The p53 pathway plays a critical role in maintaining genomic stability and preventing tumor formation. Given the roles of both MDM4 and HPV16 E6 oncoproteins in inhibition of p53 activity, we tested the hypothesis that MDM4 polymorphisms are associated with the risk of HPV16-associated squamous cell carcinoma of head and neck (SCCHN).
Genotyping was conducted on three tagging single nucleotide polymorphisms (rs11801299 G>A, rs10900598 G>T, and rs1380576 C>G) in MDM4, and serology was used to determine HPV 16 exposure in 380 cases and 335 cancer-free controls that were frequency-matched by age, sex, smoking, and drinking status.
None of three MDM4 polymorphisms alone was significantly associated with risk of overall SCCHN. With further analysis stratified by HPV16 serology and tumor site, we found that each polymorphism individually modified the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly pronounced in never smokers and never drinkers.
The risk of HPV16-associated SCCOP could be modified by MDM4 polymorphisms. Large and prospective studies are needed to validate our findings.
MDM4 polymorphisms; genetic susceptibility; human papillomavirus; molecular epidemiology; squamous cell carcinoma of head and neck cancer; squamous cell carcinoma of the oropharynx
Thyroid cancer incidence in the United States, particularly in women, has increased dramatically since 1980s. While the causes of thyroid cancer in most patients remain largely unknown, evidence suggests the existence of an inherited predisposition to development of differentiated thyroid cancer (DTC). Therefore, we explored the association between sporadic DTC and family history of cancer.
In a retrospective hospital-based case-control study of prospectively recruited subjects who completed the study questionnaire upon enrollment, unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as estimates of the DTC risk associated with first-degree family history of cancer.
The study included 288 patients with sporadic DTC and 591 cancer-free controls. Family history of thyroid cancer in first-degree relatives was associated with increased DTC risk (adjusted OR = 4.1, 95% CI: 1.7–9.9). All DTC cases in patients with a first-degree family history of thyroid cancer were cases of papillary thyroid carcinoma (PTC) (adjusted OR = 4.6, 95 CI%: 1.9–11.1). Notably, the risk of PTC was highest in subjects with a family history of thyroid cancer in siblings (OR = 7.4, 95% CI: 1.8–30.4). In addition, multifocal primary tumor was more common among PTC patients with first-degree family history of thyroid cancer than among PTC patients with no first-degree family history of thyroid cancer (68.8% vs. 35.5%, p = 0.01).
Our study suggests that family history of thyroid cancer in first-degree relatives, particularly in siblings, is associated with an increased risk of sporadic PTC.
Differentiated thyroid carcinoma; papillary thyroid carcinoma; benign thyroid disease; multifocal; family history of cancer
DNA repair pathway genes play an important role in maintaining genomic integrity and protecting against cancer development. This study aimed to identify novel SNPs in the DNA repair–related genes associated with melanoma risk from a genome-wide association study (GWAS).
A total of 8,422 SNPs from the 165 DNA repair–related genes were extracted from a GWAS of melanoma risk, including 494 cases and 5,628 controls from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). We further replicated the top SNPs in a GWAS of melanoma risk from the MD Anderson Cancer Center (1,804 cases and 1,026 controls).
A total of 3 SNPs with P value < 0.001 were selected for in silico replication. One SNP was replicated: rs3902093 [A] in EXO1 promoter region (Pdiscovery = 6.6×10-4, Preplication = 0.039, Pjoint = 2.5×10-4; ORjoint = 0.80, 95% CI: 0.71, 0.90). This SNP was associated with the expression of the EXO1; carriers of the A allele showed lower expression (P = 0.002).
Our study found that a promoter region SNP in the editing and processing nucleases gene EXO1 was associated with decreased expression of EXO1 and decreased melanoma risk. Further studies are warranted to validate this association and to investigate the potential mechanisms.
Both microRNAs and human papillomavirus (HPV) infection play an important role in the development and progression of oral squamous cell carcinoma (OSCC). In addition, microRNAs affect all facets of the immune/inflammation responses to infection, which may control HPV clearance. We thus hypothesized that microRNA polymorphisms modify the association between HPV16 seropositivity and OSCC risk.
Four single-nucleotide polymorphisms in microRNAs were genotyped and HPV16 serology was determined in 325 cases and 335 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using univariate and multivariable logistic regression models.
