For Physicians

BRCA Mutations and Cancers Other Than Female Breast and Ovary

The presence of breast cancer in multiple generations with an apparent autosomal dominant pattern of transmission has long been recognized. These “familial cancers” account for an estimated 5 to 10% of breast cancers overall. The search for the genes responsible for this cancer susceptibility resulted in the discovery of two mutations found in studies of Ashkenazi Jews (AJ) in the BRCA1 gene on chromosome 13 and one mutation in BRCA2 on chromosome 171. These BRCA mutations proved to be detrimental since carriers were found to have a striking increase in the lifetime risk of breast and ovarian cancer. The reported figures for the relative risk (RR) for carriers is quite variable from series to series, but in general for breast cancer RR is about 65% and 45%, and ovarian 40% and 18% for BRCA 1 and 2 respectively.

Subsequent reports found these same BRCA mutations in multiple unrelated families, an observation consistent with a founder effect, wherein a mutation can be traced back in history to a small group of “founders”, in this case most commonly Ashkenazi Jews. The prevalence of BRCA1 mutations in patients with breast cancer sorted by ethnicity is: 8.3-10.2% Ashkenazi Jews; 2.2-2.9% non-Ashkenazi Caucasians; 3.5% Hispanics; 1.3% African Americans; 0.5% Asian Americans. The prevalence of BRCA2 mutations is 2.6% in African Americans and 2.1% in Caucasians with cancer². In the non-cancer population the prevalence of a BRCA gene mutation is about 0.25% (or 1 in 400-800) for non-Ashkenazi individuals, and about 1.1-2.5% (or 1 in 40-90) for the general AJ population^3,9. Although these mutations initially seemed to target only breast, ovaries, and fallopian tubes, subsequent reports have described an association with stomach, pancreas, prostate, and a non-statistical trend for colon cancer ⁴.

The cellular protein products associated with BRCA1/2 genes are involved with pathways important for the recognition of DNA damage and repair of double-strand breaks, cell cycle control, regulation of transcription, and chromatin remodeling⁴. In the course of the cell cycle of all normal cells, BRCA genes play an essential role in recognizing and repairing aberrations in DNA that may occur. Although many mutations in BRCA1/2 genes have been identified, two distinct BRCA1 and one BRCA2 mutation are considered amongst Ashkenazi Jews to be the critical pathogenic germline mutations responsible for breast, ovarian, and possibly other cancers.

When these particular mutations are present, the cellular proteins they encode are missing or non-functional causing a lack of DNA repair and other important mechanisms. This potentiates a cascade of genetic changes affecting the cell cycle and drives carcinogenesis. Thus, normal BRCA1/2 genes have been classified as tumor suppressor genes, and the mutations have been designated cancer susceptibility genes. Simple, inexpensive screening methods are available to identify these mutations but have the drawback that they vary widely in their sensitivity and miss nearly a third of the mutations which otherwise could have been detected by DNA sequencing and other accurate, commercially available, but expensive genetic techniques. Even after complete genetic sequencing, 10-15% of individuals will have mutations that are not clearly deleterious and instead are classified as variant mutations of uncertain significance (VUS). In this situation, the personal and family cancer history and other information becomes important to characterize VUS as benign or deleterious.

BRCA genes perform these very important functions in every cell. Therefore, it is not totally surprising that mutations in these genes may produce cancers in other organs besides the main targets, female breast and ovaries. An important 1999 report by The Breast Cancer Linkage Consortium, a very large international study of familial breast/ovarian cancer, seemed to support the theory that damage to BRCA-related pathways creates a susceptibility to other cancers. The families studied had a statistically significant increased incidence of the following cancers: prostate (RR 4.65), pancreas (RR 3.5), biliary tract (RR 4.97), gastric (RR 2.59), and melanoma (RR 2.58). Other reports have noted a similar but non-statistically significant trend for colon cancer⁴.

