Loss of heterozygosity in FANCG, FANCF and BRIP1 from head and neck squamous cell carcinoma of the oral cavity

Abstract

Recent advances have been made in the understanding of Fanconi anemia (FA), a hereditary disease that increases the risk for head and neck squamous cell carcinomas (HNSCC) by 500- to 700-fold. FA patients harbour germline mutations in genes of cellular DNA repair pathways that are assumed to facilitate the accumulation of mutations during HNSCC development. Mutations in these FA genes may also contribute to HNSCC in general. In the present study, we analysed three FA genes; FANCF, FANCG and BRIP1, that are involved in the repair of DNA inter strand cross-links, in HNSCC and their potential role for patient survival. We measured loss of heterozygosity (LOH) mutations at eight microsatellite loci flanking three FA genes in 54 HNSCC of the oral cavity and corresponding blood samples. Survival analyses were carried out using mutational data and clinical variables. LOH was present in 17% (FANCF region), 41% (FANCG region) and 11% (BRIP1 region) of the patients. Kaplan-Meier survival curves and log-rank tests indicated strong clinical predictors (lymph node stages with decreased survival: p=2.69e-12; surgery with improved survival: p=0.0005). LOH in the FANCF region showed a weaker association with decreased overall survival (p=0.006), which however, did not hold in multivariate analyses. LOH may predominantly indicate copy number gains in FANCF and losses in FANCG and BRIP1. Integration of copy number data and gene expression proved difficult as the available sample sets did not overlap. In conclusion, LOH in FA genes appears to be a common feature of HNSCC development seen here in 57% of patients and other mutation types may increase this mutation frequency. We suggest larger patient cohorts would be needed to test the observed association of LOH in FANCF and patient survival comprehensively.

Improvement in the risk assessment of oral leukoplakia through morphology-related copy number analysis

“…Several genomic alterations have been identified in OL, including single nucleotide variations and mutation hotspots in genes related to the cell cycle and cancer regulatory pathways, such as TP53, Ki-67, and NOTCH1 (Zhang et al, 2017;Ding et al, 2018;Yagyuu et al, 2017;Gissi et al, 2015). Loss of heterozygosity and changes in DNA methylation are also significantly associated with clinical outcomes in OL patients (Tsao et al, 2009;Zhou et al, 2011;Zhang et al, 2012;Türke et al, 2017). However, the frequencies of these mutations and altered biomarkers are low, and only a small number of OL cases harbor these genetic alterations (Mello et al, 2020).…”

Type 2 diabetes mellitus promotes the proliferation, metastasis, and suppresses the apoptosis in oral squamous cell carcinoma

“…14 BRIP1 directly interacts with the C terminus domain of breast cancer 1 (BRCA1), thus playing a crucial role in DNA damage repair. 15 Previous studies have suggested that hyperglycemic condition interferes the genetic stability and impairs the functionality of DNA repair through down-regulating DNA repair genes, thus inducing carcinogenesis. 16 However, in the OSCC cells treated with high glucose, BRIP1 showed an overexpression in contradiction with IHC result, indicating that the decreased expression of BRIP1 in OSCC patients with T2DM might not be correlated with hyperglycemia.…”

“…BRIP1, as an anti‐oncogenic factor, has been observed to be downregulated in various cancers including head and neck squamous carcinoma 14 . BRIP1 directly interacts with the C terminus domain of breast cancer 1 (BRCA1), thus playing a crucial role in DNA damage repair 15 . Previous studies have suggested that hyperglycemic condition interferes the genetic stability and impairs the functionality of DNA repair through down‐regulating DNA repair genes, thus inducing carcinogenesis 16 .…”

Age-specific oncogenic pathways in head and neck squamous cell carcinoma - are elderly a different subcategory?

“…Fanconi anaemia (FA) results from chromosomal instability due to biallelic mutations in one of the 17 known FA genes (FANCA to FANCS), inherited in an autosomal recessive or X-linked recessive pattern [17]. Germline mutations in genes of cellular DNA repair pathways are assumed to facilitate accumulation of mutations during HNSCC development [18]. Mutations in these FA genes may also contribute to the development of HNSCC in general [18].…”