FaCD Online Syndrome Fact Sheet

Last updated: 16 Aug 2011

Name: Hereditary Breast-Ovarian Cancer, BRCA1 type

Mode of Inheritance: AD

Genes

BRCA1, mapped to 17q21

Tumor features

breast cancer
breast cancer, male
breast cancer, medullary/basal type
fallopian tube cancer
ovarian cancer (i.e. epithelial origin)
pancreatic adenocarcinoma
peritoneal (papillary serous) carcinoma
prostate cancer

Tumor features (possible)

breast, phyllodes tumor of the
carcinosarcoma, ovarian
cervical cancer
colon cancer
endometrial cancer
gastric cancer
hepatocellular cancer (hepatoma)
leukemia
papillary serous cervical cancer
skin cancer, squamous cell
uterine serous papillary carcinoma

Comment

Approximately 5-10% of breast cancer and ovarian cancer patients in the general population are estimated to be carriers of a highly penetrant cancer susceptibility gene[1;2]. Most BRCA mutations are observed in successive generations, de novo BRCA1/2 mutations appear to be very rare[79].

Breast cancer risk
The cumulative risks of breast cancer in women with a BRCA1 mutation were initially estimated to be 59% at age 50 and 82% at age 70 in the highly penetrant families used in the linkage analysis[5]. It has become clear that the breast cancer risk may be considerably lower in families with a lower number of affected relatives[65]. Mean cumulative cancer risks calculated in a meta-analysis by Chen and Parmigiani for mutation carriers at age 70 years are 57% (95% CI, 47% to 66%)[72]. A risk of 69% at age 70 has been reported for the Ashkenazi Jewish founder mutations 185delAG and 538insC [64]. Breast cancer risk for male mutation carriers at age 70 years is 1.2% [73].
Tumor risks are modified by a range of exogenous en endogenous risk factors, including some of those associated with sporadic breast cancer and variants in several genes; discussing these is beyond the scope of this text.

Contralateral breast cancer risk has been estimated in a linkage study to be as high as 64% by age 70[7] and 83% by age 60[8]. Possibly, the risk of contralateral breast cancer is higher in women with an age of <50 years at first diagnosis, compared with women with an age at first diagnosis >50 years[11].

Breast cancer in BRCA1 mutation carriers is often triple negative (ER/PgR/Her2), high grade and of medullary/basal epithelial phenotype[63,68,69,74]. However, early stage BRCA1-associated breast cancers are more frequently ERalpha and PR positive and low grade than advanced stages and receptor positivity increases with increasing age at breast cancer diagnosis[80].
A case of a malignant phyllodes tumor of the breast in a BRCA1 mutation carrier has been reported[75].

Ovarian cancer
The proportion of ovarian cancer due to germline BRCA1 mutations is estimated at 5.7 % below age at diagnosis of 40, 4.6 % between ages 40 and 49, and 2.1 % between ages 50 and 70 years[23]. A population-based study performed by Stratton et al.[41] of 101 women with invasive ovarian cancer diagnosed < 30 years failed to detect any BRCA1/2 mutations. Women in HBOC families carrying a mutated BRCA1 gene have been estimated to have an average cumulative risk of developing ovarian cancer of approximately 20-40(-60%), depending on the type of families (high or low penetrant) used for the risk calculations [8]. There is significant evidence of heterogeneity with regard to this risk and it may be considerably lower in women ascertained through families with little or no cases of breast and ovarian cancer[42]. A recent study suggests that BRCA1/2-associated ovarian cancer is biologically distinct and carries a higher risk of visceral metastasis than sporadic cases do[81]. Ovarian carcinosarcoma has been reported in a few patients[81].

In BRCA1 mutation carriers, the risk of ovarian cancer decreases with increasing age at last childbirth and, contrary to sporadic ovarian cancer, increases significantly with increasing parity[45]. Mean age at diagnosis of ovarian cancer appears to be younger for BRCA1 cases than for BRCA2 cases (54 versus 62 years in one series[47]). Mucinous ovarian cancer is underrepresented in familial ovarian cancer and the same is true for BRCA1/2 associated ovarian cancer[47,50,67]. Borderline ovarian cancer is not an indicator for BRCA1 germline mutations[42,51,52,67].

Other tumors
Fallopian tube cancer is part of the BRCA1 tumor spectrum[53-55]. The same holds true for peritoneal (papillary serous) cancer, which can occur after prophylactic oophorectomy and has also been diagnosed in mutation carriers without a personal history of ovarian cancer or prophylactic oophorectomy[56;57].

A range of other tumors has been observed. Tumors that were shown to be significantly associated with BRCA1 mutations in one or more studies, but not in others are all classified as 'possibly' associated with BRCA1 in this syndrome file.

An increased risk to develop colorectal cancer was suggested by linkage studies[7], however, this has not been confirmed by studies in families with proven BRCA1 mutations[59,60,71].

Prostate cancer risk has been found to be increased in the linkage studies[7] and studies of first-degree relatives of proven mutation carriers[61]. Germline BRCA1 mutations have been found in prostate cancer patients without a strong family history of breast and ovarian cancer[59]. However, in BRCA1 mutation carriers there was only marginal evidence for increased risk to develop prostate cancer under the age of 65 years and no evidence for increased risk at older ages[71].

Uterine cancer in general[71] and uterine serous papillary carcinoma in particular, has been observed in a few women with a germline BRCA1 mutation and loss of heterozygosity studies of these tumors suggested that this type might belong to the BRCA1 phenotype[60,61].

Among relatives (all degrees combined) of BRCA1 germline mutation carriers, relatives risk were found to be increased for gastric cancer in women (RR 5.9) and invasive squamous cell cancer of the skin in males (RR 6)[62].

Although pancreatic cancer is less common in BRCA1 mutation carriers than in BRCA2 mutation carriers, present data suggests it should be regarded as part of the BRCA1-associated tumor spectrum[76,77,78].

Links

Breast Cancer Linkage Consortium 18 1 08

References

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