Association of Genetic Variants in ANGPT/TEK and VEGF/VEGFR with Progression and Survival in Head and Neck Squamous Cell Carcinoma Treated with Radiotherapy or Radiochemotherapy.

Dorota Butkiewicz,Małgorzata Krześniak,Krzysztof Składowski,Agnieszka Gdowicz-Kłosok,Tomasz Rutkowski,Alexander Jorge Cortez,Iwona Domińczyk,Aleksandra Krzywon

doi:10.3390/cancers12061506

Dorota Butkiewicz, Małgorzata Krześniak + Show 6 more

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https://doi.org/10.3390/cancers12061506

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Abstract

Angiogenesis is essential for growth, progression, and metastasis of solid tumors. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) and angiopoietin (ANGPT)/ tyrosine kinase endothelial (TEK) signaling plays an important role in regulating angiogenesis. Very little is known about the effects of single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes on treatment outcome in head and neck squamous cell carcinoma (HNSCC). Therefore, we evaluated the association between SNPs in ANGPT1, ANGPT2, TEK, VEGF, VEGFR1, and VEGFR2 genes and five clinical endpoints in 422 HNSCC patients receiving radiotherapy alone or combined with chemotherapy. Multivariate analysis showed an association of ANGPT2 rs3739391, rs3020221 and TEK rs639225 with overall survival, and VEGF rs2010963 with overall and metastasis-free survival. VEGFR2 rs1870377 and VEGF rs699947 affected local recurrence-free survival in all patients. In the combination treatment subgroup, rs699947 predicted local, nodal, and loco-regional recurrence-free survival, whereas VEGFR2 rs2071559 showed an association with nodal recurrence-free survival. However, these associations were not statistically significant after multiple testing correction. Moreover, a strong cumulative effect of SNPs was observed that survived this adjustment. These SNPs and their combinations were independent risk factors for specific endpoints. Our data suggest that certain germline variants in ANGPT2/TEK and VEGF/VEGFR2 axes may have predictive and prognostic potential in HNSCC treated with radiation or chemoradiation.

Highlights

In Poland, head and neck cancer (HNC) accounts for 5–6% of all malignancies, and about 90% of all HNCs are squamous cell carcinomas (HNSCC) [1,2]
Our aim was to assess whether selected single-nucleotide polymorphisms (SNPs) affected progression and survival in patients with head and neck squamous cell carcinoma (HNSCC) located in the larynx, oropharynx, and hypopharynx receiving RT alone or in combination with CHT
The analysis showed that stage T3–T4 (p = 0.003), N1–N3 (p = 6 × 10−5 ), hypopharyngeal squamous cell carcinoma (HPSCC) (p = 0.0005), loco-regional relapse (p < 1 × 10−6 ), second primary cancer (SPC) (p = 0.036), and metastasis (p = 0.0001) after treatment were associated with inferior

Summary

Introduction

In Poland, head and neck cancer (HNC) accounts for 5–6% of all malignancies, and about 90% of all HNCs are squamous cell carcinomas (HNSCC) [1,2]. Cancers 2020, 12, 1506 locally advanced stage, where, in most cases, radiotherapy (RT) alone or combined with cisplatin-based chemotherapy (CHT) is the treatment of choice. These therapeutic modalities are applicable in less advanced stages. Despite advances in diagnosis and treatment, therapy results and prognosis in HNC are still unsatisfactory. Factors determining the choice of treatment, such as anatomic site, local and regional stage, and general patient condition, do not allow for a precise assessment of the expected therapy results, while patients with similar clinico-pathological features significantly differ in response and prognosis [4,5]. There is a growing interest in the search for inherited genetic factors that could provide additional information and potentially help to identify subgroups of patients at higher risk of treatment failure and disease progression

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