RGD Reference Report - Genetic sequence variants and the development of secondary primary cancers in patients with head and neck cancers. - Rat Genome Database

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

Authors: Azad, AK  Bairati, I  Samson, E  Cheng, D  Cheng, L  Mirshams, M  Savas, S  Waldron, J  Wang, C  Goldstein, D  Xu, W  Meyer, F  Liu, G 
Citation: Azad AK, etal., Cancer. 2012 Mar 15;118(6):1554-65. doi: 10.1002/cncr.26446. Epub 2011 Aug 25.
RGD ID: 9589077
Pubmed: PMID:22009713   (View Abstract at PubMed)
DOI: DOI:10.1002/cncr.26446   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
DNMT3BHumanMultiple Primary Neoplasms treatmentIAGP associated with Head and Neck Neoplasms and DNA:SNP: :149C>T(rs2424913)(human)RGD 
Dnmt3bRatMultiple Primary Neoplasms treatmentISODNMT3B (Homo sapiens)associated with Head and Neck Neoplasms and DNA:SNP: :149C>T(rs2424913)(human)RGD 
Dnmt3bMouseMultiple Primary Neoplasms treatmentISODNMT3B (Homo sapiens)associated with Head and Neck Neoplasms and DNA:SNP: :149C>T(rs2424913)(human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dnmt3b  (DNA methyltransferase 3 beta)

Genes (Mus musculus)
Dnmt3b  (DNA methyltransferase 3B)

Genes (Homo sapiens)
DNMT3B  (DNA methyltransferase 3 beta)


Additional Information