Overall, each polymorphism had no significant main effect on OSCC risk. Compared with the risk among individuals with both miR146 rs2910164 GG genotype and HPV16 seronegativity, risk of OSCC was increased among those with CG or CC genotype and HPV16 seronegativity (OR, 1.2; 95% CI, 0.9–1.8), GG genotype and HPV16 seropositivity (OR, 3.0; 95% CI, 1.8–5.0), and CG or CC genotype and HPV16 seropositivity (OR, 4.7; 95% CI, 2.3–9.4). Similar results were found for miR149 rs2292832, miR196 rs11614913, and miR499 rs3746444. Analyses stratified by tumor sites and smoking status showed that each polymorphism significantly increased the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly prominent in never smokers.
Our results indicate that microRNA polymorphisms modify the risk of OSCC associated with HPV16 seropositivity, particularly in patients with SCCOP and never smokers. Larger studies are needed to verify our findings.
Non-homologous end joining (NHEJ) is a pathway that repairs DNA double-strand breaks (DSBs) to maintain genomic stability in response to irradiation. We hypothesized that single nucleotide polymorphisms (SNPs) in NHEJ repair genes may affect clinical outcomes among non-small cell lung cancer (NSCLC) patients treated with definitive radio(chemo)therapy.
We genotyped five potentially functional SNPs (i.e., XRCC4 rs6869366 [-1394G>T] and rs28360071 [intron 3, del/ins], XRCC5 rs3835 [2408G>A], XRCC6 rs2267437 [-1310C>G] and LIG4 rs1805388 [T9I]) and estimated their associations with severe radiation pneumonitis (RP, ≥ grade 3) in 195 NSCLC patients.
We found a predictive role of LIG4 rs1805388 SNP in RP development (adjusted hazard ratio [HR] = 2.08, 95% confidence interval [CI], 1.04-4.12, P = 0.037 for CT/TT vs. CC). In addition, male patients with the TT genotype of XRCC4 rs6869366 SNP and female patients with AG/AA genotypes of XRCC5 rs3835 SNP were also at increased risk of severe RP development.
Our results suggest that NHEJ genetic polymorphisms, particularly LIG4 rs1805388, may modulate the risk of radiation pneumonitis in NSCLC patients treated with definitive radio(chemo)therapy. Large studies are needed to confirm our findings.
Radiation pneumonitis; Polymorphism; Non-small cell lung cancer
Due to the structural and biochemical similarities between the anti-tumor p53 and p73 proteins, we hypothesized that individuals who carry high risk genotypes of p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms have a higher risk of developing second primary malignancy (SPM) in patients after an index squamous cell carcinomas of the head and neck (SCCHN).
A cohort of 1,269 patients with index cases of SCCHN was recruited between May 1995 and January 2007 at M.D. Anderson Cancer Center and followed for SPM development. Patients were genotyped for p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms. A log-rank test and Cox proportional hazard models were used to compare SPM-free survival and SPM risk among different risk groups with the combined risk genotypes of the two polymorphisms.
Our data demonstrated that patients with p53 WP + PP and p73 GC/GC genotypes had a worse SPM-free survival and an increased SPM risk compared with the corresponding p53 WW and p73 GC/AT +AT/AT genotypes. After combining the two polymorphisms, a borderline significantly or significantly reduced SPM-free survival and increased SPM risk were observed in medium-risk group (p53 WW and p73 GC/GC or p53 P carrier and p73 AT carriers) and high-risk group (p53 P carriers and p73 GC/GC) compared with low-risk group (p53 WW and p73 AT carriers), respectively.
Our results suggest an increased risk of SPM after index SCCHN with both p53 and p73 polymorphisms individually and in combination.
p53; p73; Polymorphisms; Squamous cell carcinoma of the head and neck; Second primary malignancy
MicroRNA (miRNA)-related single nucleotide polymorphisms (SNPs) may compromise miRNA binding affinity and modify mRNA expression levels of the target genes, thus leading to cancer susceptibility. However, few studies have investigated roles of miRNA-related SNPs in the etiology of cervical carcinoma.
In this case–control study of 1,584 cervical cancer cases and 1,394 cancer-free female controls, we investigated associations between two miR-218-related SNPs involved in the LAMB3-miR-218 pathway and the risk of cervical carcinoma in Eastern Chinese women.
