BRCA1 and BRCA2 in Indian breast cancer patients

S Saxena MD^a, A Chakraborty MSc^a, S Kotwal MS^b, L Barjhoux BS^c, O Sinilnikova PhD^c, D Goldgar PhD^c, RS Mohil MS^b, D Bhatanagar MS^b, G Lenoir MD^c,d, C Szabo PhD^c

^aTumor Biology Lab, Institute of Pathology-ICMR, Safdarjung Hospital Campus, New Delhi, India, ^bDepartment of Surgery, Safdarjung Hospital Campus, New Delhi, India, ^cInternational Agency for Research on Cancer, Lyon, France, ^dInstitut Gustav-Roissy, Villejuif, France

BACKGROUND: Breast cancer is the second most common cancer in Indian women, with the age adjusted incidence rate per 100,000 women (AAR) ranging from 15-25 cases. Incidence of breast cancer in the Indian population is not as high as in western countries, nonetheless, since 1990, incidence rates of breast cancer in India have increased approximately 20%, and it is the leading cause of cancer mortality among Indian women. Interestingly, early onset breast cancer (diagnosed under age 40 years) does not show significant variation between populations, with AARs ranging from 12-33 cases worldwide. Early-onset disease as well as family history of breast cancer are hallmarks of genetic susceptibility, and the relatively high proportion of early onset cases in countries with lower overall incidence rates, such as India (nearly 20%), suggests an important role for hereditary disease in these populations. To date, little is known about the role of the breast cancer susceptibility genes, BRCA1 and BRCA2, in the Indian population. AIM: We have undertaken mutation analysis of BRCA1 and BRCA2 in a hospital-based series of incident breast cancer patients ascertained at Safdarjung hospital, New Delhi, since 1998. Characterization of the BRCA1 and BRCA2 mutation spectrum and prevalence among Indian breast cancer patients will lead to better understanding of the roles of these genes in disease for this population. METHODS: DNA was obtained from blood of 100 breast cancer patients and 45 age-matched controls by phenol-chloroform extraction. Mutation screening of the BRCA1 and BRCA2 genes is being carried out by heteroduplex analysis. Sequencing of DNA fragments showing an abnormal heteroduplex pattern is carried out by manual and/or automated Sanger dideoxy chain termination methods. RESULTS: Sequence variants in the BRCA1 gene were identified in 28 patients. 32% of patients with family history of disease showed the presence of a BRCA1 sequence variant. BRCA1 variants identified include 4 splice site variants, 3 recurrent frame-shift mutations, and 4 missense mutations, one of which is likely to be a polymorphism. Similarly, BRCA2 heteroduplex variants have been identified in 16 patients, 18% of whom have family history and 50% of whom were diagnosed with early onset disease. Complete sequence information will be presented for all variants identified in this patient series. CONCLUSIONS: We have characterized several novel mutations and polymorphisms that are unique to the Indian population, as well as identifying ancestral founder mutations that occur within ethnic subgroups of the population.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 796 (Genetic instability).