The prevalence of BRCA1 and BRCA2 mutations among young Mexican women with triple-negative breast cancer.

Various guidelines recommend that women with triple-negative breast cancer should be tested for BRCA1 mutations, but the prevalence of mutations may vary with ethnic group and with geographic region, and the optimal cutoff age for testing has not been established. We estimated the frequencies of BRCA1 and BRCA2 (BRCA) mutations among 190 women with triple-negative breast cancer, unselected for family history, diagnosed at age 50 or less at a single hospital in Mexico City. Patients were screened for 115 recurrent BRCA mutations, which have been reported previously in women of Hispanic origin, including a common large rearrangement Mexican founder mutation (BRCA1 ex9-12del). A BRCA mutation was detected in 44 of 190 patients with triple-negative breast cancer (23 %). Forty-three mutations were found in BRCA1 and one mutation was found in BRCA2. Seven different mutations accounted for 39 patients (89 % of the total mutations). The Mexican founder mutation (BRCA1 ex9-12del) was found 18 times and accounted for 41 % of all mutations detected. There is a high prevalence of BRCA1 mutations among young triple-negative breast cancer patients in Mexico. Women with triple-negative breast cancer in Mexico should be screened for mutations in BRCA1.

Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Peru.

The prevalence of BRCA1 and BRCA2 mutations among breast cancer patients in Peru has not yet been explored. We enrolled 266 women with breast cancer from a National cancer hospital in Lima, Peru, unselected for age or family history. DNA was screened with a panel of 114 recurrent Hispanic BRCA mutations (HISPANEL). Among the 266 cases, 13 deleterious mutations were identified (11 in BRCA1 and 2 in BRCA2), representing 5% of the total. The average age of breast cancer in the mutation-positive cases was 44 years. BRCA1 185delAG represented 7 of 11 mutations in BRCA1. Other mutations detected in BRCA1 included: two 2080delA, one 943ins10, and one 3878delTA. The BRCA2 3036del4 mutation was seen in two patients. Given the relatively low cost of the HISPANEL test, one should consider offering this test to all Peruvian women with breast or ovarian cancer.

BRCA1 mRNA levels following a 4-6-week intervention with oral 3,3'-diindolylmethane.

BACKGROUND: Haploinsufficiency may contribute to the development of breast cancer among women with a BRCA1 mutation. Thus, interventions that enhance BRCA1 expression may represent avenues for prevention. Studies have shown that 3,3'-diindolylmethane (DIM) can upregulate BRCA1 expression in breast cancer cells. This has yet to be demonstrated in vivo. METHODS: We conducted a study to evaluate the ability of oral DIM to upregulate BRCA1 mRNA expression in white blood cells. A total of 18 women were enroled in the study, including 13 BRCA1 mutation carriers who received 300 mg per day of Rx Balance BioResponse DIM for 4-6 weeks (intervention group) and 5 BRCA1 mutation carriers who did not take DIM (control group). BRCA1 mRNA expression was assessed at baseline and at 4-6 weeks by real-time, quantitative PCR and the relative change in BRCA1 mRNA expression (that is, 2(-ΔΔCT)) was calculated. RESULTS: The relative change in BRCA1 mRNA expression among women in the intervention group achieved borderline significance (P paired t-test=0.05). In the intervention group, BRCA1 mRNA expression increased in 10 of the participants, decreased in 2 and remained unchanged in 1 of the participants following DIM intervention (P sign test=0.02). On average, women in the intervention group experienced a 34% increase in BRCA1 mRNA expression (range -24 to 194%). There was no significant difference in the relative change in BRCA1 mRNA expression among women in the control group (P paired t-test=0.45). CONCLUSIONS: Under the tested conditions, oral DIM was associated with an increase in BRCA1 mRNA expression in women with a BRCA1 mutation. The possibility of mitigating the effect of an inherited deleterious BRCA1 mutation by increasing the physiologic expression of the gene and normalising protein levels represents a clinically important paradigm shift in the prevention strategies available to these high-risk women. Future studies with a larger sample size and higher doses of DIM are warranted.

Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study.