We found that the pri-miR-218 rs11134527 variant GG genotype was significantly associated with a decreased risk of cervical carcinoma compared with AA/AG genotypes (adjusted OR=0.77, 95% CI=0.63-0.95, P=0.015). However, this association was not observed for the miR-218 binding site SNP (rs2566) on LAMB3. Using the multifactor dimensionality reduction analysis, we observed some evidence of interactions of these two SNPs with other risk factors, especially age at primiparity and menopausal status, in the risk of cervical carcinoma.
The pri-miR-218 rs11134527 SNP was significantly associated with the risk of cervical carcinoma in Eastern Chinese women. Larger, independent studies are warranted to validate our findings.
Case–control study; Cervical cancer; LAMB3-miR-218 pathway; Polymorphism; Genetic susceptibility
Xeroderma pigmentosum group G (XPG) protein is essential for the nucleotide excision repair (NER) system, and genetic variations in XPG/ERCC5 that affect DNA repair capacity may contribute to the risk of tobacco-induced cancers, including squamous cell carcinoma of the head and neck (SCCHN). We investigated the association between XPG/ERCC5 polymorphisms and risk of squamous cell carcinoma of the head and neck (SCCHN).
We genotyped 12 tagging and potentially functional single nucleotide polymorphisms (SNPs) of XPG/ERCC5 in a case-control study of 1,059 non-Hispanic white patients with SCCHN and 1,066 cancer-free age-and sex matched controls and evaluated their associations with SCCHN risk.
Multivariate logistic regression showed that only an intronic tagging SNP (rs4150351A/C) of XPG/ERCC5 was associated with a decreased risk of SCCHN (adjusted OR=0.76, 95% CI=0.62–0.92 for AC vs. AA; adjusted OR=0.81, 95% CI=0.67–0.98 for AC/CC vs. AA), but this association was nonsignificnant after corrections by the permutation test (empirical P=0.105). In the genotype-phenotype correlation analysis using peripheral lymphocytes from 44 SCCHN patients, we found that rs4150351 AC/CC was associated with a statistically significant increase in XPG/ERCC5 mRNA expression.
These findings suggest that genetic variation in XPG/ERCC5 may not affect the SCCHN risk, although rs4150351 C variant genotypes were associated with the increased expression of XPG/ERCC5 mRNA and nonsignificantly decreased risk of SCCHN. Larger population-based and additional functional studies are warranted to validate our findings.
ERCC5; polymorphism; SCCHN; risk
Recent data showed that melanoma was more common among patients with Parkinson’s disease (PD) than individuals without PD and vice versa. It has been hypothesized that these two diseases may share common genetic and environmental risk factors.
We evaluated the association between single-nucleotide polymorphisms (SNPs) selected based on recent genome-wide association studies (GWAS) on PD risk and the risk of melanoma using 2,297 melanoma cases and 6,651 controls.
The PD SNP rs156429 in the chromosome 7p15 region was nominally associated with melanoma risk with p-value of 0.04, which was not significant after the Bonferroni correction for multiple comparisons. No association was observed between the remaining 31 PD SNPs and the risk of melanoma. The genetic score based on the number of PD risk allele was not associated with melanoma risk (odds ratio for the highest genetic score quartile (30–35) vs. the lowest (15–20), 1.13, 95% confidence interval, 0.47–2.70).
The PD SNPs identified in published GWAS do not appear to play an important role in melanoma development.
The PD susceptibility loci discovered by GWAS contribute little to the observed epidemiological association between the PD and melanoma.
Breast cancer 1, early onset (BRCA1) is a vital DNA repair gene, and the single nucleotide polymorphisms (SNPs) of this gene have been studied in diverse cancer types. In this study, we investigated the association between eight common BRCA1 functional SNPs and the risk of differentiated thyroid carcinoma (DTC).
This cancer center-based case–control study included 303 DTC cases and 511 controls. A polymerase chain reaction-based restriction fragment length polymorphism assay was performed for genotyping. Unconditional logistical regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) in single-SNP analysis and haplotype analysis.
A decreased risk of DTC was found for the A1988G heterozygous AG genotype (adjusted OR=0.63, 95% CI: 0.45–0.87, Bonferroni-adjusted p-value=0.036). AATAATA and ATAA haplotypes that carry C33420T variant allele were associated with reduced papillary thyroid cancer risk (adjusted OR=0.52, 95% CI: 0.33–0.84; adjusted OR=0.62, 95% CI: 0.40–0.95, respectively). Also, having a combination of ≥3 favorable genotypes was associated with a DTC risk reduction (adjusted OR=0.69, 95% CI: 0.50–0.95). The A31875G AG/GG genotype was associated with a 69% reduced risk of multifocal primary tumor in DTC patients (adjusted OR=0.31, 95% CI: 0.12–0.81).
