BRCA1 and TP53 mutation spectrum of breast carcinoma in an ethnic population of Kashmir, an emerging high-risk area.

Breast cancer shows geographical variation in its incidence, even within areas of ethnic homogeneity. Kashmir valley (India), over past few years, witnesses an increase in incidence and occurrence of familial, early onset, and male breast cancer in its unexplored ethnic population. Here, we make a preliminary attempt to estimate the nature and frequency of BRCA1 and TP53 gene mutations of breast cancer patients from Kashmir. PCR-SSCP analysis followed by direct sequencing revealed the presence of only two germline intronic variations (c.199+67T>C and c.5396+187T>C) in BRCA1 gene in only 5.26% (2/38) patients while as 44% (11/25) of sporadic breast cancer patients harboured significant amount of somatic mutations in TP53 (p=0.0074; OR=0.053). The 17 mutations found in TP53 in 11 patients, comprised of 13 substitutions [11 single-base (9 transitions+2 transversions), 1 double-base and 1 complex] and four insertions. The 11 substitutions represent missense mutations, leading to aminoacid substitution while as rest two were silent mutations. The four insertions represented three frame-shifts and one non-sense mutation. The mutation effect data was found to be significant (p=0.0002). Significant amount of mutations were found in exon 6 (p=0.04; OR=0.273) and a combination of exons 6 and 7 (p=0.0145; OR=14.22) of TP53. Comparison of mutation profile with other ethnic populations and regions reflected both differences and similarities indicating co-exposure to a unique set of risk factors. The differences could be due to exposure to particular environmental carcinogens; different lifestyle, reproductive pattern; dietary or cultural practices of Kashmiri women that need further investigations. The infrequent presence of germline BRCA1 mutations in our study agree with the idea that a great proportion of moderate risk breast cancer population could be due to the susceptibility genes distinct from BRCA1. However, high frequency of somatic TP53 gene mutations implicates TP53 as a predominant factor for breast carcinogenesis in moderate risk ethnic Kashmiri population. The study also suggests TP53 as a potential molecular marker and prognostic tool, at least in a subset of sporadic breast tumors.