Types Of Cancer Associated With Brca12 Mutations Ovarian Cancer

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The most significant cancer, other than breast cancer, in individuals with BRCA1 2 mutations is ovarian cancer, as reflected in the nomenclature, hereditary breast ovarian cancer (HBOC) syndrome. As with breast cancer, early linkage studies probably overestimated the penetrance of ovarian cancer for BRCA1/2 mutation carriers with estimates by the age of 70 years of 44% for BRCA1 carriers (51) and 27% for BRCA2 carriers (97). In contrast, later studies, utilizing nonlinkage-based ascertainments, derived lower penetrances. Struewing et al. (28) estimated the penetrance for ovarian cancer in those who harbored one of the three Ashkenazi Jewish BRCA1/2 founder mutations to be

16% by the age of 70 years. The Anglian Breast Cancer Study Group (59) estimated the combined penetrance of BRCA1/2 for ovarian cancer by the age of 80 years at 22%. In 2002, Antoniou et al. (91) estimated the penetrance of BRCA1 for ovarian cancer by the age of 70 years to be 25.9% and the corresponding estimate for BRCA2 was 9.1%. A meta-analysis of 22 studies with a total of over 8000 index cases of breast and/or ovarian cancer patients unselected for family history, 500 of whom carried BRCA1/2 mutations, was performed by Antoniou et al. (61). The average cumulative risk of ovarian cancer by the age of 70 years for BRCA1 was 39% and for BRCA2 was 11%. The corresponding figures were higher in families with early-onset index cases: 51% for BRCA1; 32% for BRCA2. In this analysis, for BRCA1, the ovarian cancer risk was highest when a breast cancer index case was <35 years of age. For BRCA2, the cumulative risks were higher when based on ovarian cancer index cases. In an Italian study by Marroni et al. (56), ovarian cancer penetrances were 43% at the age of 70 years in BRCA1 carriers and 15% at the age of 70 years in BRCA2 carriers. A paper by Chen et al. (38) estimated the cumulative ovarian cancer risk at the age of 70 years to be 39% in BRCA1 carriers and 22% in BRCA2 carriers. The study by Chen et al. included 676 Ashkenazi kindreds and 1272 non-Ashkenazi kindreds with greater than three diagnoses of breast or ovarian cancer in each family. Thus, as was the case for estimates of breast cancer penetrance when broken down by BRCA1 versus BRCA2 subtypes, ovarian cancer penetrance estimates are generally higher in BRCA1 mutation carriers, ranging from 16% to 44%, compared to 9.1% to 27% for BRCA2 mutation carriers.

Fallopian tube (FT) cancers are generally grouped with ovarian cancer because of the clinico-pathologic similarities of the two. Somatic loss of wild-type BRCA alleles in FT tumor tissue supports a link to HBOC (99). The BCLC (36) estimated a 500-fold excess of FT cancer among known and suspected BRCA2 mutation carriers when compared with the general population rate calculated from the East Anglian Cancer Registry in England. A number of studies have found associations between FT cancer and BRCA1 (100,101); a systematic study of the frequency of BRCA mutations in 44 unselected FT index cases from the Ontario Cancer Registry in Canada revealed five with a BRCA1 mutation (11.4%) and two with a BRCA2 mutation (4.5%) (102). The authors also found a roughly twofold excess risk of ovarian and breast cancers among first-degree relatives of mutation carriers. A subsequent study of 381 BRCA1 mutation-positive women calculated a 120-fold excess risk of FT cancers in this group compared to the estimated general population risk (55). Levine et al. (103) examined all Ashkenazi cases of both FT cancer and primary peritoneal cancer at two New York City medical centers during the period 1981-2001. Of 29 FT cancer cases thus ascertained, five (17%) had mutations; all five had BRCA1 mutations and one patient had an additional BRCA2 mutation. The estimated RR of FT cancer for BRCA mutation carriers was 11.3.

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