BRCA1 genetic polymorphisms may play a role in DTC risk, while the possible associations warrant confirmation in independent studies.
Poly(ADP-ribose) polymerase-1 (PARP-1 catalyzes poly(ADP-ribosyl)ation to various proteins involved in many cellular processes, including DNA damage detection and repair, and cell proliferation and death. PARP-1 has been implicated in human carcinogenesis, but the association between the most-studied PARP-1 V762A polymorphism (rs1136410) and risk of various cancers was reported with inconclusive results.
To assess the association between the PARP-1 V762A polymorphism and cancer risk.
A meta-analysis of 21 studies with 12027 cancer patients and 14106 cancer-free controls was conducted to evaluate the strength of the association using odds ratio (OR) with 95% confidence interval (CI).
Overall, no significant association was found between the PARP-1 V762A polymorphism and cancer risk. In the stratified analyses, however, it was found that the variant A allele of the PARP-1 V762A polymorphism was associated with an increased risk of cancer among Asian populations (VA+AA vs.VV: OR = 1.11, 95% CI: 1.01-1.23; Pheterogeneity = 0.210) but a decreased risk of cancer (VA+AA vs.VV: OR =0.89, 95% CI: 0.80-1.00; Pheterogeneity = 0.004), among Caucasian populations, especially for glioma risk (OR = 0.79, 95% CI: 0.69-0.90; Pheterogeneity = 0.800).
This meta-analysis found evidence for an association of the PARP-1 V 762A polymorphism with increased risk of cancer among Asians but decreased risk of cancer among Caucasians, particularly of glioma. Further well designed studies with large sample sizes of different ethnic populations and different cancer types are warranted to confirm these findings.
DNA repair; Case-control study; Meta-analysis; Polymorphism; Susceptibility
The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.
The phosphatidylinositol 3-kinase (PI3K)/PTEN/AKT/mTOR and Ras/Raf/MEK/ERK pathways have been implicated in endometrial tumorigenesis. In this candidate pathway analysis, we investigated associations between genetic variations in these two pathways and both risk and clinical outcomes of endometrial cancer.
We genotyped a total of 48 potentially functional SNPs in 11 key genes (AKT1, AKT2, AKT3, BRAF, FRAP1, KRAS, PDPK1, PIK3CA, PIK3CB, PIK3R1, and PTEN) with the Sequenom genotyping platform in 115 endometrial cancer patients and 230 cancer-free women to evaluate their associations with risk, survival, and recurrence of endometrial cancer.
We found the following: (1) PIK3CA rs6443624 and rs9838411 variants either borderline or significantly decreased risk of endometrial cancer in a dominant model (adjusted odds ratio [OR], 0.62; 95% CI, 0.39–1.00 and 0.59; 95% CI, 0.36–0.95, respectively). Furthermore, there was a statistically significant multiplicative interaction (Pint = 0.036) between these two loci in risk of endometrial cancer. In contrast, the AKT1 rs2498801 genotype significantly increased risk of endometrial cancer (adjusted OR, 1.94; 95% CI, 1.02–3.67 in a recessive model). (2) In Cox regression analyses, three SNPs (PIK3R1 rs1862162, AKT2 rs892119, and PIK3CA rs2699887) showed significant associations with survival of endometrial cancer patients. (3) KRAS rs7312175 and PIK3CA rs6443624 had significant effects on recurrence of endometrial cancer individually and combined in a locus–dosage manner (adjusted Ptrend = 0.003).
These results suggest that common genetic variations in these pathways may modulate risk and clinical outcomes of endometrial cancer. Further replication and functional studies are needed to confirm these findings.
PI3K/PTEN/AKT/mTOR and RAS/RAF/MEK/ERK pathways; Polymorphisms; Endometrial cancer risk; Survival; Recurrence
HER-2/neu-targeted therapy has been successfully used in advanced gastric cancer, but the role of HER-2/neu in the prognosis of gastric cancer is not yet clear. In this study, we investigated the correlation between HER-2/neu expression and amplification as well as their association with clinic outcomes in patients with curatively resected gastric cancer.
