Head and neck squamous cell cancer as part of the germline p16/INK4a mutation-induced FAMMM syndrome

Abstract

6052 Background: p16/INK4a constitutes an important cancer susceptibility locus. Germline mutations at this locus have been implicated in several human cancer syndromes, including familial atypical multiple mole melanoma (FAMMM) syndrome, FAMMM-pancreatic cancer (FAMMM-PC) syndrome, and more recently, in familial head and neck cancer syndrome. Methods: We present an individual with a family history of both pancreatic cancer and melanoma, who developed squamous cell carcinoma of the tongue at 21 years old, multiple melanomas, a second squamous cell cancer of the tongue at 40 years old, and ultimately a pancreatic cancer. Results: We identify a germline mutation in INK4a that leads to a substitution of tryptophan for glycine in the Ankyrin III domain of the p16 protein (G101W). We demonstrate loss of heterozygosity at the INK4a locus and lack of p16 expression in the second head and neck squamous cell cancer (HNSCC) tissue. Based on these and on previously published data, we propose that HNSCC resulting from an INK4a germline mutation is a variant of the FAMMM/FAMMM-PC syndrome. Further studies will determine whether there is genotype-phenotype correlation between these syndrome variants. Conclusions: We conclude that young individuals who develop HNSCC should be considered at high-risk for other cancers, including pancreatic cancer and melanoma. They should be advised to avoid cigarette smoking and should be considered for pancreas cancer screening. No significant financial relationships to disclose.