Mutational analysis of head and neck squamous cell carcinoma stratified by smoking status

Abstract

Smoking has historically been recognized as a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). This study aimed to assess the mutational differences between heavy smokers (>20 pack years) and never smokers among the HNSCC patients within The Cancer Genome Atlas (TCGA). Single nucleotide variation and copy number aberration differences between heavy smokers and never smokers were compared within human papillomavirus-positive (HPV-positive) (n = 67) and HPV-negative (n = 431) TCGA cohorts with HNSCC, and the impact of these mutations on survival were assessed. No genes were differentially mutated between smoking and never-smoking patients with HPV-positive tumors. By contrast, in HPV-negative tumors, NSD1 and COL1A11 were found to be more frequently mutated in heavy smokers, while CASP8 was more frequently altered in never smokers. HPV-negative patients with NSD1 mutations experienced significantly improved overall survival compared with NSD1 WT patients. This improved prognosis was validated in an independent cohort of 77 oral cavity cancer patients and a meta-analysis that included 2 additional data sets (688 total patients, hazard ratio for death 0.44, 95% CI, 0.30-0.65). NSD1 mutations are more common in HPV-negative heavy smokers, define a cohort with favorable prognosis, and may represent a clinically useful biomarker to guide treatment deintensification for HPV-negative patients.

Keywords: Genetics; Head & neck cancer; Oncology.

Figure 1. Top 20 differentially mutated genes between never smokers and heavy smokers in the HPV-negative patient group.

NSD1, CASP8, and COL11A1 are mutated at significantly different frequencies after correction for the FDR. Fisher’s exact test was used for comparison, and FDR correction was done through Benjamini-Hochberg method.

Figure 2. Overall survival comparison between NSD1-mutant and WT patients.

Survival rate in (A) the HPV-negative TCGA HNSCC cohort and (B) an independent cohort of 77 locally advanced HPV-negative oral cavity squamous cell carcinomas (OSCCs) from London Health Sciences Centre (LHSC).

Figure 3. Meta-analysis comparing overall survival stratified by NSD1 mutation status in HPV-negative tumors.

IV, Inverse Variance; df, degrees of freedom.

Figure 4. Analysis of somatic SNVs between NSD1-mutant and WT HPV-negative HNSCC tumors.

Genes associated with the ECM are highlighted in red. Fisher’s exact test was used for comparison, and FDR correction was done through Benjamini-Hochberg method.