Age-adjusted incidence rates of breast cancer vary more than 10-fold worldwide, with the highest rates reported in North America and Europe. The highest breast cancer incidence rates in Southeast Asia have been reported for the Manila Cancer Registry in the Philippines, with an age-standardized rate of 47.7 per 100,000 per year. The possible contribution of hereditary factors to these elevated rates has not been investigated. We conducted a case-control study of 294 unselected incident breast cancer cases and 346 female controls from Manila, Philippines. Cases and controls were selected from women below the age of 65 undergoing evaluation at the PGH in Manila because of a suspicious breast mass. Molecular analysis identified 12 BRCA2 mutations and 3 BRCA1 mutations. We estimate the prevalence of BRCA mutations among unselected breast cancer cases in the Philippines to be 5.1% (95% CI: 2.6 -7.6%), with a prevalence of 4.1% (95% CI: 1.8 -6.4%) for BRCA2 mutations alone. The BRCA2 4265delCT and 4859delA mutations were found in 2 and 4 unrelated cases, respectively; haplotype analysis confirmed that these, and the BRCA1 5454delC mutation, are founder mutations. BRCA2 mutations were also found in 2 of 346 controls (0.6%; 95% CI: 0.2-1.4%). Compared with non-carrier cases, the cumulative risk of breast cancer for firstdegree relatives of mutation carriers was 24.3% to age 50, compared with <4% for first-degree relatives of non-carrier cases (RR ؍ 6.6; 95% CI: 2.6 -17.2; p؍ 7.5 ؋ 10 ؊6 ). Our data suggest that penetrance of BRCA mutations is not reduced in the Philippines. Germline mutations in the BRCA2 gene contribute more than mutations BRCA1 to breast cancer in the Philippines, due in large part to the presence of 2 common founder mutations. © 2002 Wiley-Liss, Inc.
Key words: BRCA1, BRCA2, Philippines; breast cancer; Asia; unselectedThe incidence of breast cancer varies as much as 10-fold between countries. 1 Breast cancer incidence rates in North America, Western Europe and Scandinavia are much higher than rates in Southeast Asia. Studies of Japanese and Chinese migrants to North America show that the incidence rates of breast cancer in migrants assume the rate in the host country within 1-2 generations, implicating environmental factors. The Philippine Manila Cancer Registry has reported the highest incidence rates of breast cancer in Asia. 1 The (world-standardized) rate of 47.7 per 100,000 exceeds the rate reported for several Western countries, including Spain, Italy and most Eastern European countries.Following the identification of the breast and ovarian cancer susceptibility genes BRCA1 (MIM 113705) and BRCA2 (MIM 600185), the frequency and spectrum of disease-related mutations has been investigated in various geographic regions and ethnic groups (Breast Cancer Information Core at http://www.nhgri.nih. gov/Intramural_research/Lab_transfer/Bic/). The contribution of BRCA1 and BRCA2 mutations to breast cancer rates has been examined in North America, 2-6 United Kingdom, 7,8 Iceland, 9,10 Spain, 11,12 the ...