Cutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi Anemia (FA) pathway involved in DNA crosslinks repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2339 common single nucleotide polymorphisms (SNPs) in 14 autosomal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 [AG vs. GG: adjusted hazard ratio (adjHR)=1.85, 95% confident interval (CI)=1.16-2.95, P=0.010], rs206118 (CC vs. TT+TC: adjHR=2.44, 95% CI=1.27-4.67, P=0.007), rs3752447 (CC vs. TT+TC: adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.
cutaneous melanoma; Fanconi Anemia pathway; survival; single nucleotide polymorphisms; Cox regression
Epistasis, or gene–gene interaction, results from joint effects of genes on a trait; thus, the same alleles of one gene may display different genetic effects in different genetic backgrounds. In this study, we generalized the coding technique of a natural and orthogonal interaction (NOIA) model for association studies along with gene–gene interactions for dichotomous traits and human complex diseases. The NOIA model which has non-correlated estimators for genetic effects is important for estimating influencing from multiple loci. We conducted simulations and data analyses to evaluate the performance of the NOIA model. Both simulation and real data analyses revealed that the NOIA statistical model had higher power for detecting main genetic effects and usually had higher power for some interaction effects than the usual model. Although associated genes have been identified for predisposing people to melanoma risk: HERC2 at 15q13.1, MC1R at 16q24.3 and CDKN2A at 9p21.3, no gene–gene interaction study has been fully explored for melanoma. By applying the NOIA statistical model to a genome-wide melanoma dataset, we confirmed the previously identified significantly associated genes and found potential regions at chromosomes 5 and 4 that may interact with the HERC2 and MC1R genes, respectively. Our study not only generalized the orthogonal NOIA model but also provided useful insights for understanding the influencing of interactions on melanoma risk.
The promoter variants of TNF-α, a major regulator of immune and inflammation responses, have been implicated in cancer development and prognosis. Thus, we investigated associations between four TNF-α promoter variants and risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated associations of four TNF-α polymorphisms with risk of recurrence in a cohort of 846 patients with SCCOP. Log-rank test and multivariable Cox models were used to evaluate associations. Compared with patients with variant genotypes of the TNF-α −308 and TNF-α −863 polymorphisms, patients with common homozygous genotypes had worse disease-free survival (log-rank P = 0.0002 and P < 0.0001, respectively) and increased risk of SCCOP recurrence (HR, 1.9, 95% CI, 1.3–2.8 and HR, 1.9, 95% CI, 1.3–2.7, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of the TNF-α −308 and −863 polymorphisms had worse disease-free survival (log-rank P = 0.005 and P = 0.007, respectively) and higher recurrence risk than patients with variant genotypes of these polymorphisms (HR, 5.1, 95% CI, 1.4–18.4 and HR, 3.7, 95% CI, 1.5–9.1, respectively), while no such significant associations were found for TNF-α −857 or −1031 polymorphisms. Our findings suggest that TNF-α −308 and −863 polymorphisms may modulate the risk of SCCOP recurrence in patients with HPV16-positive tumors. However, larger studies are needed to validate these results.
TNF-α variant; recurrence; genetic polymorphisms; biomarkers; human papillomavirus; head and neck cancer; oropharyngeal cancer
Polymorphisms in Caspase-7 (CASP7) may modulate the programmed
cell death and thus contribute to cervical cancer risk. In this case-control
study of 1,486 cervical cancer cases and 1,301 controls, we investigated associations
between four potentially functional polymorphisms in CASP7 and cervical
cancer risk and evaluated their locus-locus interaction effects on the risk.
The genotype-phenotype correlation was performed by a generalized linear regression
model. We found that the rs4353229 polymorphism was associated with cervical
cancer risk (under a recessive model: crude OR = 1.20, 95% CI = 1.02–1.40).
Compared with the TT genotype, the rs10787498GT genotype was associated with
an increased cervical cancer risk (adjusted OR = 1.19, 95% CI = 1.00–1.41).
Combination analysis showed that subjects with four putative risk genotypes
had a 1.54-fold increased cancer risk, compared with those who carried three
or less putative risk genotypes. We also observed significant locus-locus
joint effects on the risk, which may be mediated by the polymorphisms regulating CASP7
mRNA expression. Subsequent multifactor dimensionality reduction and classification
and regression tree analyses indicated that the CASP7 genotypes might
have a locus-locus interaction effect that modulated cervical cancer risk.
