Germline Variants in Angiogenesis-Related Genes Contribute to Clinical Outcome in Head and Neck Squamous Cell Carcinoma

SIMPLE SUMMARY: A high risk of relapse and treatment resistance are among the major challenges in locally advanced head and neck squamous cell carcinoma (HNSCC). Data show that common germline alterations in genes regulating angiogenesis may modulate treatment sensitivity, cancer progression, and prognosis, but relatively little is known about their role in HNSCC. Thus, our goal was to examine the effect of variation in these genes on survival outcomes in HNSCC patients receiving radiotherapy and cisplatin-based chemoradiotherapy. We identified genetic variants significantly affecting therapy results, constituting independent prognostic factors in these patients. Our results suggest that some polymorphisms in angiogenesis genes may be determinants of treatment efficacy and tumor aggressiveness in HNSCC, which may be of importance in standard therapy. These findings emphasize the potential value of the host genetic profile related to angiogenesis in assessing the risk of treatment failure. ABSTRACT: Fibroblast growth factor (FGF)/FGF receptor (FGFR), and platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR) systems, as well as some matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), are involved in various steps of angiogenesis. Data indicate that common germline variations in angiogenesis-regulating genes may modulate therapy results and cancer progression. However, whether these variants affect clinical outcome in head and neck squamous cell carcinoma (HNSCC) is unclear. Hence, we assessed the relationship between FGF/FGFR, PDGF/PDGFR, MMP, and TIMP genetic variants and treatment outcomes in HNSCC patients receiving radiotherapy (RT) alone or combined with cisplatin-based chemotherapy. In multivariate analysis, FGF2 rs1048201 CC homozygotes showed a higher risk of death (p = 0.039), while PDGFRA rs2228230 T was strongly associated with an increased risk of locoregional relapse (HR 2.49, p = 0.001) in the combination treatment subgroup. In the RT alone subset, MMP2 rs243865 TT carriers had a higher risk of locoregional recurrence (HR 2.92, p = 0.019), whereas PDGFRB rs246395 CC homozygotes were at increased risk of metastasis (HR 3.06, p = 0.041). The MMP2 rs7201 C and TIMP2 rs7501477 T were associated with a risk of locoregional failure in the entire cohort (p = 0.032 and 0.045, respectively). Furthermore, rs1048201, rs2228230, rs246395, rs243865, rs7201, and rs7201/rs7501477 were independent indicators of an unfavorable outcome. This study demonstrates that the FGF2, PDGFRA, PDGFRB, MMP2, and TIMP2 variants may contribute to treatment failure and poor prognosis in HNSCC.