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TCGA Study Describes Mutations Commonly Found in Head and Neck Cancers

NEW YORK (GenomeWeb) – The Cancer Genome Atlas has characterized the genomic landscape of 279 head and neck squamous cell carcinomas, underscoring pathways that go awry in the disease.

While the tumors harbored some 37,000 non-synonymous mutations in total and a mean 141 copy-number alterations each, some of these mutations were recurrent and common to certain head and neck cancer subtypes like HPV-positive tumors or tumors linked to smoking, as the consortium reported today in Nature. A number of the mutations the researchers described also presented possible therapeutic targets.

"Collectively, these findings provide new insights into HNSCC and suggest that shared and unique alterations might be leveraged to accelerate progress in prevention and therapy across tumor types," the University of North Carolina-Chapel Hill's Neil Hayes and his TCGA colleagues wrote in their paper.

Previous profiling studies of head and neck squamous cell carcinomas have been limited to single platforms. But, to get a more comprehensive view, the TCGA set out to characterize 500 tumors using a range of platforms.

In this paper, Hayes and his team reported on their findings from the first 279 tumors they've analyzed. These tumors were from mostly male patients and smokers, and represented oral, oropharynx, and laryngeal tumors. They examined the tumors by site, stage, molecular subtype, HPV status, putative biomarkers, and more.

About a quarter of head and neck cancers in general can be traced to HPV infection, though the US National Institute noted that the incidence of such tumors is on the rise, emphasizing the need to better understand these types of tumors.

"We're uncovering differences between tumors with and without HPV infection, and these new data are allowing us to rethink how we approach head and neck cancers," Hayes said in a statement.

As he and his colleagues reported, HPV-positive tumors shared a number of characteristics. For instance, 22 percent of HPV-positive tumors had either a deletion or truncating mutation affecting TRAF3, which has been linked to innate and acquired anti-viral response.

Loss of TRAF3 has also been associated with abnormal NF-κB signaling, and it has been found in hematological and nasopharyngeal cancers, though the researchers noted this is the first time it has been tied to HPV-associated carcinomas.

HPV-positive tumors also tended to have activating mutations in PIK3CA and E3F1 amplifications, which also implicates aberrant activation of the NF-κB signaling pathway. A handful of HPV-associated tumors also had FGFR3 fusion genes.

In addition, HPV-positive tumors showed evidence of viral integration into the host genome, the researchers said.

Meanwhile, HPV-negative, or smoking-associated, tumors were more likely to harbor co-amplifications of 11q13 and 11q22, both of which contain genes involved in cell death/NF-κB and Hippo signaling pathways.

Additionally, they tended to have a suite of inactivating mutations that affected the cell cycle and survival genes CDKN2A and TP53 as well as the Wnt/β-catenin signaling genes FAT1 and AJUBA.

HPV-negative tumors also had a number of focal deletions at NSD1 and amplifications at receptor tyrosine kinases like EGFR, ERBB2, and FGFR1.

EGFR mutations, Hayes noted, are rarely found in HPV-positive tumors, but other alterations like those to the FGFR3 and PIK3CA genes could be found across tumor types.

Other frequently mutated genes in head and neck carcinomas included NSD1, NOTCH1, and HLA-A.

More than 70 percent of the tumors harbored changes to growth factor receptor, signaling molecule, and cell division regulation genes — such as EGFR, FGFR, PIK3CA, and CCND1 — which suggests that therapies targeting those pathways, some of which are available or are in development, represent a possible treatment avenue.

Hayes and his colleagues also identified alterations that may explain drug resistance in head and neck cancers. Many of the mutations they uncovered affected cell survival and programmed cell death, and extra copies of growth genes like E2F1 or missing copies of the TRAF3 gene HPV-associated tumors could increase resistance. Likewise, in smoking-related cancers, extra copies of the FADD and BIRC2 genes or missing copies of the CASP8 gene could influence resistance.

"While many head and neck cancers are preventable, they are increasingly common throughout the world, and often challenging to effectively treat over the long term," NCI Director Harold Varmus, the director of the National Cancer Institute said in a statement. "This type of broad analysis provides important new clues for future research and treatment directions."