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Mod Pathol. 2018 Feb;31(2):275-287. doi: 10.1038/modpathol.2017.128. Epub 2017 Oct 6.

Analysis of clinically relevant somatic mutations in high-risk head and neck cutaneous squamous cell carcinoma.

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Central Clinical School, The University of Sydney, Sydney, Australia.
Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, Australia.
Illawarra and Shoalhaven Local Health District (ISLHD), Wollongong, Australia.
School of Biological Sciences, University of Wollongong, Wollongong, Australia.
Illawarra Health and Medical Research Institute (IHMRI), Wollongong, Australia.
Centre for Oncology Education and Research Translation (CONCERT), Liverpool, Australia.
The Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, Australia.
Kinghorn Cancer Centre and Garvan Institute of Medical Research, Sydney, Australia.
St Vincent's Clinical School, UNSW Sydney, Sydney, Australia.
Singhealth/Duke-NUS Head and Neck Center, National Cancer Center Singapore (NCCS), Singapore.
Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.


Cutaneous squamous cell carcinoma is the second most prevalent malignancy, most frequently occurring in the head and neck (head and neck cutaneous squamous cell carcinoma). Treatment of locally advanced or metastatic disease is associated with functional morbidity and disfigurement. Underlying genetic mechanisms are poorly understood. Targeted sequencing of 48 clinically relevant genes was performed on DNA extracted from formalin-fixed and paraffin-embedded high-risk primary head and neck cutaneous squamous cell carcinomas that remained non-metastatic at minimum follow-up of 24 months. Associations of somatic mutations with clinicopathologic characteristics were evaluated and compared with those described in the literature for metastatic disease. Alterations in 44 cancer-associated genes were identified. TP53 was mutated in 100% of cases; APC, ATM, ERBB4, GNAQ, KIT, RB1 and ABL1 were altered in 60% of cases. FGFR2 mutations (40%) were exclusively seen in patients with perineural invasion. MLH1 mutations were exclusively seen in the two younger patients (<45 years). Lower incidences of NOTCH1 mutations were observed compared with that described in metastatic head and neck cutaneous squamous cell carcinoma in the literature. Somatic mutations susceptible to EGFR inhibitors, and other small molecular targeted therapeutics were seen in 60% of cases. This study provides insights into somatic mutations in non-metastatic, high-risk head and neck cutaneous squamous cell carcinoma and identifies potential therapeutic targets. Alterations in FGFR2 and NOTCH1 may have roles in local and distant disease progression.

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