Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups

Abstract

Gingivo-buccal oral squamous cell carcinoma (OSCC-GB), an anatomical and clinical subtype of head and neck squamous cell carcinoma (HNSCC), is prevalent in regions where tobacco-chewing is common. Exome sequencing (n=50) and recurrence testing (n=60) reveals that some significantly and frequently altered genes are specific to OSCC-GB (USP9X, MLL4, ARID2, UNC13C and TRPM3), while some others are shared with HNSCC (for example, TP53, FAT1, CASP8, HRAS and NOTCH1). We also find new genes with recurrent amplifications (for example, DROSHA, YAP1) or homozygous deletions (for example, DDX3X) in OSCC-GB. We find a high proportion of C>G transversions among tobacco users with high numbers of mutations. Many pathways that are enriched for genomic alterations are specific to OSCC-GB. Our work reveals molecular subtypes with distinctive mutational profiles such as patients predominantly harbouring mutations in CASP8 with or without mutations in FAT1. Mean duration of disease-free survival is significantly elevated in some molecular subgroups. These findings open new avenues for biological characterization and exploration of therapies.

Association between FAT1 mutation and overall survival in patients with human papillomavirus–negative head and neck squamous cell carcinoma

“…The ICGC cohort of patients with HPV‐negative GBSCC treated with curative surgery was used as an independent validation set 14. The clinical dataset released on September 12, 2014, was obtained from the ICGC data portal.…”

“…In the ICGC cohort, the presence of HPV DNA was determined by polymerase chain reaction and Sanger sequencing, and the specific HPV types were determined by Basic Local Alignment Search Tool analysis with the HPV DNA sequences. Detailed information on the HPV detection methods is described elsewhere 13, 14…”

“…Whole‐exome sequencing was performed using the Illumina Genome Analyzer IIX platform. For the ICGC cohort, whole‐exome somatic mutation data released on September 12, 2014, were obtained from the ICGC data portal 14. Whole‐exome sequencing was performed using the Illumina HiSeq 2000 and Roche GS‐FLX platforms, and some of the mutations that were sequenced only on one platform were verified using Ion Torrent PGM.…”

“…Whole‐exome sequencing was performed using the Illumina HiSeq 2000 and Roche GS‐FLX platforms, and some of the mutations that were sequenced only on one platform were verified using Ion Torrent PGM. Detailed information on the sequencing, quality control, raw data processing, and validation procedure is provided elsewhere 13, 14…”

“…That study further revealed that loss‐of‐function mutation of FAT1 causes Wnt pathway activation and tumorigenesis, and affects patient survival in several human cancers, such as glioma and ovarian cancer, suggesting that FAT1 is a bona fide tumor‐suppressor gene that can drive tumor development in those cancer types. Furthermore, 2 recent large‐scale exome sequencing studies revealed that FAT1 is significantly and frequently altered in HNSCCs 13, 14. However, it remains to be determined whether these FAT1 mutations influence the overall survival of patients with HPV‐negative HNSCC.…”