BACKGROUND: The BRCA1 and BRCA2 genes confer increased susceptibility to breast and ovarian cancer and to a spectrum of other cancers. There is controversy regarding the risk of colorectal cancer conferred by germline mutations in these two genes. METHODS: We followed 7015 women with a BRCA mutation for new cases of colorectal cancer. Incidence rates in carriers were compared with population-specific incidence rates, and standardised incidence ratios (SIRs) were estimated. The expected numbers of cancers were computed by multiplying person-years at risk by the appropriate age-, sex- and country-specific incidence rates from the five countries. RESULTS: Twenty-one incident colorectal cancer cases were observed among all mutation carriers, compared with 23.6 cases expected. The SIR for BRCA1 carriers was 0.92 (95% confidence interval (CI), 0.54-1.40, P=0.7) and for BRCA2 carriers was 0.82 (95% CI, 0.30-1.81, P=0.7). The SIR for colon cancer was 3.81 (95% CI 1.77-7.23) for women below the age of 50 years (both genes combined) and was 0.60 (95% CI 0.33-1.00) for women aged 50 years and above. CONCLUSION: The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women.

A comparison of the detection of BRCA mutation carriers through the provision of Jewish population-based genetic testing compared with clinic-based genetic testing.

BACKGROUND: Guidelines for genetic testing for BRCA1 or BRCA2 stipulate that a personal or family history of cancer is necessary to be eligible for testing. Approximately 2% of Ashkenazi Jewish women carry a mutation, but to date population-based testing has not been advocated. Little is known about the relative yield of a conventional genetic testing programme versus a programme of widespread testing in a population with common founder mutations. METHODS: We provided both referral-based and Jewish population-based testing between 2008 and 2012. We compared the numbers of BRCA mutation carriers identified through the two streams and estimated the number of genetic counselling hours devoted to each programme. RESULTS: From 2008 to 2012, 38 female carriers were identified through 487 referrals to our genetics centre (29 unaffected with cancer). During the same time, 6179 Jewish women were tested through our population-based programme and 93 mutation carriers were identified (92 unaffected with cancer). Fewer counsellor hours were devoted to the population-based than to the clinical referral-based testing programme. CONCLUSION: Genetic testing of all Jewish women above the age of 25 years will greatly expand the number of BRCA mutation carriers identified without a commensurate increase in the number of hours required for counselling.

Parental origin of mutation and the risk of breast cancer in a prospective study of women with a BRCA1 or BRCA2 mutation.

The objective is to estimate the risk of breast cancer in women who carry a deleterious BRCA1 or BRCA2 mutation, according to parental origin of mutation. We conducted a cohort study of women with a BRCA1 mutation (n = 1523) or BRCA2 mutation (n = 369) who had not been diagnosed with breast or ovarian cancer. For each woman, the pedigree was reviewed and the origin of the mutation was assigned as probable paternal or maternal. The hazard ratio (HR) for developing breast cancer in the follow-up period was estimated for women with a paternal mutation compared to a maternal mutation. The risk of breast cancer was modestly higher in women with a paternal BRCA1 mutation compared to women with a maternal BRCA1 mutation (HR = 1.46; 95% CI = 0.99-2.16) but the difference was not significant (p = 0.06). The parental mutation origin did not affect the risk in women with a BRCA2 mutation. Our results are consistent with the hypothesis that there is an increased risk of breast cancer among women with a paternally inherited BRCA1 mutation compared to a maternally inherited mutation. However, the data are not sufficiently compelling to justify different screening recommendations for the two subgroups.

The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Germline mutations in BRCA1 and BRCA2 predispose to pancreatic cancer. We estimated the incidence of pancreatic cancer in a cohort of female carriers of BRCA1 and BRCA2 mutation. We also estimated survival rates in pancreatic cancer cases from families with a BRCA mutation. METHODS: We followed 5149 women with a mutation for new cases of pancreatic cancer. The standardised incidence ratios (SIR) for pancreatic cancer were calculated based on age group and country of residence. We also reviewed the pedigrees of 8140 pedigrees with a BRCA1 or a BRCA2 mutation for those with a case of pancreatic cancer. We recorded the year of diagnosis and the year of death for 351 identified cases. RESULTS: Eight incident pancreatic cancer cases were identified among all mutation carriers. The SIR for BRCA1 carriers was 2.55 (95% CI=1.03-5.31, P=0.04) and for BRCA2 carriers was 2.13 (95% CI=0.36-7.03, P=0.3). The 5-year survival rate was 5% for cases from a BRCA1 family and 4% for cases from a BRCA2 family. CONCLUSION: The risk of pancreatic cancer is approximately doubled in female BRCA carriers. The poor survival in familial pancreatic cancer underscores the need for novel anti-tumoural strategies.

BRCA1 and BRCA2 mutations among familial breast cancer patients from Costa Rica.