We constructed tissue microarray blocks containing >70% of gastric cancer tissue and matched adjacent normal gastric tissue for 227 patients. Expression of the HER-2/neu protein in these specimens was analyzed using immunohistochemical staining. Amplification of HER-2/neu was also analyzed for the same samples using fluorescence in situ hybridization. Data on clinicopathological features and relevant prognostic factors in these patients were analyzed.
Of the 227 gastric cancer samples, 11.89% were positive for HER-2/neu overexpression/amplification under the new scoring system. HER-2/neu overexpression/amplification was closely correlated to the Lauren type, degree of differentiation, tumor size and lymph node metastasis. HER-2/neu overexpression/amplification predicted poor survival in univariate analysis but not in a Cox proportional hazards model.
HER-2/neu overexpression/amplification was not an independent predictor for survival in patients with curatively resected gastric cancer.
FISH; Gastric cancer; HER-2/neu; IHC; Prognosis
Hypersensitivity to radiation exposure has been suggested to be a risk factor for the development of breast cancer. In this case–control study of 515 young women (≤55 years) with newly diagnosed sporadic breast cancer and 402 cancer-free controls, we examined the radiosensitivity as measured by the frequency of chromatid breaks induced by gamma-radiation exposure in the G2 phase of phytohemagglutinin-stimulated and short-term cultured fresh lymphocytes. We found that the average chromatid breaks per cell from 50 well-spread metaphases were statistically significantly higher in 403 non-Hispanic White breast cancer patients (0.52 ± 0.22) than that in 281 non-Hispanic White controls (0.44 ± 0.16) (P value < 0.001), and in 60 Mexican American breast cancer patients (0.52 ± 0.19) than that in 65 Mexican American controls (0.44 ± 0.16) (P value = 0.021), but the difference was not significant in African Americans (52 cases [0.45 ± 0.16] versus 56 controls [0.47 ± 0.16], P = 0.651). The frequency of chromatid breaks per cell above the median of control subjects was associated with two-fold increased risk for breast cancer in non-Hispanic Whites and Mexican Americans. A dose–response relationship was evident between radiosensitivity and risk for breast cancer (Ptrend < 0.001) in these two ethnic groups. We concluded that gamma-ray-induced mutagen sensitivity may play a role in susceptibility to breast cancer in young non-Hispanic White and Mexican American women.
Radiation; Chromosomal instability; Breast neoplasm; Molecular epidemiology
We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10−10). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.
Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rises rapidly to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions that pinpoint the locations of genes previously associated with hematological cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer prior to DNA sampling, those without a prior diagnosis have an estimated 10-fold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).
Recent studies reported associations of the relative telomere length (RTL) and TERT variants with risk of several cancers, which has not been comprehensively investigated in squamous cell carcinoma of the head and neck (SCCHN).
We detected RTL in peripheral blood lymphocytes and genotyped six selected functional single nucleotide polymorphisms (SNPs) of the TERT gene in 888 SCCHN cases and 885 cancer-free controls of non-Hispanic whites.
Overall, we did not observe significant associations between RTL and SCCHN risk (adjusted OR, 0.97; 95% CI, 0.80–1.17 for below versus above the median; Ptrend = 0.618) nor between the six TERT SNPs and SCCHN risk. We also found no associations between RTL and TERT SNPs.
Our results suggest that RTL and TERT functional polymorphisms may not play a major role in the etiology of SCCHN. Large prospective studies are needed to validate our findings.
Although our results suggest no association among RTL, TERT functional polymorphisms, and SCCHN risk, this study may contribute to future meta-analysis.