Out data suggest that CASP7 polymorphisms may interact to modify cervical
cancer risk by a possible mechanism of regulating CASP7 mRNA expression.
DNA repair is a complicated biological process, consisting of several distinct pathways, that plays a fundamental role in the maintenance of genomic integrity. The very important field of DNA repair and cancer risk has developed rapidly in the past decades. In this review of selected published data from our laboratory, we describe mostly our work on the study of phenotypic markers of nucleotide excision repair (NER), as measured by the benzo(a)pyrene diol epoxide (BPDE)/ultraviolet (UV)-induced mutagen sensitivity assays, BPDE-induced adduct assay, host cell reactivation (HCR)-DNA repair capacity (DRC) assay, reverse transcription-polymerase chain reaction (RT-PCR) assay and reverse-phase protein lysate microarray (RPP) assay, by using peripheral blood lymphocytes in a series of molecular epidemiological studies. Results of our studies suggest that individuals with reduced DRC have an elevated cancer risk. This finding needs additional validation by other investigators, and we also discussed issues in conducting this kind of research in the future.
DNA repair; biomarkers; molecular epidemiology; genetic susceptibility; cancer prevention
Single nucleotide polymorphisms (SNPs) in the PI3K/PTEN/AKT/mTOR signaling pathway may contribute to carcinogenesis. We genotyped five potentially functional PIK3R1 and mTOR SNPs in 1116 esophageal squamous cell cancer (ESCC) patients and 1117 cancer-free controls to assess their associations with ESCC risk. We observed no association with ESCC risk for any of the selected SNPs. However, the combined analysis of these SNPs revealed that subjects with one-to-three risk genotypes had an increased ESCC risk. Stratified analysis by body mass index (BMI) found that ESCC risk was significantly associated with each of three mTOR SNPs among subjects with BMI < 25.0. Specifically, we found that subjects carrying ≥ 1 risk genotypes had significantly increased ESCC risk, particularly for males, ever-smokers, ever-drinkers, and those with age > 60, or BMI < 25.0. Moreover, three mTOR haplotypes were associated with an increase in ESCC risk. Our meta-analysis of mTOR rs2295080 and cancer risk provided further evidence that mTOR SNPs might modulate cancer susceptibility. In this population, such risk effects might be modified by other risk factors, highlighting the importance of gene-environment interaction in esophageal carcinogenesis. Additional, larger studies are warranted to validate our findings.
ARF and human papillomavirus (HPV) 16 E6/E7 oncoproteins are important regulators participating in the p53/Rb pathways, genetic variations of p14
ARF may modify tumor HPV16 status and survival of HPV16-positive squamous cell carcinoma of the oropharynx (SCCOP) patients. We determined tumor HPV16 status and expression of p14/p53 and genotyped p14
ARF-rs3731217 and -rs3088440 polymorphisms in 552 incident SCCOP patients. We found that patients having variant genotypes for each p14
ARF polymorphism were approximately two or three times as likely to have HPV16-positive tumors compared with patients with corresponding common homozygous genotype, and such an association was particularly pronounced in patients with variant genotypes of both polymorphisms. After definitive chemoradiotherapy, patients having p14
ARF rs3731217 TG/GG variant genotypes had significantly better overall, disease-specific and disease-free survival than those having TT genotype, respectively. Multivariable analysis found that patients with p14
ARF-rs3731217 TT genotype had an ~7-, 11- and 3-fold increased risk for death overall, death due to SCCOP and recurrence than those with TG/GG variant genotypes, respectively. Furthermore, such significantly prognostic effect was also found when survival analysis was limited to HPV16-positive patients. Additionally, potentially functional relevance of the two variants was characterized to explore the genotype–phenotype correlation. Our findings indicate p14
ARF variants may predict tumor HPV16-positive SCCOP patients and survival.
The incidence of oropharyngeal and oral tongue cancers have increased over the last twenty years which parallels increased use of marijuana among individuals born after 1950.
Pooled analysis of individual-level data from nine case-control studies from the U.S. and Latin America in the INHANCE consortium. Self-reported information on marijuana smoking, demographic, and behavioral factors was obtained from 1,921 oropharyngeal cases, 356 oral tongue cases, and 7,639 controls.
