ERCC2 gene single-nucleotide polymorphism as a prognostic factor for locally advanced head and neck carcinomas after definitive cisplatin-based radiochemotherapy

Abstract

Identifying patients with locally advanced head and neck carcinoma on high risk of recurrence after definitive concurrent radiochemotherapy is of key importance for the selection for consolidation therapy and for individualized treatment intensification. In this multicenter study we analyzed recurrence-associated single-nucleotide polymorphisms (SNPs) in DNA repair genes in tumor DNA from 132 patients with locally advanced head and neck carcinoma (LadHnSCC). Patients were treated with definitive radiotherapy and simultaneous cisplatin-based chemotherapy at six partner sites of the German Cancer Consortium (DKTK) Radiation Oncology Group from 2005 to 2011. For validation, a group of 20 patients was available. Score selection method using proportional hazard analysis and leave-one-out cross-validation were performed to identify markers associated with outcome. The SNPs rs1799793 and rs13181 were associated with survival and the same SNPs and in addition rs17655 with freedom from loco-regional relapse (ffLRR) in the trainings datasets from all patients. The homozygote major rs1799793 genotype at the ERCC2 gene was associated with better (Hazard ratio (HR): 0.418 (0.234–0.744), p = 0.003) and the homozygote minor rs13181 genotype at ERCC2 with worse survival (HR: 2.074, 95% CI (1.177–3.658), p = 0.017) in comparison to the other genotypes. At the ffLRR endpoint, rs1799793 and rs13181 had comparable prognostic value. The rs1799793 and rs13181 genotypes passed the leave-one-out cross-validation procedure and associated with survival and ffLRR in patients with LadHnSCC treated with definitive radiochemotherapy. While findings were confirmed in a small validation dataset, further validation is underway within a prospective biomarker study of the DKTK.

Gene polymorphisms and prognosis of head and neck squamous cell carcinoma: a systematic review

“…In HNSCCs, in most studies, the XRCC1 rs25487 polymorphism was not associated with survival [ 4 , 14 , 19 , 39 , 48 , 51 , 52 , 62 , 64 , 67 , 68 , 71 ], although, in a few studies, this polymorphism was significantly associated with OS [ 16 , 21 , 34 ]; the results on the favorable variant in these studies were inconsistent so that the GG genotype was associated with worse OS compared to GA + AA genotypes in two studies [ 16 , 21 ] and the GA + AA variant was associated with worse OS in one study [ 34 ]. In the same way, in most studies, the XRCC1 rs1799782 polymorphism was not significantly associated with survival [ 7 , 14 , 51 , 52 ]; in one study, CT + TT variant was significantly associated with OS, but not DFS, compared to CC genotype in OSCC patients [ 64 ].…”

“…In the same way, in most studies, the XRCC1 rs1799782 polymorphism was not significantly associated with survival [ 7 , 14 , 51 , 52 ]; in one study, CT + TT variant was significantly associated with OS, but not DFS, compared to CC genotype in OSCC patients [ 64 ]. The ERCC1 rs11615 polymorphism was not significantly associated with survival [ 30 , 35 , 51 , 56 , 60 , 67 , 68 ]. In most studies, the ERCC1 rs3212986 polymorphism was not associated with survival [ 21 , 34 , 60 , 68 ]; in studies with a significant association, there is no agreement on the favorable variant so that in one study, the CC genotype was associated with poor PFS compared to CA + AA variant in NPC [ 39 ] while in another study, CA + AA variant was associated with worse OS compared to CC genotype in pharyngolaryngeal SCC (PLSCC) patients [ 4 ].…”

“…In two studies, the ERCC1 rs735482 polymorphism was significantly associated with survival [ 19 , 60 ]; the CC genotype was significantly associated with poor DFS, but not OS, compared to AC + AA genotypes in OSCC [ 60 ]. There are conflicting results regarding the association between ERCC2/XPD rs13181 and rs1799793 , ERCC5/XPG rs1047768 and rs17655 , XRCC3 rs861539 , RAD51 rs1801320 polymorphisms with HNSCC prognosis; the ERCC2 rs13181 polymorphism was significantly associated with survival in some studies [ 21 , 32 , 48 , 67 , 74 ]; the AA genotype was associated with poor OS compared to AC + CC genotypes [ 21 ]; the AA genotype was associated with worse OS in stage III–IV HNSCCs treated with radiation compared to AC + CC genotypes but it was associated with better survival in stage III–IV HNSCC patients who were not treated with radiation; also, this polymorphism was not associated with OS in stage I–II HNSCC patients [ 32 ]. In contrast, the AA genotype was associated with a significantly better OS and/ or DFS compared to AC + CC genotypes [ 48 , 74 ]; the CC genotype was associated with worse OS and DFS compared to AC + AA genotypes [ 67 ].…”

“…There are conflicting results regarding the association between ERCC2/XPD rs13181 and rs1799793 , ERCC5/XPG rs1047768 and rs17655 , XRCC3 rs861539 , RAD51 rs1801320 polymorphisms with HNSCC prognosis; the ERCC2 rs13181 polymorphism was significantly associated with survival in some studies [ 21 , 32 , 48 , 67 , 74 ]; the AA genotype was associated with poor OS compared to AC + CC genotypes [ 21 ]; the AA genotype was associated with worse OS in stage III–IV HNSCCs treated with radiation compared to AC + CC genotypes but it was associated with better survival in stage III–IV HNSCC patients who were not treated with radiation; also, this polymorphism was not associated with OS in stage I–II HNSCC patients [ 32 ]. In contrast, the AA genotype was associated with a significantly better OS and/ or DFS compared to AC + CC genotypes [ 48 , 74 ]; the CC genotype was associated with worse OS and DFS compared to AC + AA genotypes [ 67 ]. In a few studies, the ERCC2 rs1799793 polymorphism was significantly associated with survival [ 21 , 67 ]; the GG genotype was the unfavorable variant in one study [ 21 ] and the favorable variant in another study [ 67 ].…”

“…In contrast, the AA genotype was associated with a significantly better OS and/ or DFS compared to AC + CC genotypes [ 48 , 74 ]; the CC genotype was associated with worse OS and DFS compared to AC + AA genotypes [ 67 ]. In a few studies, the ERCC2 rs1799793 polymorphism was significantly associated with survival [ 21 , 67 ]; the GG genotype was the unfavorable variant in one study [ 21 ] and the favorable variant in another study [ 67 ]. In one study, the ERCC5 rs1047768 polymorphism was significantly associated with OS [ 19 ].…”