Expressed HNSCC variants by HPV-status in a well-characterized Michigan cohort

Tingting Qin,Shama Virani,Katie R Zarins,Gregory T Wolf,Lisa A Peterson,Tamara R Jones,Maureen A Sartor,Laura S Rozek,Yanxiao Zhang,Douglas Chepeha,Jonathan B Mchugh

doi:10.1038/s41598-018-29599-w

Tingting Qin, Shama Virani + Show 9 more

Open Access

https://doi.org/10.1038/s41598-018-29599-w

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Abstract

While whole-exome DNA sequencing is the most common technology to study genetic variants in tumors in known exonic regions, RNA-seq is cheaper, covers most of the same exonic regions, and is often more readily available. In this study, we show the utility of mRNA-seq-based variant analysis combined with targeted gene sequencing performed on both tumor and matched blood as an alternative when exome data is unavailable. We use the approach to study expressed variant profiles in the well-characterized University of Michigan (UM) head and neck squamous carcinoma (HNSCC) cohort (n = 36). We found that 441 out of 455 (~97%) identified cancer genes with an expressed variant in the UM cohort also harbor a somatic mutation in TCGA. Fourteen (39%) patients had a germline variant in a cancer-related Fanconi Anemia (FA) pathway gene. HPV-positive patients had more nonsynonymous, rare, and damaging (NRD) variants in those genes than HPV-negative patients. Moreover, the known mutational signatures for DNA mismatch repair and APOBEC activation were attributive to the UM expressed NRD variants, and the APOBEC signature contribution differed by HPV status. Our results provide additional support to certain TCGA findings and suggest an association of expressed variants in FA/DNA repair pathways with HPV-associated HNSCC tumorigenesis. These results will benefit future studies on this and other cohorts by providing the genetic variants of key cancer-related genes.

Highlights

While whole-exome DNA sequencing is the most common technology to study genetic variants in tumors in known exonic regions, RNA sequencing (RNA-seq) is cheaper, covers most of the same exonic regions, and is often more readily available
Using mRNA-seq data from 36 University of Michigan head and neck squamous carcinoma (HNSCC) patients (18 human papillomavirus (HPV)+ and 18 HPV−), we identified expressed germline and somatic variants that were rare and predicted to potentially have deleterious effects on the encoded proteins
We demonstrated that the majority of cancer genes harboring these variants were documented in the somatic mutation profile of HNSCC patients by The Cancer Genome Atlas (TCGA)

Summary

Introduction

While whole-exome DNA sequencing is the most common technology to study genetic variants in tumors in known exonic regions, RNA-seq is cheaper, covers most of the same exonic regions, and is often more readily available. Our results provide additional support to certain TCGA findings and suggest an association of expressed variants in FA/DNA repair pathways with HPV-associated HNSCC tumorigenesis. These results will benefit future studies on this and other cohorts by providing the genetic variants of key cancer-related genes. We appreciate tremendous interand intra-tumor heterogeneity among the patients These results are complicated by multiple sites of specimen collection and unbalanced HPV status in the TCGA samples (427 HPV− and 99 HPV + samples)[13,16]

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