Compared with never marijuana smokers, ever marijuana smokers had an elevated risk of oropharyngeal (adjusted odds ratio [aOR]: 1.24; 95% confidence interval [CI]: 1.06, 1.47) and a reduced risk of oral tongue cancer (aOR: 0.47; 95% CI: 0.29, 0.75). The risk of oropharyngeal cancer remained elevated among never tobacco and alcohol users. The risk of oral tongue cancer decreased with increasing frequency (ptrend=0.005), duration (ptrend=0.002), and joint-years of marijuana use (ptrend=0.004), and was reduced among never users tobacco and alcohol users. Sensitivity analysis adjusting for potential confounding by HPV exposure attenuated the association of marijuana use with oropharyngeal cancer (aOR: 0.99; 95% CI: 0.71, 1.25), but had no effect on the oral tongue cancer association.
These results suggest that the association of marijuana use with Head and Neck Carcinoma may differ by tumor site.
The associations of marijuana use with oropharyngeal and oral tongue cancer are consistent with both possible pro- and anti-carcinogenic effects of cannabinoids. Additional work is needed to rule out various sources of bias, including residual confounding by HPV infection and misclassification of marijuana exposure.
marijuana; oropharynx; oral tongue; INHANCE; human papillomavirus
XRCC4 plays a crucial role in the non-homologous end joining pathway that maintains genome stability. In this two-stage case-control study with 1,764 non-BRCA1/2 breast cancer patients and 1,623 cancer-free controls, we investigated the contribution of genetic variants of XRCC4 to breast cancer susceptibility in Chinese women. We identified a recessive missense variant, rs3734091 (c.739G>T, p.Ala247Ser), of XRCC4 that was significantly associated with an increased risk of breast cancer (odds ratio [OR] = 3.92, P = 0.007), particularly with the risk of developing triple-negative breast cancer (OR = 18.65, P < 0.0001). This p.Ala247Ser variant disturbed the nuclear localization of XRCC4 in cells homozygous for the rs3734091-T allele but not in heterozygous cells at both the cellular and tissue levels. In heterozygous cells, wild-type XRCC4 facilitated the nuclear localization of the XRCC4A247S mutant, thus compensating for the impaired localization of XRCC4A247S. This provided a biological mechanism by which rs3734091 conferred an increased susceptibility to non-BRCA1/2 breast cancer exclusively under a recessive model. Further functional analyses revealed that p.Ala247Ser impaired the DNA damage repair capacity and ultimately perturbed genomic stability. Taken together, our findings document the role of XRCC4 in non-BRCA1/2 breast cancer predisposition and reveal its underlying biological mechanism of action.
XRCC4; homozygous variant; nuclear localization; susceptibility; breast cancer
Sexual transmission of human papillomavirus, particularly HPV16, has been associated with an increasing incidence of oropharyngeal squamous cell carcinoma (OPC). Telomere shortening results in chromosomal instability, subsequently leading to cancer development. Given that HPV16 can affect telomerase activity and telomere length (TL), we conjectured that TL in peripheral blood lymphocytes (PBLs) may affect the risk of HPV16-associated OPC and tumor HPV16 status in patients. TL in PBLs and HPV16 serological status were measured in peripheral blood samples in 188 patients with OPC, 137 patients with oral cavity cancer (OCC) and 335 controls of non-Hispanic whites. Tumor HPV status was determined in 349 OPC cases. Odds ratios and 95% confidence intervals were calculated in univariate and multivariable logistic regression models. Overall, compared with long TL, short TL was associated significantly with a moderately increased risk of OPC but no increased risk of OCC. When we stratified the data by HPV16 serological status, using long TL and HPV16 seronegativity as the reference group, we found that the risk associated with HPV16 seropositivity was higher among OPC patients with short TL. Notably, such risk was particularly pronounced in never smokers, never drinkers and those >50 years of age. Furthermore, short TL was also associated significantly with tumor HPV-positive OPC. Together, our findings suggest that TL in PBLs may be associated with higher risk of HPV16-associated OPC and tumor HPV16 status, particularly in certain patient subgroups. Larger studies are needed to validate these findings.
telomere length; HPV; molecular epidemiology; oropharyngeal cancer
BACKGROUND AND PURPOSE
Human papillomavirus–positive oropharyngeal cancers typically have younger age of onset, limited tobacco exposure, and more favorable prognosis than HPV-negative oropharyngeal cancers. We assessed whether HPV-positive and HPV-negative oropharyngeal cancers have consistent differences in pretreatment imaging characteristics.
