Julian Peto

Cancer mortality in relatives of women with ovarian cancer: the OPCS Study. Office of Population Censuses and Surveys.

Mortality from cancer and other causes in male and female first‐degree relatives of women with breast cancer diagnosed before age 60 has been examined in a large population‐based cohort study, providing estimates of familial risks free from ascertainment or recall bias. Relatives of 3,295 patients with breast cancer diagnosed in the UK between 1954 and 1981 were identified through a register of households established in 1939. The 11,678 first‐degree relatives thus identified were followed up through national records until the end of 1992. Over this period 5,421 deaths (including 1,527 cancer deaths) occurred in these relatives. Mortality from breast cancer was significantly raised in first‐degree relatives (SMR 187, 248 deaths), and there was also significant excess mortality from cancers of the larynx (SMR 177, 17 deaths), endometrium (SMR 166, 29 deaths) and unspecified neoplasms (SMR 153, 70 deaths). The SMR for ovarian cancer was 130, based on 58 deaths (p = 0.06). There was no marked excess for other sites or for non‐neoplastic causes of death, but there was a significant deficit in mortality from cervical cancer (SMR 63, 18 deaths). The SMR for breast cancer increased significantly with decreasing age of the relative. After allowing for age, sisters of cases had a slightly (though non‐significantly) higher risk than mothers (ratio of SMRs 1.22). These results, together with penetrance estimates from linked families, suggest that approximately one woman in 800 carries BRCAI, the susceptibility gene on chromosome 17q, and that this gene causes about 1% of all breast cancers.

The A-T gene does not make a major contribution to familial breast cancer

Breast cancer is known to have a strong familial component, consistent in some families with autosomal dominant inheritance. It has been estimated that approximately 5% of breast cancers may be the result of a highly penetrant autosomal dominant gene (Claus et al., 1991). Such individuals tend to develop breast cancer at an early age, have a high prevalence of bilaterality and are at an elevated risk of other neoplasms (Lynch and Hirayam, 1989). Recently the location of a gene predisposing to both breast and ovarian cancer on chromosome 17q (BRCA1) has been established by genetic linkage analysis (Hall et al., 1990). In an analysis of 214 breast cancer families worldwide, the proportion of families linked to this locus was estimated to be 100% for breast-ovarian cancer families and 45% for families with multiple cases of breast cancer only (Easton et al., 1993). Among breast cancer families without cases of ovarian cancer, a small minority have features of the Li-Fraumeni syndrome (sarcomas in children associated with early onset breast cancer in female relatives) and a proportion of these families are associated with germline mutations in the p53 gene on chromosome 17p (Malkin et al., 1990).