Common Genetic Variation and Risk of Gallbladder Cancer in India

Key Points

  • Significant genome-wide associations were found for a number of single-nucleotide polymorphisms in the chromosomal region containing both ABCB1 and ABCB4 genes.
  • In combined analysis, an increased risk of gallbladder cancer was associated with rs1558375, rs17209837, and rs4148808.

Several single-nucleotide polymorphisms in the chromosomal region containing both ABCB1 and ABCB4 genes were associated with an increased risk of gallbladder cancer, in an Indian case-control genome-wide association study reported in The Lancet Oncology by Mhatre et al.

Study Details

The study involved a genome-wide association study discovery cohort of 1,042 gallbladder cancer cases and 1,709 controls from a single center (Tata Memorial Hospital) and a replication cohort of 428 cases from the same center and 420 controls from another single site. Cases had to have no history of other cancers. Enrollment in the discovery cohort occurred between September 2010 and June 2015. Several of the most significant single-nucleotide polymorphisms identified in the genome-wide association study were analyzed in the replication cohort, and a combined analysis of the discovery and replication sets was performed.

Genome-Wide Associations

Significant genome-wide associations were identified for 19 moderately to highly correlated single-nucleotide polymorphisms in the 7q21.12 chromosomal region in or near the ABCB4 gene and 1 in the ABCB1 gene. The most notable single-nucleotide polymorphisms after replication cohort analysis and combined were rs1558375 (genome-wide association study cohort P =3.8 × 10-9; replication cohort P =.01; combined P = 2.3 × 10-10); rs17209837 (genome-wide association study P = 2.0 × 10-8; replication P = .02; combined P = 2.3 × 10-9), and rs4148808 (genome-wide association study P = 2.4 × 10-8; replication P = .008; combined P = 2.7 × 109). Per allele trend odds ratios for the combined analysis were 1.47 (P = 2.31 × 10-10) for rs1558375, 1.61 (P = 2.26 × 10-9) for rs17209837, and 1.57 (P = 2.71 × 10-9) for rs4148808.

Analysis of heritability indicated that approximately 23% of cancer risk variation could be explained by the common single-nucleotide polymorphisms included the analysis, with this estimate supporting an identified sibling relative risk of 3.15 (95% confidence interval = 1.80–5.49).

The investigators concluded: “To our knowledge, this study is the first report of common genetic variation conferring gallbladder cancer risk at genome-wide significance. This finding, along with in-silico and biological evidence indicating the potential functional significance of ABCB1 and ABCB4, underlines the likely importance of these hepatobiliary phospholipid transporter genes in the pathology of gallbladder cancer.”

The study was funded by the Tata Memorial Centre and Department of Biotechnology.

Rajesh Dikshit, PhD, of the Tata Memorial Centre, Navi Mumbai, India, is the corresponding author of The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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