateral mastectomy.

SMARCA4 germline gene mutation in a patient with epithelial ovarian: A case report

Background SMARCA4 is gene whose protein product participates in chromatin remodeling. Somatic mutations in this gene are associated with non-small cell lung cancer and malignant rhabdoid tumors, and both germline and somatic mutations are seen with small cell carcinoma of the ovary, hypercalcemic type. To date, there are no data identifying an association with more common epithelial carcinomas of the ovary. Case The patient is a 57-year-old female without any significant family history of cancer, diagnosed with high-grade serous carcinoma of the ovary. Per guideline, she underwent genetic testing, and was found to have a deleterious germline SMARCA4 mutation. She was treated with standard chemotherapy and an optimal tumor reduction, with a complete response to treatment. Conclusion The etiology of this patients high-grade serous carcinoma is unknown. If the SMARCA4 gene plays a role in serous ovarian carcinoma it is with variable expressivity. Further investigation into the role of SMARCA4 as a susceptibility gene for epithelial ovarian cancer is warranted.

A high frequency of PALB2 mutations in Jamaican patients with breast cancer

PurposeJamaica is an island nation with one of the highest breast cancer incidence rates in the Caribbean (40/100,000 per year). The contribution of cancer susceptibility gene mutations to the burden of breast cancer in Jamaica has not yet been explored. We sought to determine the prevalence of germline mutations in BRCA1, BRCA2, and PALB2 in 179 unselected Jamaican women with breast cancer.MethodsWe sequenced the entire coding regions of BRCA1, BRCA2, and PALB2 for all the study subjects.ResultsOverall, 8 of 179 patients (4.5%) had a mutation in one of the three genes: one in BRCA1, two in BRCA2, and five in PALB2.ConclusionsThese data suggest that in addition to BRCA1 and BRCA2, PALB2 should be included in genetic testing for breast cancer patients in Jamaica.