MATERIALS AND METHODS
A retrospective review of 136 pretreatment CT examinations of paired HPV-positive and HPV-negative oropharyngeal cancers matched for T stage, tumor subsite, and smoking status was performed with the reviewing radiologist blinded to HPV status and clinical stage. Demographic/clinical characteristics and imaging characteristics of primary lesions and metastatic nodal disease were compared by use of Fisher exact testing. The McNemar χ2 test was used for the matched-pair analysis.
By imaging, HPV-negative tumors were more likely to demonstrate invasion of adjacent muscle (26% versus 6%, P = .013). HPV-positive primary tumors were more likely to be enhancing and exophytic with well-defined borders, whereas HPV-negative primary tumors were more likely to be isoattenuated and demonstrate ill-defined borders, though these results were not statistically significant. HPV-positive tumors were more likely to demonstrate cystic nodal metastases than HPV-negative tumors (36% versus 9%, P = .002).
In this matched and blinded analysis of the imaging differences between HPV-positive and HPV-negative oropharyngeal cancers, HPV-positive carcinomas often had primary lesions with well-defined borders and cystic nodal metastases, whereas HPV-negative primaries more often had poorly defined borders and invasion of adjacent muscle.
The promoter of p53 induced gene 3 (PIG3) contains a variable number of tandem repeats (VNTRs) of pentanucleotides (TGYCC)n that is known as a p53 binding site. In this study, we investigated whether other potential molecules could bind to this PIG3 promoter (TGYCC)n motif. Ligand-chromatography combined with liquid chromatography–tandem mass spectrometry analyses indicated direct interactions of prohibitin and/or prohibiton with the (TGYCC)15 motif, which was confirmed by electrophoretic mobility shift assay and super-gel shift analysis with anti-prohibitin and anti-prohibiton antibodies. Using the chromatin immunopercipipation assay, we further demonstrated that prohibitin and prohibiton associated with the (TGYCC)15 motif in vivo regardless of the p53 status and apoptotic stress. We also found that prohibitin and prohibiton up-regulated PIG3 transcription independent of p53, although p53 obviously enhanced this process, and that the knock-down of prohibitin and prohibiton inhibited camptothecin-induced apoptosis. Taken together, our findings suggest that prohibitin and prohibiton contribute to PIG3-mediated apoptosis by binding to the PIG3 promoter (TGYCC)15 motif.
PIG3; Prohibitin; Prohibiton; (TGYCC)n motif
LIN28 is an RNA-binding protein that not only plays key roles in multiple cellular developmental processes and tumorigenesis, but also is involved in tissue inflammatory response. However, no published study has investigated associations between genetic variants in LIN28 and radiation-induced pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with definitive radiation therapy.
We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) of LIN28A (rs11247946 T>C, rs3811464 C>T, rs11581746 T>C, and rs12728900 G>A), and LIN28B (rs314280 A>G, rs12194974 G>A, rs17065417 A>C and rs314276 C>A) in 362 patients with NSCLC, who received definitive radio (chemo) therapy. The associations between RP risk and genotypes were assessed by hazards ratio (HR) in Cox proportional hazards regression analysis with time to event considered with and without adjustment for potential confounders.
Multivariate analyses found that patients carrying LIN28B rs314280 AG and AA/AG or rs314276 AC and AA/AC genotypes had a higher risk of grade ≥3 RP (for rs314280 AG and AA/AG versus GG, adjusted HR= 2.97 and 2.23, 95% CI, 1.32–6.72 and 1.01–4.94, P = 0.009 and 0.048, respectively; for rs314276 AC and AA/AC versus CC, adjusted HR = 2.30 and 2.00, 95% CI, 1.24–4.28 and 1.11–3.62, and P = 0.008 and 0.022, respectively). Further stratified analyses showed a more profound risk in the subgroups of the age <65 years subjects, males, stage III/IV, ever smokers and MLD ≥19.0 Gy.
Genetic variants of LIN28B, but not LIN28A, may be biomarkers for susceptibility to severe RP in NSCLC patients. Large, prospective studies are needed to confirm our findings.
