Unraveling most abundant mutational signatures in head and neck cancer

Head and Neck Cancer

Int J Cancer. 2020 Sep 15. doi: 10.1002/ijc.33297. Online ahead of print.


Genomic alterations are a driving force in the multistep process of head and neck cancer (HNC) and result from the interaction of exogenous environmental exposures and endogenous cellular processes. Each of these processes leaves a characteristic pattern of mutations on the tumor genome providing the unique opportunity to decipher specific signatures of mutational processes operative during HNC pathogenesis and to address their prognostic value. Computational analysis of whole exome sequencing

data of the HIPO-HNC (n=83) and TCGA-HNSC (n=506) cohorts revealed five common mutational signatures (COSMIC signature 1, 2, 3, 13 and 16), and demonstrated their significant association with etiological risk factors (tobacco, alcohol and HPV16). Unsupervised hierarchical clustering identified four clusters (A, B, C1 and C2) of which sub-cluster C2 was enriched for cases with higher frequency of signature 16 mutations. Tumors of sub-cluster C2 had significantly lower p16INK4A expression accompanied by homozygous CDKN2A deletion in almost one half of cases. Survival analysis revealed an unfavorable prognosis for patients with tumors characterized by a higher mutation burden attributed to signature 16 as well as cases in sub-cluster C2. Finally, a LASSO-Cox regression model was applied to prioritize clinically relevant signatures and to establish a prognostic risk score for HNSCC patients. In Conclusion, this study provides a proof-of-concept that computational analysis of somatic mutational signatures is not only a powerful tool to decipher environmental and intrinsic processes in the pathogenesis of HNC, but could also pave the way to establish reliable prognostic patterns.