Validation of Genetic Sequence Variants as Prognostic Factors in Early-Stage Head and Neck Squamous Cell Cancer Survival

Abstract

Purpose: From the published literature, we identified 23 germ line sequence variants in 17 genes from hypothesis-generating studies that were associated with prognosis of head and neck cancer, including sequence variants of DNA repair (ERCC1, ERCC4, ERCC5, MSH2, XPA, ERCC2, XRCC1, XRCC3), DNA methylation (DNMT3B), cell cycle and proliferation (CCND1, TP53), xenobiotic metabolism (GSTM1, GSTT1, CYP2D6), metastatic -potential (MMP3), immunologic (CTLA4), and growth factor pathways (FGFR4). The purpose of this study was to validate the role of these 23 sequence variants for overall (OS) and disease-free survival (DFS) in a large, comprehensive, well-annotated data set of patients with head and neck cancer.Experimental Design: We genotyped these sequence variants in 531 patients with stage I and II radiation-treated head and neck cancer (originally recruited for an alpha-tocopherol/beta-carotene placebo-controlled secondary prevention study), and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors.Results: Two OS associations were statistically significant for each variant allele when compared with the wild-type: CTLA4:A49G [rs231775; adjusted HR (aHR), 1.32 (1.1-1.6); P ¼ 0.01] and XRCC1:Arg339Gln [rs25487; aHR, 1.28 (1.05-1.57); P ¼ 0.02]. Both of these sequence variants had significant results in the opposite direction as prior published literature. Two DFS associations were of borderline significance in the same direction as prior literature: ERCC2:Lys751Gln [rs13181; aHR, 0.80 (0.6-1.0); P ¼ 0.05] and TP53: Arg72Pro [rs1042522; aHR, 1.28 (1.0-1.6); P ¼ 0.03], comparing number of variant alleles with reference of zero variants.Conclusions: None of the prognostic sequence variants previously published was validated for OS in our patients with early-stage radiation-treated head and neck cancer, though rs1381and rs1042522 had borderline significant association with DFS.

Implication of Polymorphisms in DNA Repair Genes in Prognosis of Hepatocellular Carcinoma

“…The chemotherapy for HCC is to induce the DNA damage of cancer cells, the low activity of XRCC1 and XPD polymorphisms would strengthen the efficacy of therapy. The role of XRCC1 and XPD polymorphisms has been reported to be associated with increased function of chemotherapy of several cancers, including non-small cell lung cancer, breast cancer, head and neck squamous cell cancer as well as pancreatic cancer (Giovannetti et al, 2011;Azad et al, 2012). Our study was in line with previous studies, which provided solid evidence for the above hypothesis.…”

FGFR4 Is a Potential Predictive Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma

“…Multiple previous studies detected the FGFR4 388Arg allele in HNSCC and observed it at similar rates [19,20,22,23,24,25]. They reported contradicting findings on the prognostic value of FGFR4 protein expression and the FGFR4 Gly388Arg SNP [26].…”

“…They reported contradicting findings on the prognostic value of FGFR4 protein expression and the FGFR4 Gly388Arg SNP [26]. Regarding overall survival, Streit et al [19] and da Costa Andrade et al [22] related the FGFR4 388Arg allele to poor overall survival, while Ansell et al [23] related it to better overall survival and Azad et al [24] and Choi et al [25] found no relationship. Our findings confirm that the FGFR4 Gly388Arg SNP holds no prognostic value.…”

Association of the XPA A23G polymorphism with the risk of head and neck carcinomas: Evidence from 5,491 subjects

“…The XPA protein is involved in the DNA damage recognition process and plays a pivotal role in the NER pathway, which is a key defense mechanism against the major carcinogens of HNSCC (21)(22)(23). The A23G polymorphism regulated XPA gene expression through transcriptional and post-transcriptional control mechanisms.…”