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Genetic sequence variants and the development of secondary primary cancers in patients with head and neck cancers
Author(s) -
Azad Abul Kalam,
Bairati Isabelle,
Samson Elodie,
Cheng Dangxiao,
Cheng Lu,
Mirshams Maryam,
Savas Sevtap,
Waldron John,
Wang Changshu,
Goldstein David,
Xu Wei,
Meyer Francois,
Liu Geoffrey
Publication year - 2011
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.26446
Subject(s) - medicine , oncology , dnmt3b , field cancerization , hazard ratio , head and neck cancer , genotype , proportional hazards model , cancer , gastroenterology , methyltransferase , genetics , gene , methylation , biology , confidence interval
BACKGROUND: Secondary primary cancers (SPCs), a major cause of morbidity and mortality in head and neck cancers (HNCs), are commonly associated with field cancerization. We comprehensively evaluated 23 germline sequence variants (from published literature) in 17 genes from 7 biological pathways associated with the HNC survival. Because cancer prognosis correlates with disease aggressiveness, the factors that determine aggressive disease may influence field cancerization process to favor SPC development. We thus hypothesized that the same sequence variants associated with HNC survival can also be associated with SPC. METHODS: Germline DNA from 531 stage I‐II radiation‐treated HNC patients (originally recruited for an alpha‐tocopherol/beta‐carotene placebo‐controlled secondary prevention clinical trial) were genotyped, and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors. RESULTS: The majority of SPCs were of lung and HNCs. Median follow‐up time was 5 years. SPCs were diagnosed in 21% of patients. The 5‐year SPC‐free survival was 79%. All but 1 evaluated sequence variant were not associated with SPC. There was a strong association of the DNA (cytosine‐5‐)‐methyltransferase 3 beta ( DNMT3B ) sequence variant, DNMT3B :C149T (rs2424913) with SPC: the adjusted hazard ratio (aHR) for TT versus CC was 2.23 (1.32‐3.78; P = .003), whereas each variant T allele was associated with an aHR of 1.49 (1.15‐1.95; P = .003). CONCLUSIONS: A functional sequence variant in DNMT3B is associated with the development of SPCs in HNC early stage patients treated with radiation. Aberrant DNA methylation may be an important modulator of SPC development in at‐risk individuals with HNCs. Cancer 2011;. © 2011 American Cancer Society.