Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants

Abstract

This study was aimed to identify novel susceptibility variants for second primary tumor (SPT) or recurrence in curatively treated early-stage head and neck squamous cell carcinoma (HNSCC) patients.We constructed a custom chip containing a comprehensive panel of 9,645 chromosomal and mitochondrial single nucleotide polymorphisms (SNP) representing 998 cancer-related genes selected by a systematic prioritization schema. Using this chip, we genotyped 150 early-stage HNSCC patients with and 300 matched patients without SPT/recurrence from a prospectively conducted randomized trial and assessed the association of these SNPs with risk of SPT/recurrence.Individually, six chromosomal SNPs and seven mitochondrial SNPs were significantly associated with risk of SPT/recurrence after adjustment for multiple comparisons. A strong gene-dosage effect was observed when these SNPs were combined, as evidenced by a progressively increasing SPT/recurrence risk as the number of unfavorable genotypes increased (P for trend < 1.00 × 10 −20). Several polygenic analyses suggest an important role of interconnected functional network and gene-gene interaction in modulating SPT/recurrence. Furthermore, incorporation of these genetic markers into a multivariate model improved significantly the discriminatory ability over the models containing only clinical and epidemiologic variables. This is the first large-scale systematic evaluation of germ-line genetic variants for their roles in HNSCC SPT/recurrence. The study identified several promising susceptibility loci and showed the cumulative effect of multiple risk loci in HNSCC SPT/recurrence. Furthermore, this study underscores the importance of incorporating germ-line genetic variation data with clinical and risk factor data in constructing prediction models for clinical outcomes.Approximately 10% of early-stage head and neck squamous cell carcinoma (HNSCC) patients develop locoregional recurrence and 15% to 25% develop second primary tumors (SPT) within 5 years of initial diagnosis (1, 2). As diagnostic and therapeutic approaches continue to improve, the ability to accurately predict SPT/recurrence in early-stage HNSCC patients would facilitate intensive surveillance or targeted interventions for high-risk patients and thereby reduce mortality and morbidity.Clinical (index tumor site and disease stage) and lifestyle (continued smoking and alcohol drinking) factors contribute to the risk of SPT and recurrence (3,4). HNSCC tumorigenesis is a multistep process involving an accumulation of progressive genetic alterations (5), including genomic alterations of multiple chromosomes (3p, 9p, 13q, and 17p; refs. 6, 7) and mutations of essential oncogenes and tumor suppressor genes (p53, p16, cyclin D1, KRAS, and FHIT; refs. 8,9). Many of these somatic alterations have also been linked to SPT/recurrence development.We previously reported that high mutagen sensitivity measured by an in vitro lymphocytic assay, reflecting constitutional genetic instability, was associated with increased risk ...

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“…Our findings are in line with previous reports on the cumulative effect of these risk alleles on CRC risk (17). Similar cumulative effects have been described for other cancers, including prostate cancer and head and neck cancer (26)(27)(28).…”

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“…Other current science in this area is modeling germline and somatic markers of risk and predictive markers (of agents' beneficial and toxic effects) toward personalizing cancer prevention (5,(33)(34)(35)(36)(37)(38). These efforts are leading toward comprehensive, complex modeling in clinical cohorts that will depend on evolving statistical methodology, highlighting the crucial role of biostatistical researchers in developing new methods needed for studies of cancer prevention, detection, and treatment.…”

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“…For example, the RXRA SNP was not observed to be significantly associated with SPT/recurrence risk in the unstratified analysis of Wu and colleagues (18). Its effect was essentially "washed-out" by the difference in the placebo and 13-cRA arms.…”

“…A previous analysis of this phase-III 13-cRA trial involved the first comprehensive global genotyping approach to analyzing clinical trial results in this setting (18). That analysis assessed associations between certain single-nucleotide polymorphisms (SNP) and an increased risk of SPT/recurrence among 150 patients with and 300 matched controls without SPT/recurrence from the original trial population.…”

“…Lee and colleagues (4) have gone a step (13-cRA or placebo) further by stratifying the same genotyping data by treatment in the same patient population used by Wu and colleagues (18). This new study first identified prognostic loci for increased SPT/recurrence risk in the placebo group, focusing on the previously genotyped chromosomal SNPs (not the much lower number of mitochondrial SNPs), and then examined whether these loci also identified individuals who received benefit from 13-cRA treatment.…”