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Cancer. 2017 Oct 15;123(20):3943-3954. doi: 10.1002/cncr.30802. Epub 2017 Jul 5.

Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50.

Author information

1
Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
2
Department of Otolaryngology-Head and Neck Surgery, The University of Michigan, Ann Arbor, Michigan.
3
Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, Kansas City, Kansas.
4
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
5
Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
6
The University of Texas Health Science Center School of Medicine, Houston, Texas.
7
Department of Dermatology, The University of Texas Health Science Center School of Medicine, Houston, Texas.
8
Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
9
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Abstract

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.

KEYWORDS:

Fanconi anemia; germline variations; head and neck cancers; recessive inherited disorders; squamous cell carcinoma

PMID:
28678401
PMCID:
PMC5853120
DOI:
10.1002/cncr.30802
[Indexed for MEDLINE]
Free PMC Article

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