Three primary malignancies related to BRCA mutation successively occurring in a BRCA1 185delAG mutation carrier.

The 185delAG and 5382insC mutations in the BRCA1 gene and the 6174delT mutation in the BRCA2 gene (the Ashkenazi mutations) have been found to be significantly more common among Jews of eastern European ancestry (1 in 40, 2.5%) in comparison to the general population (1 in 800 to 1 in 300, 0.12-0.33%). Carriers of these mutations, especially the BRCA1 185delAG mutation, have a significantly increased lifetime risk of breast and ovarian carcinoma and other carcinomas as compared to non-carriers. A case of three primary malignancies related to the BRCA1 185delAG mutation successively occurring in a carrier of this mutation, is described. The patient successively developed breast carcinoma, ovarian micropapillary serous carcinoma and peritoneal papillary serous carcinoma. Immunohistochemical staining results have indicated that these tumors are three separate primary malignancies. This case illustrates that ovarian serous borderline tumors (including micropapillary serous carcinoma) and peritoneal papillary serous carcinomas should be considered, like breast and ovarian carcinomas, tumors expressed in BRCA mutation carriers.     

BRCA1-related malignancies in a family presenting with von Recklinghausen's disease

BACKGROUND: The association between neurofibromatosis and gynecologic malignancies is rarely reported in the literature. Both BRCA1 and NF1 genes are located on the long arm of chromosome 17. CASE: We have observed a pedigree showing several individuals affected by both type 1 neurofibromatosis (NF1) and breast or coelomatic cancers. The number of individuals affected, their degree of relationship, and the early age at onset were suggestive of an hereditary breast/ovarian cancer syndrome. Linkage analysis was performed in order to establish whether markers in the chromosome 17 region containing the BRCA1 and NF1 loci were shared by affected individuals. Screening for BRCA1 mutations was performed by PTT and SSCP. Analysis of chromosome 17 DNA markers in the five family members tested show that three individuals affected by both NF1 and carcinomas share a common haplotype including the NF1 and BRCA1 loci on chromosome 17. Mutation analysis showed the presence of a nonsense mutation within BRCA1 exon 12 in two individuals, mother and daughter, affected by breast and peritoneal cancer, respectively, as well as in the son, who had rectal cancer at the early age of 27 years. All three subjects also had NF1. CONCLUSION: The concurrence of NF1 and hereditary breast/ovarian cancer in this family is likely due to the presence of two linked mutations at the NF1 and BRCA1 loci.     

Transitional cell ovarian carcinoma in a BRCA1 mutation carrier

BACKGROUND:BRCA1 mutation carriers are at high risk of developing epithelial ovarian cancer, but the transitional cell variant has not been previously reported in these patients.CASE:A nulligravid, perimenopausal woman underwent exploratory laparotomy for a pelvic mass, ascites, and omental caking. Intraoperatively, frozen section of a tumor implant revealed high-grade epithelial ovarian carcinoma. Optimal surgical cytoreduction was performed. The final surgical pathology confirmed International Federation of Gynecology and Obstetrics stage IIIC transitional cell ovarian carcinoma. Her family history was significant for a sister with premenopausal breast cancer and a paternal aunt with ovarian cancer. The patient was counseled and elected to undergo genetic testing. Comprehensive gene sequence analysis detected the germline BRCA1 5382insC mutation.CONCLUSION:Transitional cell ovarian carcinoma is a rare histologic variant of epithelial ovarian cancer that may occur in BRCA1 mutation carriers.     

Survival of BRCA1 negative ovarian cancer patients based on family history

OBJECTIVE: To compare survival of ovarian cancer patients with and without a family history of breast or ovarian cancer who are known to be without mutations in BRCA1. METHODS: Patients with ovarian cancer were tested for germline mutations in BRCA1 by polymerase chain reaction amplification of DNA for single-strand conformation polymorphism and direct sequencing analysis to examine the 22 coding exons of BRCA1 in fresh and archived tumor specimens. Demographic and survival data were collected for statistical analysis. Survival data were calculated by the method of Kaplan and Meier and compared by the log-rank test. RESULTS: Of the 110 patients tested at our institution, 100 were noted to be negative for BRCA1 mutations. After exclusion of nonepithelial histologies, benign tumors, primary peritoneal carcinoma, and incomplete staging, 87 patients remained for analysis, of which 37 demonstrated a family history of breast or ovarian cancer. The two groups showed similar age at diagnosis, stage, grade, residual disease, and type of chemotherapy. Median actuarial survival was 75 months for those patients with a family history versus 70 months for those without (P = 0.73). Evaluation of patients with two or more relatives with breast or ovarian cancer also revealed no differences in survival. CONCLUSIONS: Family history of breast or ovarian cancer does not affect survival of patients with ovarian cancer in the absence of mutations in BRCA1. Previously described differences in survival among patients with BRCA1 mutations may be more related to genetic factors than to biases introduced by the presence of family history.     

