Abstract
Oral squamous cell carcinoma (OSCC) is a common cancer of the oral cavity in India. Cigarette smoking and chewing tobacco are known risk factors associated with OSCC. However, genomic alterations in OSCC with varied tobacco consumption history are not well-characterized. In this study, we carried out whole-exome sequencing to characterize the mutational landscape of OSCC tumors from subjects with different tobacco consumption habits. We identified several frequently mutated genes, including TP53, NOTCH1, CASP8, RYR2, LRP2, CDKN2A, and ATM. TP53 and HRAS exhibited mutually exclusive mutation patterns. We identified recurrent amplifications in the 1q31, 7q35, 14q11, 22q11, and 22q13 regions and observed amplification of EGFR in 25% of samples with tobacco consumption history. We observed genomic alterations in several genes associated with PTK6 signaling. We observed alterations in clinically actionable targets including ERBB4, HRAS, EGFR, NOTCH1, NOTCH4, and NOTCH3. We observed enrichment of signature 29 in 40% of OSCC samples from tobacco chewers. Signature 15 associated with defective DNA mismatch repair was enriched in 80% of OSCC samples. NOTCH1 was mutated in 36% of samples and harbored truncating as well as missense variants. We observed copy number alterations in 67% of OSCC samples. Several genes associated with non-receptor tyrosine kinase signaling were affected in OSCC. These molecules can serve as potential candidates for therapeutic targeting in OSCC.
Highlights
Oral cancer is a prevalent cancer in the Indian subcontinent among men [1]
We identified FBXW7 mutated at hotspot variant in WD40 domain which blocks the degradation of active NOTCH1 which eventually results in tumorigenesis [50]
A subset of oral cavity tumors in the The cancer genome atlas (TCGA)-head and neck squamous cell carcinoma (HNSCC) study with fewer Copy number alterations (CNA) is broadly categorized as M-class cancer suggesting tumorigenesis driven by point variants instead of copy number alteration
Summary
Usage of tobacco in both smoking and chewing forms is a significant risk factor associated with oral cancer development [2]. Oral cancer is generally diagnosed at a late stage due to ignorance of early onset lesions. This is common in developing countries due to lack of awareness and poor access to medical care [3, 4]. There are an estimated 354,864 new cases of oral cancer worldwide (2% of all cancers). 227,906 (64.22%) cases are reported from Asia, where India accounted for 107,424 (30.27%) incidences in 2018. The estimated number of deaths is recorded to be approximately 177,757, of which (75,290 deaths) 42% are recorded from India [5]
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