Male breast cancer constitutes less than 1% of all cases of breast cancer, and may occur at any age, but most commonly develops in men ages 60-70. It resembles female cancer pathologically, except for the virtual absence of lobular lesions⁵. In the overall male breast cancer population the likelihood of identifying a BRCA mutation is 6% , and the cancer risk for a BRCA carrier is 7-8.6% by age 80⁶. Amongst Ashkenazi Jews with male breast cancer, the incidence of BRCA gene mutation identification is 17%⁷. In contrast to female cases, most familial male breast cancer is associated with BRCA2.

The treatment, natural history, and survival for men are similar to women with breast cancer diagnosed at the same stage. However, the diagnosis for men often is established at a more advanced stage and for that reason is less likely to be cured.

The existence of familial pancreatic cancer first was suggested in 1989 by a large study of families with this disease. Currently it is estimated that about 10% of patients with pancreatic cancer have an inherited disease, and BRCA1 and 2 have been implicated. A family history of pancreatic cancer in first and second degree relatives has been found to predict the presence of a BRCA2 mutation, and pancreatic cancer is more common in breast cancer families with BRCA2 mutations (2-9 fold relative risk)¹⁰.

A recent study of 187 Jewish patients undergoing pancreatic resection found 5.4% with BRCA mutations, 1.3% BRCA1 and 4.1% BRCA2. This was more than a 5-fold increase in BRCA prevalence as compared to the non-cancer control Jewish population of this study (1.1%). BRCA and non-BRCA cancer patients had virtually the same long-term outcomes following surgery. Furthermore, statistical analysis of the non-cancer control population of BRCA2 positive Jewish men and women found that their estimated lifetime risk for pancreatic cancer risk was 4.9%⁹.

Familial clustering of prostate cancer has been reported frequently, and from 5-10% of cases is believed due to inheritance of cancer susceptibility genes. In men with a positive family history many population-based series have demonstrated an overall increased relative risk (RR) mainly in the range of 3.3. However, the RR is greater when a brother and a father are affected (RR 9.4), and even higher if a family member was diagnosed younger than age 55¹¹.

Some, but not all, studies have reported that the risk of prostate cancer is higher in men with a family history of breast cancer. This association may be explained by the purported increased risk of prostate cancer in carriers of the BRCA genes. In a general population study of more than 5000 Ashkenazi men, of the 120 BRCA gene carriers the cumulative prostate cancer risk to age 70 was estimated as 16% (95% Cl,4-30), compared to 3.6% for non-carriers³. (This study was done during the 1990s when techniques for diagnosis of prostate cancer were less sophisticated than now). Later studies confirmed this finding, although RR calculations differed somewhat and the risk was shown to be primarily with BRCA2.

Studies of Ashkenazi Jews with prostate cancer documented that 5.2% were found to have BRCA mutations (almost all BRCA2), as compared to a 1.9% prevalence in the general non-cancer control AJ population¹³. A study of sporadic prostate cancer in Britain reported a 2.3% prevalence for patients diagnosed at age less than 55, all BRCA2; however, a similar U.S. study of early-onset cancer did not confirm this 14. A recent report confirmed the 3-fold risk for prostate cancer in AJ BRCA2 carriers, and also found that the tumors were more poorly differentiated, and that BRCA1/2-mutation cancers had a higher recurrence (2-4 fold) and cancer specific death rate (5 fold) than non-mutation cancer controls15.

Furthermore, the question of the effect BRCA mutations may have on non-cancer mortality has been addressed in a study of 5287 genotyped Ashkenazi Jews. Using mortality data after censoring female carriers for breast, ovarian, pancreatic cancers, and melanoma, the estimated average life-expectancy for carriers was 6.8 years less than non-carriers. After censoring men for melanoma, pancreatic, and prostate cancer, the life expectancy of carriers was 3.7 years less. The conclusion of this study was that BRCA genes had a negative effect on non-cancer mortality, but the precise explanation for this increased biological risk is unknown¹⁶. More studies of the relation of BRCA mutations to all-cause and non-cancer mortality are required to confirm this intriguing observation.

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