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Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50
Author(s) -
Chandrasekharappa Settara C.,
Chinn Steven B.,
Donovan Frank X.,
Chowdhury Naweed I.,
Kamat Aparna,
Adeyemo Adebowale A.,
Thomas James W.,
Vemulapalli Meghana,
Hussey Caroline S.,
Reid Holly H.,
Mullikin James C.,
Wei Qingyi,
Sturgis Erich M.
Publication year - 2017
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.30802
Subject(s) - head and neck squamous cell carcinoma , fanconi anemia , medicine , oncology , germline , germline mutation , cancer research , population , cancer , carcinogenesis , nonsynonymous substitution , head and neck cancer , genetics , mutation , gene , biology , dna repair , genome , environmental health
BACKGROUND Patients with Fanconi anemia (FA) have an increased risk for head and neck squamous cell carcinoma (HNSCC). The authors sought to determine the prevalence of undiagnosed FA and FA carriers among patients with HNSCC as well as an age cutoff for FA genetic screening. METHODS Germline DNA samples from 417 patients with HNSCC aged <50 years were screened for sequence variants by targeted next‐generation sequencing of the entire length of 16 FA genes. RESULTS The sequence revealed 194 FA gene variants in 185 patients (44%). The variant spectrum was comprised of 183 nonsynonymous point mutations, 9 indels, 1 large deletion, and 1 synonymous variant that was predicted to effect splicing. One hundred eight patients (26%) had at least 1 rare variant that was predicted to be damaging, and 57 (14%) had at least 1 rare variant that was predicted to be damaging and had been previously reported. Fifteen patients carried 2 rare variants or an X‐linked variant in an FA gene. Overall, an age cutoff for FA screening was not identified among young patients with HNSCC, because there were no significant differences in mutation rates when patients were stratified by age, tumor site, ethnicity, smoking status, or human papillomavirus status. However, an increased burden, or mutation load, of FA gene variants was observed in carriers of the genes FA complementation group D2 ( FANCD2 ), FANCE , and FANCL in the HNSCC patient cohort relative to the 1000 Genomes population. CONCLUSIONS FA germline functional variants offer a novel area of study in HNSCC tumorigenesis. FANCE and FANCL , which are components of the core complex, are known to be responsible for the recruitment and ubiquitination, respectively, of FANCD2 , a critical step in the FA DNA repair pathway. In the current cohort, the increased mutation load of FANCD2, FANCE , and FANCL variants among younger patients with HNSCC indicates the importance of the FA pathway in HNSCC. Cancer 2017;123:3943‐54 . © 2017 American Cancer Society .