The contribution of mutations in BRCA1 and BRCA2 genes to the burden of breast cancer in Costa Rica has not been studied. We estimated the frequency of BRCA mutations among 111 Costa Rican women with breast cancer and a family history of breast cancer. These women were mainly from the metropolitan area of San José. A detailed family history was obtained from each patient and a blood sample was processed for DNA extraction. Mutations in BRCA1 and BRCA2 were sought using a combination of techniques and all mutations were confirmed by direct sequencing. Four different mutations were identified in five patients (four in BRCA2 and one in BRCA1) representing 4.5% of the total. Two unrelated patients were found to have a BRCA2 5531delTT mutation. Other BRCA2 mutations included C5507G and 6174delT. Only one BRCA1 mutation was found (C3522T). The family with the BRCA1 mutation had five cases of gastric cancer. Families with BRCA2 mutations were also reported to have cases of gastric and prostate cancers; however, the full range of cancers associated with BRCA1 and BRCA2 mutations in Costa Rica has not yet been established.

Family history, BRCA mutations and breast cancer in Vietnamese women.

The purpose of this report is to estimate the proportions of familial and hereditary breast cancers among unselected cases of breast cancer in Vietnam. Two hundred and ninety-two unselected cases of incident breast cancer were recruited from the National Cancer Hospital, Hanoi, the largest cancer centre in Vietnam. Family histories were collected for 292 cases and a DNA sample was obtained for 259 cases. DNA samples were screened for mutations in the large exons of BRCA1 and BRCA2 using the protein truncation test and by allele-specific testing for 17 founder mutations which have been reported in other Asian populations. Complete gene sequencing was performed on two cases of familial breast cancer. Seven of 292 cases reported a relative with breast cancer and one patient reported a relative with ovarian cancer. A pathogenic BRCA mutation was detected in 2 of 259 cases; one BRCA1 carrier was diagnosed at age 51 and one BRCA2 carrier was diagnosed at age 42. Neither case reported a relative with breast or ovarian cancer. A family history of breast cancer is very uncommon among Vietnamese breast cancer patients. The frequency of pathogenic BRCA mutations in Vietnamese breast cancer patients is among the lowest reported worldwide.

Patient satisfaction and cancer-related distress among unselected Jewish women undergoing genetic testing for BRCA1 and BRCA2.

It is not known to what extent participation in a genetic testing program for BRCA1 and BRCA2, which does not include an extensive pre-test counselling session, influences cancer-related distress, cancer risk perception and patient satisfaction. Unselected Jewish women in Ontario were offered genetic testing for three common Jewish BRCA mutations. Before testing and 1-year post-testing, the women completed questionnaires which assessed cancer-related distress, cancer risk perception, and satisfaction. A total of 2080 women enrolled in the study; of these, 1516 (73%) completed a 1-year follow-up questionnaire. In women with a BRCA mutation, the mean breast cancer risk perception increased from 41.1% to 59.6% after receiving a positive genetic test result (p = 0.002). Among non-carriers, breast cancer risk perception decreased slightly, from 35.8% to 33.5% (p = 0.08). The mean level of cancer-related distress increased significantly for women with a BRCA mutation, but did not change in women without a mutation; 92.8% expressed satisfaction with the testing process. The results of this study suggest that the majority of Jewish women who took part in population genetic screening for BRCA1 and BRCA2 were satisfied with the delivery of genetic testing and would recommend testing to other Jewish women. However, women with a BRCA mutation experienced increased levels of cancer-related distress.

Does family history predict the age at onset of new breast cancers in BRCA1 and BRCA2 mutation-positive families?

Women who carry BRCA mutations are advised to begin breast cancer screening based on the age-specific risks of breast cancer development. It is not clear to what extent the family history of breast cancer influences age of onset. We evaluated the use of family history to predict the age of breast cancer onset in BRCA mutation carriers. Pedigrees from an Ontario-based registry were reviewed to identify the index case of breast cancer (most recent diagnosis) and other family cases of breast cancer. The youngest age of breast cancer diagnosis and mean age at breast cancer diagnosis in the other family cases were compared to the age of onset in the index case. The 260 BRCA1 and 213 BRCA2 pedigrees were reviewed. In BRCA2 families, the index case was diagnosed on average at 44.4 years when the youngest reported family case was less than or equal to 35 years, compared to 51.9 years when the earliest cases were diagnosed after age 50 (p = 0.04). A modest trend was seen for BRCA1 carriers, but this was not statistically significant. To a small extent, the onset of breast cancer in a BRCA2 mutation carrier can be predicted from her family history of cancer, however, the trend is modest and should not alter clinical recommendations regarding initiation of screening.