Contribution of germ line BRCA2 sequence alterations to risk of familial esophageal cancer in a high-risk area of India.

The incidence of esophageal squamous cell carcinoma (ESCC) is very high in the northeast region of India. An earlier study from China and Iran suggested that mutations in BRCA2 gene may play a role in the etiology of familial ESCC. However, the frequency of BRCA2 gene germ line mutations and its contribution to risk of familial aggregation of ESCC in high-risk region of India are not known. In the current study of 317 cases of esophageal cancer, 92 (29%) cases had a family history of esophageal and/or other cancers. Of these 92 patients, 45 (49%) patients had a family history of esophageal cancer. The risk of developing esophageal cancer was higher in cases where family history showed occurrence of cancers in first-degree relatives (odds ratio [OR]: 3.1; confidence interval [CI]: 1.9-5.3) than in second-degree relatives (OR: 1.3; CI: 0.25-3.2). Moreover, the risk of developing esophageal cancer was higher in subjects whose predegree suffered from esophageal cancer (OR: 2.4; CI: 1.1-4.1) than from any other cancers (OR: 1.1; CI: 0.32-3.3). The subjects with family history of cancer were more likely to develop ESCC if they were tobacco chewers (OR: 4.2; CI: 2.1-5.8) and betel quid users (OR: 3.6; CI: 1.8-4.6). Screening for mutations of the BRCA2 gene in the germ line DNA was carried out for 20 familial and 80 nonfamilial ESCC patients. One hundred unrelated healthy controls from the same population were included in this study. Nonsynonymous variants in exon 18 (K2729N) and exon 27 (I3412V) of BRCA2 gene were found in 3 of 20 patients with familial ESCC. No sequence alterations were found in 80 nonfamilial ESCC cases (P=0.01) and 100 healthy controls (P=0.0037), suggesting that germ line BRCA2 gene mutation may play a role in familial aggregation of ESCC in high-risk region of India.