Fallopian tube cancer in a BRCA1 mutation carrier: rapid development and failure of screening.

We report a case of fallopian tube cancer that developed in a woman with a germ-line BRCA1 mutation. The notable feature of this case was the extremely rapid growth of the cancer, which precluded early diagnosis. Preventive gynecologic surgery in BRCA1/2 mutation carriers should probably always include bilateral salpingectomy.     

Hormone replacement therapy and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

OBJECTIVE: Hormone replacement therapy (HRT) is commonly prescribed to alleviate the climacteric symptoms of menopause. Recent findings from the Women's Health Initiative has raised questions about the routine use of HRT due to the increased observed incidence of cardiovascular disease and of breast and ovarian cancers in the treatment arm of the trial. In the general population, the association between HRT use and risk of ovarian cancer has not yet been resolved. This association has not been evaluated in BRCA1 or BRCA2 mutation carriers who face very high lifetime risks of both breast and ovarian cancers. METHODS: We conducted a matched case-control study on 162 matched sets of women who carry a deleterious mutation in either the BRCA1 or BRCA2 gene. Women who had been diagnosed with ovarian cancer were matched to control subjects by mutation, year of birth, and age at menopause. Information on HRT use was derived from a questionnaire routinely administered to women who were found to be carriers of a mutation in either gene. Conditional logistic regression was used to estimate the association between HRT use and the risk of ovarian cancer, stratified by mutation status and type of HRT. RESULTS: Compared with those who had never used HRT, the odds ratio associated with ever use of HRT was 0.93 (95% CI = 0.56-1.56). There was no significant relationship with increasing duration of HRT use. There was a suggestion that progestin-based HRT regimens might protect against ovarian cancer (odds ratio = 0.57) but this association was not statistically significant (P = 0.20). CONCLUSION: HRT use does not appear to adversely influence the risk of ovarian cancer in BRCA mutation carriers.     

The importance of family history in young patients with endometrial cancer

Endometrial cancer occurs primarily in postmenopausal women older than 60 years of age. Especially in young patients with endometrial cancer, a positive family history with respect to cancer and/or development of synchronous or metachronous tumors can be indicative of hereditary factors. One genetic disorder, playing an important role in the development of endometrial cancer in young women, is hereditary non-polyposis colorectal cancer (HNPCC). The mean age to develop endometrial cancer because of a mutation in one of the HNPCC-genes is below 50 years. Mutation carriers have a life-time risk of about 50% for endometrial cancer. Especially young patients with endometrial cancer should always be asked for the family history and after primary treatment the family history should regularly be updated during follow-up.     

Occult cancer of the fallopian tube in a BRCA2 germline mutation carrier at prophylactic salpingo-oophorectomy

BACKGROUND: Women with a germline BRCA1 or BRCA2 mutation have a significantly increased risk of developing ovarian cancer compared with women in the general population and may consider bilateral prophylactic oophorectomy as a risk-reducing option. CASE: We report a case of occult fallopian tube cancer diagnosed at prophylactic surgery in a patient with a BRCA2 mutation. CONCLUSIONS: This report acts as a reminder of the importance of removing as much of the fallopian tube as possible during prophylactic surgery in BRCA1 and BRCA2 carriers and of the need for careful pathological examination of surgical specimens after surgery.     

No BRCA1 germline mutation in a family with uterine papillary serous carcinoma: a case report.

The purpose of the study was to examine BRCA1 germline mutation and its relationship to BRCA1 expression in two patients, a mother and a daughter, both diagnosed with uterine papillary serous carcinoma (UPSC). DNA was screened for BRCA1 and BRCA2 germline mutations common in the Jewish population (185delAG, 5382insC, and 6174delT) by PCR-based assay and with a protein truncation test (PTT) to detect mutation in exon 11 of BRCA1 and exons 10 and 11 of BRCA2. BRCA1 expression in fixed tumor tissues was assessed by immunocytochemistry (IHC). No germline mutation in either BRCAI or BRCA2 gene was found in the two patients. Both samples showed reduced levels of BRCAI expression. Taken together, these results suggest that undetected or unscreened for germline mutation may be associated with occurrence of this rare tumor type in two members of the same family. Alternatively, an epigenetic mechanism such as BRCA1 promoter hypermethylation may be responsible for reduced expression of BRCA1 in the absence of DNA mutations.     

