Journal Article

Mutational and Functional Analysis of FANCB as a Candidate Gene for Sporadic Head and Neck Squamous Cell Carcinomas

Grässlin, Rene, Plettenberg, Christian, Balz, Vera, Wagenmann, Martin, Schipper, Jörg, Wiek, Constanze, Hanenberg, Helmut, Okpanyi, Vera, Roellecke, Katharina, Glaas, Marcel F, Scheckenbach, Kathrin, Wolter, Linda-Maria, Hoffmann, Thomas Karl

2018

Overview

Head and neck squamous cell carcinomas (HNSCCs) form a heterogeneous tumor entity located throughout the oral cavity, pharynx and larynx that is caused predominantly by chemically or virally induced carcinogenesis. Heterozygous germline mutations in cancer susceptibility genes might also lead to increased incidence of HNSCCs. As DNA stability is typically impaired in HNSCC cells and genes of the Fanconi anemia/BRCA DNA repair pathway can be mutated or down-regulated in HNSCCs, we investigated here whether germline mutations occur in the X-chromosomal FANCB as candidate gene. Germline DNA of 85 consecutive HNSCC patients was sequenced. Missense alterations in FANCB were functionally tested in reference cells. Four single nucleotide polymorphisms were identified, three of which were located in untranslated regions of FANCB (rs2188383, rs2375729, rs2905223) and predicted to be associated with normal function. One missense alteration, c.1004G>A resulting in p.G335E (rs41309679), in exon 4 was detected in five men in homozygous and in five women in heterozygous state. Four in silico prediction programs uniformally predicted p.G335E to be associated with loss-of-function of the protein. To clarify these predictions, we expressed the FANCB p.G335E protein in primary human FANCB deficient fibroblasts. Cell cycle analysis of these fibroblasts established that the FANCB p.G335E was functionally indistinguishable from the wildtype FANCB protein. Thus, functional studies in genetically defined cells showed that the p.G335E germline alteration in FANCB is not associated with impaired function.

• Publisher: International Institute of Anticancer Research
• Subject: Adult / Aged / Anemia / Breast cancer / Cancer / Carcinogenesis / Carcinogens / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - pathology / Cell cycle / Cell Cycle - genetics / Chromosomes / Cloning / Deoxyribonucleic acid / DNA / DNA methylation / DNA repair / Esophagus / Fanconi Anemia Complementation Group Proteins - genetics / Fanconi syndrome / Female / Females / Fibroblasts / Fibroblasts - metabolism / Functional analysis / Gene Frequency / Genes / Genetic Predisposition to Disease - genetics / Genomes / Genotype / Germ-Line Mutation / Head and neck carcinoma / Head and Neck Neoplasms - genetics / Head and Neck Neoplasms - pathology / Humans / Larynx / Male / Males / Middle Aged / Mutation / Mutation, Missense / Neck / Nucleotide sequence / Nucleotides / Oral cavity / Pharynx / Polymorphism, Single Nucleotide / Predictions / Proteins / Single-nucleotide polymorphism / Squamous cell carcinoma / Tumors