Genetic sequence variants and the development of secondary primary cancers in patients with head and neck cancers

Abul Kalam Azad, Isabelle Bairati, Elodie Samson, Dangxiao Cheng, Lu Cheng, Maryam Mirshams, Sevtap Savas, John Waldron, Changshu Wang, David Goldstein, Wei Xu, Francois Meyer, Geoffrey Liu

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1554-1565
Number of pages12
JournalCancer
Volume118
Issue number6
DOIs
StatePublished - Mar 15 2012
Externally publishedYes

Keywords

  • DNMT3B
  • genetic sequence variant
  • head and neck cancer
  • secondary primary cancer
  • splicing

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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