Researchers identify key genetic factors causing oral cancer early among Indian tobacco chewers

Researchers at the Advanced Centre for Treatment, Research and Education in Cancer (ACTREC) at Tata Memorial Centre (TMC), Mumbai, have identified key genetic factors that cause oral cancer among some tobacco chewers in India nearly a decade earlier than others.

The new research, published in eBioMedicine, part of The Lancet Discovery Science, has identified specific genetic markers that significantly increase susceptibility to oral cavity cancer, one of the most common and preventable cancers in India, primarily linked to tobacco use.

Study findings

The Genome-Wide Association study (GWAS) was done by researchers at Centre for Cancer Epidemiology (CCE), ACTREC.

Researchers compared 2,160 cases of Buccal Mucosa cancer with 2,325 controls from various geographical regions in India and conducted a genome-wide scan to understand the role of genetic susceptibility in the development of oral cancer.

They discovered genetic risk loci on chromosomes 5 and 6, near the genes CLPTM1L-TERT, HLA-DRB1, HLA-DQB1, and CEP43. Additionally, a meta-analysis that included data from Europe and Taiwan identified novel risk loci near the NOTCH1 gene.

The investigators calculated a polygenic risk score and found that tobacco chewers with a high polygenic risk score (indicating higher genetic susceptibility) developed Buccal Mucosa cancer 10 years earlier than those with a low polygenic risk score.

In India, there are around 1,41,342 cases of oral cancer, with an average age-standardised rate of 10.0 per 1,00,000 people. In some states, this rate ranges from 25 to 33 per 100,000.

Despite similar lifestyle factors, the onset and progression of the disease can vary significantly among individuals.

Genetic susceptibility markers

This study offers the first clear genetic explanation for those differences, demonstrating that genetic makeup plays a crucial role in enhancing the risk of oral cancer among tobacco chewers.

“Tobacco chewing is a significant risk factor for oral cancers. The risk of developing oral cancer is 26 times higher among tobacco chewers, compared to non-users of tobacco. The risk attributed to genetic susceptibility markers is double for those with high genetic risk score compared to those with low genetic risk score,” ACTREC Director Dr Pankaj Chaturvedi told reporters on Saturday.

Better detection

The findings suggest that understanding genetic predisposition can lead to better prediction of oral cavity cancer development among tobacco chewers, explained Dr Rajesh Dikshit, Director of CCE.

“The analysis of the current study indicated distinct immune pathways and highly calcium-permeable nicotine receptor-encoding genes are involved in the development of oral cavity cancer. Further exploration of these pathways could enhance our understanding of carcinogenesis and help develop precise targets for early detection and prevention,” Dikshit added.

Dr Sharayu Mhatre, scientific officer at CCE and lead author of the study, said while tobacco use is the strongest risk factor for developing Buccal Mucosa cancer, there is also a genetic susceptibility component involved.

“There is about 24% relative excess of oral cavity cancer cases among tobacco chewers with high genetic risk scores compared to chewers with low genetic risk scores. When compared to the European population, similarities and distinct differences in their genetic architectures were observed. Therefore, there is a need for Indian-specific genetic data,” she added.

Oral cancer ranks among the top three cancers among men in India and is also prevalent in women. The high prevalence of smokeless tobacco and betel quid consumption significantly contributes to this burden.

Oral cancers are often diagnosed at advanced stages, leading to high mortality rates and considerable challenges in treatment.