A Genome-Wide Association Study (GWAS) conducted by the Centre for Cancer Epidemiology (CCE) of the Advanced Centre for Treatment, Research and Education in Cancer (ACTREC) at the Tata Memorial Centre here has uncovered critical genetic factors that explain why some tobacco chewers in India develop oral cancer nearly a decade earlier than others. The findings were published in eBioMedicine, part of The Lancet Discovery Science.

The study compared 2,160 Buccal Mucosa cancer cases with 2,325 controls from different regions of India. Through a comprehensive genome-wide scan, researchers identified significant genetic risk loci on chromosomes 5 and 6, near these genes: 

    CLPTM1L-TERT
    HLA-DRB1
    HLA-DQB1
    CEP43

A meta-analysis incorporating data from Europe and Taiwan further identified novel risk loci near the NOTCH1 gene, underscoring genetic pathways shared across populations.

The investigators generated a polygenic risk score (PRS) and discovered that tobacco chewers with a high PRS developed Buccal Mucosa cancer 10 years earlier than those with a low PRS. Despite similar lifestyle exposures, genetics emerged as a powerful differentiator in cancer onset.

India reports over 141,000 cases of oral cancer annually, with age-standardized incidence rates reaching 25–33 per 100,000 in some states. This study provides the first genetic explanation for why certain individuals are significantly more vulnerable despite similar tobacco habits.

During a media briefing here on Saturday, Dr Sudeep Gupta, director, Tata Memorial Centre, highlighted the importance of studying gene environment interactions in common cancers in India. He stressed that although genetics influence susceptibility, more than 80% of oral cancers can be prevented through effective tobacco-control measures.

Dr Pankaj Chaturvedi, director, ACTREC, reiterated that tobacco chewing increases oral cancer risk 26-fold. He added that individuals with high genetic susceptibility have double the risk compared to those with a low genetic risk score.

The study has been hailed by international experts. Dr Elisabete Weiderpass, director, International Agency for Research on Cancer (IARC–WHO), described the work as a “significant advance in understanding the interplay of genetics and tobacco chewing”. She emphasized its value in shaping tailored prevention and screening strategies for high-risk populations.

Dr Nilanjan Chatterjee, Johns Hopkins University, noted that the study is the first to clarify how genes amplify the carcinogenic effect of tobacco chewing. “We don’t choose the genes we’re born with,” he said, “which makes healthy behavioural choices even more critical.”

Dr  Rajesh Dikshit, director of CCE, explained that pathway analysis from the study identified distinct immune mechanisms and nicotine receptor encoding genes involved in the development of oral cancer. Understanding these pathways may lead to targeted strategies for early detection and prevention.

Lead author Dr  Sharayu Mhatre, scientific officer at CCE, noted that while tobacco remains the dominant risk factor, Indian-specific genetic architecture differs notably from European populations. She reported a 24% relative excess of oral cancer cases among tobacco chewers with high genetic risk scores compared to low-risk groups.

Dr  Preetha Rajaraman, Radiation Effects Research Foundation (Japan), emphasized the potential for personalized screening by combining behavioral risk (tobacco) with genetic susceptibility.

Dr   Siddhartha Kar, University of Cambridge, called the work a “major milestone for cancer genomics in India,” citing its identification of uniquely Indian genetic risk factors.

CCE is now conducting GWAS on several other common cancer types in India to build genetic risk scores that can inform prevention and early detection strategies nationwide.

Dr  Sharayu Mhatre highlighted the critical need for large sample sizes to fully understand the genetic factors contributing to cancer causation.