Special Lecture The Search for '

BRCAJ, a gene predisposing to breast and ovarian cancer, was mapped to chromosome 17q21 by linkage analysis. Loss of heterozy gosity In breast and ovarian tumors from BRCAJ-linked patients al ways involved loss of wild-type alleles from chromosome 17q21, sug gesting that BRCAI acts as a tumor suppressor gene. Melotic recombinatlon in linked families constrained the BRCA1 region to an estimated physical size of 650 kilobases. Twenty-two candidate genes were isolated by screening complementary DNA libraries with yeast artificial chromosomes and cosmids from the critical region. Of these, 8 were known human genes, 7 were homologues of genes identified in other species, and 7 encoded novel transcripts. Each gene was Se quenced and analyzed for variation, revealing 44 varIants, Including two missense mutations in two genes which segregated with breast cancer and were not found in controls. However, no frame-shift, nonsense, or regulatory mutations were found. Genetic Epidemiology of Breast and Ovarian Cancer Linkage of early-onset breast cancer to chromosome l7q2l was discovered 4 years ago ( 1). The existence of a gene that increases susceptibility to breast and ovarian cancer was verified with sub sequent work, with odds >1026: 1 (2, 3). BRCAJ has recently been cloned (4, 5), and experiments were performed to verify that the announced candidate is BRCAJ (6). In what follows, we present our approach to the search for BRCAJ, the 22 genes cloned and sequenced in the BRCAJ region, the mutations identified in these genes, and the implications of the cloning of BRCAJ for breast cancer research. BRCAJ appears to explain most of inherited breast cancer and inherited ovarian cancer. Of the 104 families in our series, predispo sition to breast and/or ovarian cancer are linked to BRCAJ in 57% of families with five or more affected relatives (14). Similarly, in a series of 214 families from Europe and America, 60% of families with at least three breast cancer cases and more than 90% of families with multiple relatives with breast and ovarian cancer trace susceptibility to BRCAJ (3). Furthermore, among families with at least three cases of ovarian cancer and no early-onset breast cancer, the proportion with cancer linked to BRCAJ is 78% if risk is assumed to be restricted to ovarian cancer, and 100% if predisposition to both breast and ovarian cancer is assumed (7). Risks of breast cancer to women inheriting BRCAJ are extremely high, exceeding 50% before age 50 years and reaching 80% by age 65 years (3, 8â€”10) However, families who have participatedin genetic studies were selected because multiple relatives developed Received 9/29/94; accepted I 1/14/94. I Based upon the Thirty-fourth G. H. A. Clowes Memorial Award Lecture presented at the 85th Annual Meeting of the American Association for Cancer Research, San Fran cisco, CA. April 10. 1994. This research was supported by grants from the National Cancer Institute (NIH ROl CA27632), the Breast Cancer Fund, and the Ensign and Lewis Foundation. 2 Susan G. Komen Breast Cancer Foundation Fellow. 3 American Cancer Society Professor of Genetics and Epidemiology. To whom requests for reprints should be addressed. breast cancer and may not be representative of all families with BRCAJ mutations. That is, there may exist other families with breast cancer linked to less severe mutations in BRCA1. Now that the BRCAJ gene is cloned, it will be possible to identify women carrying variant alleles and to begin to evaluate the risk associated with each mutant sequence. Inherited breast cancer is not restricted to early-onset disease. Inherited predisposition influences a higher proportion of breast cancer at younger ages, accounting for an estimated 30% of breast cancer diagnosed before age 40 years, compared to less than 5% of breast cancer diagnosed after age 60 years (8, 11). However, it is likely that the absolute number of patients with inherited disease is greater among older patients. Reanalysis of the original BRCAJ linkage data with a different liability class structure suggested that inherited breast cancer occurs in all age classes and that linkage of BRCAJ to early-onset disease was easier to identify because far fewer sporadic cases appear (12). This hypothesis can now be tested directly. Other genes responsible for inherited breast cancer have been identified. BRCA2, on chromosome 13ql2â€”l3, is linked to breast cancer in families with both females and males affected, as well as in some families with only female breast cancer (13). In our series, breast cancer is linked to BRCA2 in approximately 10% of families (i.e., â€”30%of high-risk families with breast cancer not linked to BRCAJ), including families with breast cancer in males and females and families with ovarian cancer (14). The first gene identified for inherited breast cancer was p53, which is responsible for the Li Fraumeni syndrome (15). In addition to female breast cancer, families with Li-Fraumeni syndrome have extremely high rates of brain tumors and adrenocortical cancers among children with a mutant p53 allele. About 1% of women diagnosed with breast cancer before age 30 years have germline mutations in p53. Additionally, a rare point mutation in the androgen receptor gene on the X chromosome can lead to breast cancer and androgen insufficiency among males (16). Breast can cer in other families with multiple cases is probably due to other, as yet unidentified, predisposing genes. However, given the very high rate of noninherited breast cancer, many remaining families with multiple cases of breast cancer may represent coincidental occurrences of breast cancer, rather than inherited predisposition due to other genes. The great majority of breast and ovarian cancers are due solely to acquired mutations: only 5 to 10% of breast cancer patients and 8 to 15% of ovarian cancer patients have inherited mutations leading to the disease. However, although inherited breast cancer is a small fraction of the breast cancer burden, it is a common genetic disease (17). Five % of a diseaseaffecting1in 10womenover the life spanmeansthat roughly 1 in 200 women, or more than 600,000 women in the United States, will develop breast cancer by reason of inherited susceptibility. Therefore, as an inherited trait, breast cancer is one of the most common genetic diseases in the world.