Submitted by Catherine Atkins on Tue, 09/12/2025 - 17:01
Early Cancer Institute Group Leader Dr Siddhartha Kar has contributed to a landmark Genome-Wide Association Study (GWAS) led by the Tata Memorial Centre in Mumbai, comprising the Tata Memorial Hospital (TMH) and the Advanced Centre for Treatment, Research and Education in Cancer (ACTREC).
TMH, founded in 1941, is India’s oldest and largest cancer hospital. ACTREC is the research wing of the cancer hospital.
The study, the biggest of its kind for any cancer in India to date, has identified key genetic factors that explain why some tobacco chewers in India develop oral cancer nearly a decade earlier than others. Oral cancer is one of the most common and preventable cancers in India, primarily linked to tobacco use.
This landmark study represents a significant advance in our understanding of the genetic and environmental factors driving buccal mucosa cancer, a disease that imposes a heavy burden in India and across South Asia.
Dr Elisabete Weiderpass, Director of the International Agency for Research on Cancer, World Health Organization, Lyon, France
The study focused specifically on cancer of the buccal mucosa (the inner lining of the cheek). Oral cancer in the West predominantly starts from or just under the tongue, while oral cancer in India more commonly develops in the inner lining of the cheek.
The work involved over 2,100 buccal mucosa cancer cases and over 2,300 controls without cancer from 6 hospitals across India.
The second step of the study followed up the findings in nearly 400 oral cancer cases and 440 controls from Taiwan and combined the new data with existing genetic data on oral cancer from Europe, North America, and South America.
The new research is published in eBioMedicine, part of The Lancet Discovery Science, and accompanied by a press release from India’s national health ministry.
Dr Elisabete Weiderpass, Director of the International Agency for Research on Cancer, World Health Organisation, Lyon, France, highlighted the significance of the study, stating: “By conducting the largest genome-wide association study of its kind and integrating data from multiple ancestries, the authors have identified novel risk loci and illuminated the complex interplay between genetic susceptibility and tobacco chewing. These findings deepen our knowledge of oral cancer etiology and highlight the urgent need for tailored prevention and screening strategies for high-risk populations.”
Siddhartha, a scientific advisor to the Centre for Cancer Epidemiology (CCE) at the Tata Memorial Centre in Mumbai, commented: “This landmark study advances our understanding of why oral cancer is so common in India, uncovering uniquely Indian genetic risk factors. By showing how inherited risk interacts with tobacco use, it lays the groundwork for targeted prevention and early detection.”
Dr. Rajesh Dikshit, Director, CCE at Tata Memorial, explained that understanding genetic predisposition can help predict oral cavity cancer development among tobacco chewers. He noted that pathway analysis from the study identified distinct immune pathways and “highly calcium-permeable nicotine receptor-encoding genes” as being involved in cancer development. Further exploration of these pathways could lead to more precise methods for early detection and prevention.
How the Study Was Conducted
The study compared 2,160 cases of Buccal Mucosa cancer with 2,325 controls from various regions in India and conducted a genome-wide scan to assess genetic susceptibility. Researchers identified significant genetic risk loci on chromosomes 5 and 6, near genes including CLPTM1L-TERT, HLA-DRB1, HLADQB1, and CEP43.
A meta-analysis incorporating data from Europe and Taiwan also identified novel risk loci near the NOTCH1 gene. The investigators calculated a polygenic risk score and found that tobacco chewers with a high score developed Buccal Mucosa cancer 10 years earlier than those with a low score.
The Indian Scenario
India records approximately 141,342 cases of oral cancer, with an average age-standardized incidence rate of 10 per 100,000 population. In certain states, this rate rises to 25–33 per 100,000. Despite similar lifestyle factors, the onset and progression of the disease vary significantly among individuals. This study provides the first clear genetic explanation for these variations, demonstrating that genetic makeup plays a crucial role in elevating oral cancer risk among tobacco chewers.
Reference:
A genome-wide association study of buccal mucosa cancer in India and multi-ancestry meta-analysis discovers risk loci and gene-environment interactions
Mhatre, Sharayu et al. eBioMedicine 2025; 106042. Published online.
https://doi.org/10.1016/j.ebiom.2025.106042
Associated press release: https://www.pib.gov.in/PressReleasePage.aspx?PRID=2196291®=3&lang=2