Preimplantation genetic diagnosis for BRCA1 exon 13 duplication mutation using linked polymorphic markers resulting in a live birth

BACKGROUND: The risk of breast cancer associated with inheriting a BRCA1 mutation is extremely high, in addition, there is a 50% chance of transmitting this familial cancer mutation to any offspring. METHODS: A 31-year-old woman with a strong maternal family history of early onset of breast cancer had experienced 3 years of primary infertility. Presymptomatic testing confirmed the woman had inherited a 6 kb duplication of exon 13 (ins6KbEx13) in BRCA1 from her mother. Neither gamete donation or adoption were acceptable options for this infertile couple, and as termination of pregnancy after prenatal diagnosis following in vitro fertilization (IVF) was not ethically acceptable, preimplantation genetic diagnosis (PGD) was sought. A single-cell PCR protocol for PGD for the breast and ovarian cancer predisposing BRCA1 exon 13 duplication mutation was developed which involved amplification of three specific gene regions, including the BRCA1 mutation (ins6KbEx13), an intragenic marker (D17S855) and a flanking marker (D17S1185). RESULTS: In the first cycle of IVF, three embryos were analyzed and two were determined to be at low risk of having inherited the maternal BRCA1 mutation. Following the transfer of both embryos on day 5, a singleton pregnancy resulted. Declining confirmatory prenatal diagnosis, a male baby was subsequently delivered at term. CONCLUSIONS: Successful PGD for BRCA1 resulted in the delivery of a live-born male. PGD using linked polymorphic markers provides an alternate option for reproduction for couples with or at risk of having inherited a BRCA1 mutation.     

The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers

OBJECTIVE: To estimate the risk of ovarian cancer after a primary diagnosis of breast cancer among women with a BRCA1 or BRCA2 mutation and to identify host and treatment-related factors that might modify the risk. PATIENTS AND METHODS: Patients were 491 women with stage I or stage II breast cancer, diagnosed from 1975 to 2000 and for whom a BRCA1 or BRCA2 mutation had been identified. Patients were followed from the initial diagnosis of breast cancer until either ovarian cancer, prophylactic oophorectomy, death, or 2002. The medical treatment records and pathology documents were reviewed. Information that was abstracted from the medical charts included date of breast cancer diagnosis, stage of disease, use of chemotherapy, use of radiation therapy, usage of tamoxifen, oophorectomy, recurrence, second malignancy, and vital status. RESULTS: The 10-year actuarial risk of ovarian cancer after breast cancer was 12.7% for BRCA1 carriers and 6.8% for BRCA2 carriers (P = 0.03). The use of tamoxifen (OR = 1.79; P = 0.16) and chemotherapy (OR = 0.59; P = 0.15) did not significantly impact on the risk of subsequent ovarian cancer. Twenty-five percent of the deaths in women with stage I breast cancer were due to a subsequent ovarian cancer. CONCLUSIONS: The high incidence of ovarian cancer suggests that oophorectomy should be recommended in female BRCA1 and BRCA2 mutation carriers with a diagnosis of breast cancer, especially those with stage I disease. Breast cancer systemic therapy did not significantly alter the risk of ovarian cancer.     

Surgical treatment in ovarian cancer prevention in carriers of the BRCA1/BRCA2 mutation

Ovarian cancer remains to be a real challenge in spite of considerable progress in many areas of modern medicine. The use of genetic testing for detecting mutations of the BRCA genes has been offering clinical scrutiny between mutated versions of the BRCA genes and higher risk of both breast and ovarian cancer A population survey is a method of choice to find out more efficient screening management in order to identify cancer patients who further will be treated effectively early A review of literature on surgical PBSO (prophylactic bilateral salpingooophorectomy) in the BRCA genes mutations carriers with focus on preventive results against morbidity of ovarian cancer has been presented in the article.     

Use of oral contraceptives in BRCA mutation carriers and risk for ovarian and breast cancer: a systematic review

BRCA mutation carriers have an increased risk of developing breast or ovarian cancer. Oral contraception (OC) is known to increase breast cancer and reduce ovarian cancer risk in the general population. This review analyses the published data on OC and risk of cancer in BRCA mutation carriers. We included all relevant articles published in English from 1995 to 2018. Literature was identified through a search on PubMed and Cochrane Library. We included four meta-analyses, one review, one case–control study and one retrospective cohort study on the association between ovarian cancer and OC in BRCA mutation carriers. All report a risk reduction for the OC users and several also describe an inverse correlation with duration of use. Regarding breast cancer, we included four meta-analyses, one review, one case–control study, two case-only studies, one prospective and one retrospective cohort study. Some studies report a risk elevation, while others did not find an association between OC use and breast cancer in BRCA mutation carriers. In other studies, the association was limited to early-onset breast cancer and/or associated with young age at first start of OC. Oral contraception leads to a risk reduction of ovarian cancer also in BRCA mutation carriers. An increase in breast cancer risk due to OC cannot be excluded. Women with BRCA mutation who consider OC use have to be informed about possible increase in breast cancer risk and alternative contraceptive methods. OC should not be used for the prevention of ovarian cancer in this population.