LIN28; polymorphisms; inflammation; Hazards ratio; Non–small cell lung cancer; radiation pneumonitis
Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend ≤ 0.0001). Odds ratios for cigar and pipe smoking were not elevated among ever cigarette smokers. Head and neck cancer risk was elevated for those who reported exclusive cigar smoking (odds ratio = 3.49, 95% CI: 2.58, 4.73) or exclusive pipe smoking (odds ratio = 3.71, 95% CI: 2.59, 5.33). These results suggest that cigar and pipe smoking are independently associated with increased risk of head and neck cancers.
head and neck neoplasms; smoking
Genetically determined capacity for NER may modulate both cancer risk and prognosis. Thus, we evaluated associations of seven selected variants in the NER core genes with recurrence risk in 658 SCCOP patients treated principally by radiation. The seven polymorphisms in the core NER genes (XPC-rs2228000, XPC-rs2228001, XPD-rs1799793, XPD-rs13181, XPG-rs17655, ERCC1-rs3212986, and XPA-rs1800975) were genotyped using PCR-RFLP method and log-rank test and multivariable Cox models were used to evaluate the associations in both dominant and recessive genetic models. In a dominant model, we found that polymorphisms of XPC-rs2228000, XPD-rs1799793, and XPG-rs17655 were significantly associated with disease-free survival (log-rank, P = 0.014; P = 0.00008; and P = 0.0007, respectively), and these polymorphisms were significantly associated with recurrence risk of SCCOP (HR = 1.6, 95% CI, 1.1–2.3 for XPC-rs2228000; HR = 0.4, 95%, 0.3–0.6 for XPD-rs1799793; and HR = 0.5, 95% CI, 0.4–0.8 for XPG-rs17655) after multivariable adjustment. Moreover, the borderline significant or significant associations were also found for these three polymorphisms in HPV16/18-positive SCCOP patients (HR= 1.6, 95% CI, 1.0–4.1 for XPC-rs2228000; HR = 0.2, 95%, 0.1–0.5 for XPD-rs1799793; and HR = 0.1, 95% CI, 0.0–0.9 for XPG-rs17655). However, similarly significant associations were not found for these polymorphisms in a recessive model. These findings suggest that polymorphisms of XPC-rs2228000, XPD-rs1799793, and XPG-rs17655 in the NER core genes may contribute to recurrence risk of SCCOP, particularly HPV-positive SCCOP, in a dominant but not in a recessive model. However, validation of these results is warranted.
genetic variants; nucleotide excision repair; human papillomavirus; oropharyngeal cancer; recurrence; DNA repair
Aiming to identify novel genetic loci for pigmentation and skin cancer, we conducted a series of genome-wide association studies on hair color, eye color, number of sunburns, tanning ability and number of non-melanoma skin cancers (NMSCs) among 10 183 European Americans in the discovery stage and 4504 European Americans in the replication stage (for eye color, 3871 males in the discovery stage and 2496 males in the replication stage). We targeted novel chromosome regions besides the known ones for replication. As a result, we identified a new region downstream of the EDNRB gene on 13q22 associated with hair color and the strongest association was the single-nucleotide polymorphism (SNP) rs975739 (P = 2.4 × 10−14; P = 5.4 × 10−9 in the discovery set and P = 1.2 × 10−6 in the replication set). Using blue, intermediate (including green) and brown eye colors as co-dominant outcomes, we identified the SNP rs3002288 in VASH2 on 1q32.3 associated with brown eye (P = 7.0 × 10−8; P = 5.3 × 10−5 in the discovery set and P = 0.02 in the replication set). Additionally, we identified a significant interaction between the SNPs rs7173419 and rs12913832 in the OCA2 gene region on brown eye color (P-value for interaction = 3.8 × 10−3). As for the number of NMSCs, we identified two independent SNPs on chr6 and one SNP on chromosome 14: rs12203592 in IRF4 (P = 7.2 × 10−14; P = 1.8 × 10−8 in the discovery set and P = 6.7 × 10−7 in the replication set), rs12202284 between IRF4 and EXOC2 (P = 5.0 × 10−8; P = 6.6 × 10−7 in the discovery set and P = 3.0 × 10−3 in the replication set) and rs8015138 upstream of GNG2 (P = 6.6 × 10−8; P = 5.3 × 10−7 in the discovery set and P = 0.01 in the replication set).
A recent review of the SEER registry suggested that patients with index squamous cell carcinoma (SCC) of the oropharynx (SCCOP) are less likely to develop second primary malignancies (SPM) than patients with index SCC of non-oropharyngeal sites (oral cavity, larynx, hypopharynx). The purpose of this study was to determine the impact of index primary tumor site on SPM risk and explore factors potentially affecting this risk within a large prospectively accrued cohort of patients with index SCC of the head and neck (SCCHN).
A cohort of 2230 patients with incident SCCHN was reviewed for development of SPM. Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards models were used to detect the impact of various factors, including index tumor site, on SPM risk.
The SPM rate was lower for patients with index SCCOP than for patients with index non-oropharyngeal cancer (P<.001). Among SCCOP patients, former-smokers had a 50% greater risk of SPM and current-smokers had a 100% greater risk of SPM than never-smokers (Ptrend=.008). Among SCCOP patients, those with classic SCCHN phenotype had SPM risk similar to that of patients with index non-oropharyngeal cancers; those with typical HPV phenotype had very low SPM risk. SPM most commonly occurred at non-tobacco-related sites in patients with index SCCOP and at tobacco-related sites in patients with index non-oropharyngeal cancers.
In patients with SCCHN, index cancer site and smoking status affect the risk and distribution of SPM.
Head and neck neoplasms; second primary malignancy; smoking; oropharyngeal cancer; oral cancer; laryngeal cancer; human papillomavirus
Previous biological studies showed evidence of a genetic link between obesity and pigmentation in both animal models and humans. Our study investigated the individual and joint associations between obesity-related single nucleotide polymorphisms (SNPs) and both human pigmentation and risk of melanoma. Eight obesity-related SNPs in the FTO, MAP2K5, NEGR1, FLJ35779, ETV5, CADM2, and NUDT3 genes were nominally significantly associated with hair color among 5,876 individuals of European ancestry. The genetic score combining 35 independent obesity-risk loci was significantly associated with darker hair color (beta-coefficient per ten alleles=0.12, P-value=4 10−5). However, single SNPs or genetic scores showed non-significant association with tanning ability. We further examined the SNPs at the FTO locus for their associations with pigmentation and risk of melanoma. Among the 783 SNPs in the FTO gene with imputation R-square quality metric >0.8 using the 1000 genome data set, ten and three independent SNPs were significantly associated with hair color and tanning ability respectively. Moreover, five independent FTO SNPs showed nominally significant association with risk of melanoma in 1,804 cases and 1,026 controls. But none of them was associated with obesity or in linkage disequilibrium with obesity-related variants. FTO locus may confer variation in human pigmentation and risk of melanoma, which may be independent of its effect on obesity.
obesity; pigmentation; melanoma; genetic association; FTO gene
Because of their important roles in mediating the stabilization and expression of p53, we hypothesized that high-risk genotypes of polymorphisms in p53-related genes, including p53, p73, p14ARF, MDM2 and MDM4, may be associated with an increased risk of second primary malignancy (SPM) after index squamous cell carcinoma of the head and neck (SCCHN). We analyzed data from a cohort of 1283 patients with index SCCHN who were recruited between 1995 and 2007 at MD Anderson Cancer Center and followed for SPM development. Patients were genotyped for nine polymorphisms of p53-related genes. A log-rank test and Cox models were used to compare SPM-free survival and risk. Our results demonstrated that each p53-related polymorphism had a moderate effect on increased SPM risk, but when we combined risk genotypes of these nine polymorphisms together, we found that SPM-free survival was significantly shorter among risk groups with a greater number of combined risk genotypes. SPM risk increased with increasing number of risk genotypes (P < 0.0001 for trend). Compared with the low-risk group (0–3 combined risk genotypes), both the medium-risk (4–5 combined risk genotypes) and high-risk (6–9 combined risk genotypes) groups had significantly increased SPM risk [hazard ratio (HR): 1.6; 95% confidence interval (CI): 1.0–2.6 and HR: 3.0; 95% CI: 1.8–5.0, respectively]. Moreover, such significant associations were even higher in several subgroups. Our findings suggest that combined risk genotypes of p53-related genes may jointly modify SPM risk, especially in patients who are smokers and those with index non-oropharyngeal cancers. However, larger studies are needed to validate our findings.
MicroRNAs are a new class of small non-protein-coding RNAs that sometimes function as tumor suppressors or oncogenes. Aberrant expression and structural alteration of microRNAs have been reported to be involved in tumorigenesis and cancer development. Recently, rs531564/pri-miR-124-1, rs4938723/pri-miR-34b/c, rs7372209/pri-miR-26a-1, rs895819/pre-miR-27a, and rs11134527/pri-miR-218 were reported to be associated with risks of various cancers. In order to evaluate the relationship of these SNPs and esophageal squamous cell carcinoma (ESCC) risk, we conducted a case-control study with 1109 ESCC patients and 1275 control subjects to examine the potential association of these pri/pre-miRNA polymorphisms with ESCC susceptibility. As a result, two SNPs were associated with a significant risk of ESCC. We found that the GG genotype of pri-miR-124-1 rs531564 was associated to a significantly decreased risk of ESCC comparing with the CC/CG genotypes (p = 0.005; OR = 0.61, 95% CI = 0.43–0.86). In addition, the CC genotype of pri-miR-34b/c rs4938723 was associated with a significant decreased risk of ESCC (CC VS. TT/TC: p = 0.007, OR = 0.82, 95% CI = 0.71–0.95) in Chinese population. The present study provides the first evidence that pri-miR-124-1 rs531564 and pri-miR-34 rs4938723 were associated with the risk of ESCC in Chinese population.
Among index oropharyngeal cancer patients, second primary malignancies (SPMs) may be less common in human papillomavirus (HPV)-associated tumors than HPV-negative tumors. Further modification of these SPM risks by smoking has not been reported.
SPM outcomes of 356 incident oropharyngeal cancer patients were analyzed using Cox proportional hazards and Kaplan-Meier models. SPM risk and SPM-free survival were compared in HPV-seronegative patients, HPV-seropositive never smokers, and HPV-seropositive ever smokers.
HPV-seropositive patients had a lower 5-year SPM rate than HPV-seronegative patients (5.6% vs. 14.6%, p=0.051). Compared to HPV-seronegative patients, HPV-seropositive never smokers had a 73% reduced SPM risk, and HPV-seropositive ever smokers had a 27% reduced SPM risk (trend p=0.028). While HPV-seronegative patients had SPMs in traditional locations, 70% of SPMs among HPV-seropositive patients were outside typical tobacco-related sites.
HPV serologic status and smoking may stratify patients with index oropharyngeal cancers in terms of risk and location of SPMs.
Head and neck neoplasms; second primary; smoking; oropharyngeal cancer; human papillomavirus
In this study, we directly sequenced the Melanocortin 1 Receptor (MC1R) gene in 2,212 individuals to detect all variants and assessed their associations with cutaneous melanoma (CM) risk in a hospital-based study of 1,106 CM patients and 1,106 control subjects. Of 61 MC1R variants identified, 16 rare variants have not been previously reported by others; three MC1R variants were associated with a significant CM risk [c.451C>T (OR = 1.78, 95% CI = 1.44–2.20), c.478C>T (OR = 1.31, 95% CI = 1.05–1.63), and c.880G>C (OR = 1.69, 95% CI = 1.15–2.48)]; and two with borderline CM risk [c.942A>G (OR =1.23, 95% CI =1.00–1.51, and c.274G>A (OR = 1.23,95% CI = 0.99–1.53)] under a dominant model. When combined these five MC1R variants for cumulative effect analysis, we found that subjects with an increased number of variant genotypes from any of these five variants had significantly increased risk of CM with ORs of 1.68 (95% CI = 1.39–2.04), 1.61 (95% CI = 1.27–2.04), and 2.64 (95% CI = 1.72–4.05) for one, two, and three or more variant genotypes, respectively (trend test: P <0.001). Further haplotype and diplotype analyses based on the above-mentioned five SNPs suggested that the c.451T allele contributed to the high risk of CM and that the five variants may have joint effects on the risk of CM. Additional analysis suggests that the three most significant SNPs may be the molecular mechanisms underlying the known risk factors of the colors of the eyes, skin and hair in this study population. In conclusion, our study provided confirmatory evidence that both common and rare variants in the MC1R coding region may be biomarkers for susceptibility to CM in US populations.
melanocortin 1 receptor gene; direct sequencing; interaction; melanoma; case-control
To mine possibly hidden causal single nucleotide polymorphisms (SNPs) in the etiology of melanoma, we investigated the association of SNPs in 76 M/G1 transition genes with melanoma risk using our published genome-wide association study (GWAS) dataset with 1804 melanoma cases and 1,026 cancer-free controls. We found multiple SNPs with P < 0.01 and performed validation studies for 18 putative functional SNPs in PSMB9 in other two GWAS datasets. Two SNPs (rs1351383 and rs2127675) were associated with melanoma risk in the GenoMEL dataset (P = 0.013 and 0.004, respectively), but failed validation in the Australia dataset. Genotype-phenotype analysis revealed these two SNPs were significantly correlated with mRNA expression levels of PSMB9. Further experiments revealed that the promoter SNP rs2071480, which is in high LD with rs1351383 and rs2127675, involved in influencing transcription factor binding and gene expression. Taken together, our data suggested that functional variants in PSMB9 may contribute to melanoma susceptibility.
GWAS; Cell cycle; PSMB9; Polymorphism; melanoma
Murine double minute 2 (MDM2) oncoprotein and p14ARF tumor suppressor play pivotal roles in regulating p53 and function in the MAPK pathway, which is frequently mutated in differentiated thyroid carcinoma (DTC). We hypothesized that functional polymorphisms in the promoters of MDM2 and p14ARF contribute to the inter-individual difference in predisposition to DTC.
MDM2-rs2279744, MDM2-rs937283, p14ARF-rs3731217, and p14ARF-rs3088440 were genotyped in 303 patients with DTC and 511 cancer-free controls. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
MDM2-rs2279744 and p14ARF-rs3731217 were associated with a significantly increased risk of DTC (MDM2-rs2279744: TT vs. TG/GG, OR = 1.5, 95% CI, 1.1–2.0; p14ARF-rs3731217: TG/GG vs. TT, OR = 1.7, 95% CI, 1.2–2.3). No association was found for MDM2-rs937283 or p14ARF-rs3088440. Individuals carrying 3–4 risk genotypes of MDM2 and p14ARF had 2.2 times (95% CI, 1.4–3.5) the DTC risk of individuals carrying 0–1 risk genotypes (Ptrend = 0.021). The combined effect of MDM2 and p14ARF on DTC risk was confined to young subjects (≤45 years), non-smokers, non-drinkers, and subjects with a first-degree family history of cancer. These associations were quite similar in strength when cases were restricted to those with papillary thyroid cancer.
Our results suggest that polymorphisms of MDM2 and p14ARF contribute to the inter-individual difference in susceptibility to DTC, either alone or more likely jointly. The observed associations warrant further confirmation in independent studies.
papillary thyroid carcinoma; p53 pathway; case-control study
Angiogenesis and lymphangiogenesis are important in the progression of melanoma. We investigated associations between genetic variants in these pathways with sentinel lymph node (SLN) metastasis and mortality in two independent series of melanoma patients.
Participants at Moffitt Cancer Center were 552 patients, all Caucasian, with primary cutaneous melanoma referred for SLN biopsy. A total of 177 patients had SLN metastasis, among whom 60 died from melanoma. Associations between 238 SNPs in 26 genes and SLN metastasis were estimated as odds ratios and 95%CI using logistic regression. Competing risk regression was used to estimate hazard ratios and 95%CI for each SNP and melanoma-specific mortality. We attempted to replicate significant findings using data from a genome-wide association study comprising 1,115 melanoma patients, who were referred for SLN biopsy from MD Anderson Cancer Center (MDACC), among whom 189 patients had SLN metastasis and 92 patients died from melanoma.
In the Moffitt dataset, we observed significant associations in 18 SNPs with SLN metastasis and 17 SNPs with mortality. Multiple SNPs in COL18A1, EGFR, FLT1, IL10, PDGFD, PIK3CA and TLR3 were associated with risk of SLN metastasis and/or patient mortality. The MDACC data set replicated an association between mortality and rs2220377 in PDGFD. Further, in a meta-analysis, three additional SNPs were significantly associated with SLN metastasis (EGFR rs723526 and TLR3 rs3775292) and melanoma specific death (TLR3 rs7668666).
These findings suggest that genetic variation in angiogenesis and lymphangiogenesis contributes to regional nodal metastasis and progression of melanoma.
Additional research attempting to replicate these results is warranted.
SNP; lymph/angiogenesis; melanoma; sentinel lymph node