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

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 radiationtreated 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 followup 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 ¼ .003), whereas each variant T allele was associated with an aHR of 1.49 (1.15-1.95; P ¼ .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 2012;118:1554-

Synchronous primary cancers of the head and neck region and upper aero digestive tract: Defining high-risk patients

“…During 5 year follow-up of head and neck cancer patients, second primary cancer free survival of 79% has been put forth. [23] The occurrence or presence of non UADT synchronous malignancies in the breast, uterine cervix, thyroid, parotid and non Hodgkin's lymphoma with head and neck squamous carcinoma suggests possible multiple etiologies and/or risk factors. Synchronous squamous cell carcinoma in the head and neck region and malignant lymphoma is rare and few have been reported.…”

Validation of Genetic Sequence Variants as Prognostic Factors in Early-Stage Head and Neck Squamous Cell Cancer Survival

“…These concerns included (i) an overrepresentation of hypothesisgenerating studies, without adequate focus on validation studies; (ii) the selection of a small number of candidate sequence variants, without consideration of prior published work of additionally relevant sequence variants; (iii) the need for systematic discovery validation studies; and (iv) a multitude of studies with small samples sizes. Head and neck cancers are a heterogeneous group of tumors with high rate of early recurrence, development of secondary primary cancers (18), and mortality. In the present study, we used a large data set of more than 500 patients with head and neck cancer (which is among the largest data sets that have both biologic germ line material and long-term prospectively collected outcome data) to validate a comprehensive set of 23 sequence variants where each individual or combination of sequence variants had been previously described to have significant associations with head and neck cancer outcomes (i.e., OS and DFS) in the published literature.…”

“…Second, the lack of replication of these studies that contained mostly a few sequence variants assessed, in addition to a suggestion of a potential DNA repair pathway interaction of XRCC1 with ERCC5 and ERCC2 with XPA sequence variants suggest that newer approaches such as comprehensive pathway analyses, or even genome-wide association studies, may yield results that have improved chances to replicate across multiple data sets. In particular, the sequence variants-drug, sequence variants-radiotherapy interaction effects on outcome, or sequence variants associated with secondary primary cancer are promising areas of future research (17,18). Sequence variants in the CTLA4 gene have been reported to be associated with susceptibility to various cancers (19)(20)(21)(22).…”

Genetic sequence variants in vitamin D metabolism pathway genes, serum vitamin D level and outcome in head and neck cancer patients

“…The diagnosis of a SPC was made according to one of the following four criteria25–28: ( i ) if the SPC is of the same histology type as the first cancer, then there must be at least 2 cm of normal epithelium separating it from the first cancer; ( ii ) any new cancer of a different histologic type qualifies as a SPC without the 2‐cm separation requirement; ( iii ) if the SPC is a lung cancer of the same histology type as the first cancer, then it must be a solitary nodule without evidence of metastasis in the anterior cervical lymph nodes; and ( iv ) any new lung cancer of a different histology type qualifies as a SPC without these restrictions.…”