genetic polymorphisms; Telomere length; TERT; head and neck cancer; molecular epidemiology
RAD52 is an important but not well characterized homologous recombination repair gene that can bind to single-stranded DNA ends and mediate the DNA-DNA interaction necessary for the annealing of complementary DNA strands. To evaluate the role of RAD52 variants in the response of tumor cells to platinum agents, we investigated their associations with platinum resistance and prognosis in cervical cancer patients. We enrolled 154 patients with cervical squamous cell carcinoma, who had radical surgery between 2008 and 2009, and genotyped three potentially functional RAD52 variants by the SNaPshot assay. We tested in vitro platinum resistance and RAD52 expression by using the MTT and immunohistochemistry methods, respectively. In 144 cases who had genotyping data, we found that both the rs1051669 variant and RAD52 protein expression were significantly associated with carboplatin resistance (P = 0.024 and 0.028, respectively) and rs10774474 with nedaplatin resistance (P = 0.018). The rs1051669 variant was significantly associated with RAD52 protein expression (adjusted OR = 4.7, 95% CI = 1.4−16.1, P = 0.013). When these three RAD52 variants were combined, progression-free survival was lower in patients who carried at least one (≥1) variant allele compared to those without any of the variant alleles (P = 0.047). Therefore, both RAD52 variants and protein expression can predict platinum resistance, and RAD52 variants appeared to predict prognosis in cervical cancer patients. Large studies are warranted to validate these findings.
The p14ARF/MDM2/p53 pathway plays an important role in modulation of DNA damage and oxidative stress responses. The aim of this study was to determine whether genetic variants in MDM2 and p14ARF are associated with risk of salivary gland carcinoma (SGC).
Four single nucleotide polymorphisms (SNPs) in MDM2 and p14ARF (MDM2-rs2279744, MDM2-rs937283, p14ARF-rs3731217, and p14ARF-rs3088440) were genotyped in 156 patients with SGC and 511 cancer-free controls. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
MDM2-rs2279744 was significantly associated with a moderately increased risk of SGC (OR, 1.5, 95% CI, 1.1–2.2). There was a trend toward significantly increased SGC risk with increasing number of risk genotypes of the four polymorphisms (Ptrend = 0.004). Individuals carrying 3–4 risk genotypes in MDM2 and p14ARF were at increased SGC risk (OR, 2.0, 95% CI, 1.1–2.7) compared with individuals carrying 0–2 risk genotypes. Moreover, the combined effect of risk genotypes of MDM2 and p14ARF was more pronounced among young subjects (≤45 years), female subjects, subjects with race/ethnicity other than non-Hispanic white, ever-smokers, and ever-drinkers.
Our results support the involvement of SNPs of MDM2 and p14ARF, either alone or more likely in combination, in susceptibility to SGC. Larger studies are needed to validate our findings.
To explore if functional single nucleotide polymorphisms (SNPs) of base-excision repair genes are predictors of radiation treatment-related pneumonitis (RP), we investigated associations between functional SNPs of ADPRT, APEX1, and XRCC1 and RP development.
Methods and Materials
We genotyped SNPs of ADPRT (rs1136410 [V762A]), XRCC1 (rs1799782 [R194W], rs25489 [R280H], and rs25487 [Q399R]), and APEX1 (rs1130409 [D148E]) in 165 patients with non-small cell lung cancer (NSCLC) who received definitive chemo-radiation therapy. Results were assessed by both Logistic and Cox regression models for RP risk. Kaplan-Meier curves were generated for the cumulative RP probability by the genotypes.
We found that SNPs of XRCC1 Q399R and APEX1 D148E each had a significant effect on the development of grade ≥2 RP (XRCC1: AA vs. GG, adjusted hazard ratio [HR] = 0.48, 95% confidence interval [CI] 0.24–0.97; APEX1: GG vs. TT, adjusted HR = 3.61, 95% CI 1.64–7.93) in an allele-dose response manner (Trend tests: P = 0.040 and 0.001, respectively). The number of the combined protective XRCC1 A or APEX1 T alleles (from 0 to 4) also showed a significant trend of predicting RP risk (P = 0.001).
SNPs of the base-excision repair genes may be biomarkers for susceptibility to RP. Larger prospective studies are needed to validate our findings.
Radiation pneumonitis; Polymorphism; Non-small cell lung cancer
Although the role of TNFAIP2 is still unclear, it is an important gene involved in apoptosis, and there are single-nucleotide polymorphisms (SNPs) at its microRNA (miRNA)-binding sites that could modulate miRNA target gene function. In this study, we evaluated associations of four selected SNPs (rs8126 T > C, rs710100 G > A, rs1052912 G > A and rs1052823 G > T) in the miRNA-binding sites of the 3′ untranslated region (UTR) with squamous cell carcinoma of the head and neck (SCCHN) risk in 1077 patients with SCCHN and 1073 cancer-free controls in a non-Hispanic White population. We found that, compared with the rs8126 TT genotype, the variant C allele were associated with increased SCCHN risk in an allele dose–response manner (adjusted odds ratio = 1.48 and 95% confidence interval = 1.06–2.05 for CC, respectively; Ptrend = 0.009). No significant associations were seen for the other three SNPs (rs710100 G > A, rs1052912 G > A and rs1052823 G > T). Additionally, we identified that the rs8126 T > C SNP is within the miR-184 seed binding region in the 3′ UTR of TNFAIP2. Further functional analyses showed that the rs8126 variant C allele led to significantly lower luciferase activity, compared with the T allele. In the genotype–phenotype correlation analysis of peripheral blood mononuclear cells from 64 SCCHN patients, the rs8126 CC genotype was associated with reduced expression of TNFAIP2 messenger RNA. Taken together, these findings indicate that the miR-184 binding site SNP (rs8126 T > C) in the 3′ UTR of TNFAIP2 is functional by modulating TNFAIP2 expression and contributes to SCCHN susceptibility. Larger replication studies are needed to confirm our findings.
Recently, several genome-wide association studies (GWAS) have identified many susceptible single nucleotide polymorphisms (SNPs) for chronic obstructive pulmonary disease (COPD) and lung cancer which are two closely related diseases. Among those SNPs, some of them are shared by both the diseases, reflecting there is possible genetic similarity between the diseases. Here we tested the hypothesis that whether those shared SNPs are common predictor for risks or prognosis of COPD and lung cancer. Two SNPs (rs6495309 and rs1051730) located in nicotinic acetylcholine receptor alpha 3 (CHRNA3) gene were genotyped in 1511 patients with COPD, 1559 lung cancer cases and 1677 controls in southern and eastern Chinese populations. We found that the rs6495309CC and rs6495309CT/CC variant genotypes were associated with increased risks of COPD (OR = 1.32, 95% C.I. = 1.14–1.54) and lung cancer (OR = 1.57; 95% CI = 1.31–1.87), respectively. The rs6495309CC genotype contributed to more rapid decline of annual Forced expiratory volume in one second (FEV1) in both COPD cases and controls (P<0.05), and it was associated with advanced stages of COPD (P = 0.033); the rs6495309CT/CC genotypes conferred a poor survival for lung cancer (HR = 1.41, 95%CI = 1.13–1.75). The luciferase assays further showed that nicotine and other tobacco chemicals had diverse effects on the luciferase activity of the rs6495309C or T alleles. However, none of these effects were found for another SNP, rs1051730G>A. The data show a statistical association and suggest biological plausibility that the rs6495309T>C polymorphism contributed to increased risks and poor prognosis of both COPD and lung cancer.
We conducted a genome-wide association study on cutaneous basal cell carcinoma (BCC) among 2045 cases and 6013 controls of European ancestry, with follow-up replication in 1426 cases and 4845 controls. A non-synonymous SNP in the MC1R gene (rs1805007 encoding Arg151Cys substitution), a previously well-documented pigmentation gene, showed the strongest association with BCC risk in the discovery set (rs1805007[T]: OR (95% CI) for combined discovery set and replication set [1.55 (1.45–1.66); P= 4.3 × 10−17]. We identified that an SNP rs12210050 at 6p25 near the EXOC2 gene was associated with an increased risk of BCC [rs12210050[T]: combined OR (95% CI), 1.24 (1.17–1.31); P= 9.9 × 10−10]. In the locus on 13q32 near the UBAC2 gene encoding ubiquitin-associated domain-containing protein 2, we also identified a variant conferring susceptibility to BCC [rs7335046 [G]; combined OR (95% CI), 1.26 (1.18–1.34); P= 2.9 × 10−8]. We further evaluated the associations of these two novel SNPs (rs12210050 and rs7335046) with squamous cell carcinoma (SCC) risk as well as melanoma risk. We found that both variants, rs12210050[T] [OR (95% CI), 1.35 (1.16–1.57); P= 7.6 × 10−5] and rs7335046 [G] [OR (95% CI), 1.21 (1.02–1.44); P= 0.03], were associated with an increased risk of SCC. These two variants were not associated with melanoma risk. We conclude that 6p25 and 13q32 are novel loci conferring susceptibility to non-melanoma skin cancer.
Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients and 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal–Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P < .001) and nicotine dependence (P = .036) were the highest in the combined CYP2A6 normal metabolizers and CHRNA5-A3-B4 AA (tag single-nucleotide polymorphism rs1051730 G>A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively.