Genetic variants in glutamine metabolic pathway genes predict cutaneous melanoma‐specific survival

Glutamine dependence is a unique metabolic defect seen in cutaneous melanoma (CM), directly influencing the treatment and prognosis. Here, we investigated the associations between 6025 common single‐nucleotide polymorphisms (SNPs) in 77 glutamine metabolic pathway genes with CM‐specific survival (CMSS) using genotyping datasets from two published genome‐wide association studies (GWASs). In the single‐locus analysis, 76 SNPs were found to be significantly associated with CMSS (P < .050, false‐positive report probability < 0.2 and Bayesian false discovery probability < 0.8) in the discovery dataset, of which seven SNPs were replicated in the validation dataset and three SNPs (HAL rs17676826T > C, LGSN rs12663017T > A, and NOXRED1 rs8012548A > G) independently predicted CMSS, with an effect‐allele attributed adjusted hazards ratio of 1.52 (95% confidence interval = 1.19‐1.93) and P < .001, 0.68 (0.54‐0.87) and P = .002 and 0.62 (0.46‐0.83) and P = .002, respectively. The model including the number of unfavorable genotypes (NUGs) of these three SNPs and covariates improved the five‐year CMSS prediction (P = .012) than the one with other covariates only. Further expression quantitative trait loci (eQTL) analysis found that the LGSN rs12663017 A allele was significantly associated with increased messenger RNA (mRNA) expression levels (P = 8.89 × 10 ^?11) in lymphoblastoid cell lines of the 1000 Genomes Project database. In the analysis of the genotype tissue expression (GTEx) project datasets, HAL rs17676826 C and NOXRED1 rs8012548 G alleles were significantly associated with their mRNA expression levels in sun‐exposed skin of the lower leg (P = 6.62 × 10^?6 and 1.37 × 10^?7, respectively) and in sun‐not‐exposed suprapubic skin (P < .001 and 1.43 × 10^?8, respectively). Taken together, these genetic variants of glutamine‐metabolic pathway genes may be promising predictors of survival in patients with CM.     

Genetic variants in ELOVL2 and HSD17B12 predict melanoma-specific survival

Fatty acids play a key role in cellular bioenergetics, membrane biosynthesis and intracellular signaling processes and thus may be involved in cancer development and progression. In the present study, we comprehensively assessed associations of 14,522 common single-nucleotide polymorphisms (SNPs) in 149 genes of the fatty-acid synthesis pathway with cutaneous melanoma disease-specific survival (CMSS). The dataset of 858 cutaneous melanoma (CM) patients from a published genome-wide association study (GWAS) by The University of Texas M.D. Anderson Cancer Center was used as the discovery dataset, and the identified significant SNPs were validated by a dataset of 409 CM patients from another GWAS from the Nurses’ Health and Health Professionals Follow-up Studies. We found 40 noteworthy SNPs to be associated with CMSS in both discovery and validation datasets after multiple comparison correction by the false positive report probability method, because more than 85% of the SNPs were imputed. By performing functional prediction, linkage disequilibrium analysis, and stepwise Cox regression selection, we identified two independent SNPs of ELOVL2 rs3734398 T>C and HSD17B12 rs11037684 A>G that predicted CMSS, with an allelic hazards ratio of 0.66 (95% confidence interval = 0.51–0.84 and p = 8.34 × 10⁻⁴) and 2.29 (1.55–3.39 and p = 3.61 × 10⁻⁵), respectively. Finally, the ELOVL2 rs3734398 variant CC genotype was found to be associated with a significantly increased mRNA expression level. These SNPs may be potential markers for CM prognosis, if validated by additional larger and mechanistic studies.     

Genetic variants in the integrin signaling pathway genes predict cutaneous melanoma survival

To identify genetic variants involved in prognosis of cutaneous melanoma (CM), we investigated associations of single nucleotide polymorphisms (SNPs) of genes in the integrin signaling pathway with CM survival by re‐analyzing a published genome‐wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated significant SNPs in another GWAS from Harvard University. In the MDACC study, 1,148 SNPs were significantly associated with CM‐specific survival (CMSS) (p ≤ 0.050 and false‐positive report probability ≤ 0.20), and nine SNPs were validated in the Harvard study (p ≤ 0.050). Among these, three independent SNPs (i.e., DOCK1 rs11018104 T > A, rs35748949 C > T and PAK2 rs1718404 C > T) showed a predictive role in CMSS, with an effect‐allele attributed adjusted hazards ratio [adjHR of 1.50 (95% confidence interval (CI) = 1.18‐1.90, p = 7.46E‐04), 1.53 (1.18‐1.97, 1.18E‐03) and 0.58 (0.45‐0.76, 5.60E‐05), respectively]. Haplotype analysis revealed that a haplotype carrying two risk alleles A‐T in DOCK1 was associated with the poorest survival in both MDACC (adjHR = 1.73, 95% CI = 1.19‐2.50, p = 0.004) and Harvard (adjHR = 1.95, 95% CI = 1.14‐3.33, p = 0.010) studies. In addition, patients with an increasing number of unfavorable genotypes (NUGs) for these three SNPs had a poorer survival. Incorporating NUGs with clinical variables showed a significantly improved ability to classify CMSS (AUC increased from 86.8% to 88.6%, p = 0.031). Genetic variants in the integrin signaling pathway may independently or jointly modulate the survival of CM patients. Further large, prospective studies are needed to validate these findings.     

Genetic variants in the PIWI‐piRNA pathway gene DCP1A predict melanoma disease‐specific survival

The Piwi‐piRNA pathway is important for germ cell maintenance, genome integrity, DNA methylation and retrotransposon control and thus may be involved in cancer development. In this study, we comprehensively analyzed prognostic roles of 3,116 common SNPs in PIWI‐piRNA pathway genes in melanoma disease‐specific survival. A published genome‐wide association study (GWAS) by The University of Texas M.D. Anderson Cancer Center was used to identify associated SNPs, which were later validated by another GWAS from the Harvard Nurses' Health Study and Health Professionals Follow‐up Study. After multiple testing correction, we found that there were 27 common SNPs in two genes (PIWIL4 and DCP1A) with false discovery rate < 0.2 in the discovery dataset. Three tagSNPs (i.e., rs7933369 and rs508485 in PIWIL4; rs11551405 in DCP1A) were replicated. The rs11551405 A allele, located at the 3' UTR microRNA binding site of DCP1A, was associated with an increased risk of melanoma disease‐specific death in both discovery dataset [adjusted Hazards ratio (HR) = 1.66, 95% confidence interval (CI) = 1.21–2.27, p =1.50 × 10^?3] and validation dataset (HR = 1.55, 95% CI = 1.03–2.34, p = 0.038), compared with the C allele, and their meta‐analysis showed an HR of 1.62 (95% CI, 1.26–2.08, p =1.55 × 10^?4). Using RNA‐seq data from the 1000 Genomes Project, we found that DCP1A mRNA expression levels increased significantly with the A allele number of rs11551405. Additional large, prospective studies are needed to validate these findings.     

Genetic variants in the metzincin metallopeptidase family genes predict melanoma survival

Metzincins are key molecules in the degradation of the extracellular matrix and play an important role in cellular processes such as cell migration, adhesion, and cell fusion of malignant tumors, including cutaneous melanoma (CM). We hypothesized that genetic variants of the metzincin metallopeptidase family genes would be associated with CM‐specific survival (CMSS). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate the associations between genetic variants of 75 metzincin metallopeptidase family genes and CMSS using the dataset from the genome‐wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC) which included 858 non‐Hispanic white patients with CM, and then validated using the dataset from the Harvard GWAS study which had 409 non‐Hispanic white patients with invasive CM. Four independent SNPs (MMP16 rs10090371 C>A, ADAMTS3 rs788935 T>C, TLL2 rs10882807 T>C and MMP9 rs3918251 A>G) were identified as predictors of CMSS, with a variant‐allele attributed hazards ratio (HR) of 1.73 (1.32‐2.29, 9.68E‐05), 1.46 (1.15‐1.85, 0.002), 1.68 (1.31‐2.14, 3.32E‐05) and 0.67 (0.51‐0.87, 0.003), respectively, in the meta‐analysis of these two GWAS studies. Combined analysis of risk genotypes of these four SNPs revealed a decreased CMSS in a dose‐response manner as the number of risk genotypes increased (P_trend < 0.001). An improvement was observed in the prediction model (area under the curve [AUC] = 81.4% vs. 78.6%), when these risk genotypes were added to the model containing non‐genotyping variables. Our findings suggest that these genetic variants may be promising prognostic biomarkers for CMSS.     

Genetic variants in RORA and DNMT1 associated with cutaneous melanoma survival

Cutaneous melanoma (CM) is considered as a steroid hormone‐related malignancy. However, few studies have evaluated the roles of genetic variants encoding steroid hormone receptor genes and their related regulators (SHR‐related genes) in CM‐specific survival (CMSS). Here, we performed a pathway‐based analysis to evaluate genetic variants of 191 SHR‐related genes in 858 CMSS patients using a dataset from a genome‐wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC), and then validated the results in an additional dataset of 409 patients from the Harvard GWAS. Using multivariate Cox proportional hazards regression analysis, we identified three‐independent SNPs (RORA rs782917 G > A, RORA rs17204952 C > T and DNMT1 rs7253062 G > A) as predictors of CMSS, with a variant‐allele attributed hazards ratio (HR) and 95% confidence interval of 1.62 (1.25–2.09), 1.60 (1.20–2.13) and 1.52 (1.20–1.94), respectively. Combined analysis of risk genotypes of these three SNPs revealed a decreased CMSS in a dose–response manner as the number of risk genotypes increased (p_trend < 0.001); however, no improvement in the prediction model was observed (area under the curve [AUC] = 79.6–80.8%, p = 0.656), when these risk genotypes were added to the model containing clinical variables. Our findings suggest that genetic variants of RORA and DNMT1 may be promising biomarkers for CMSS, but these results needed to be validated in future larger studies.     

HLA‐A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese

Nasopharyngeal carcinoma (NPC) arises from the mucosal epithelium of the nasopharynx and is constantly associated with Epstein–Barr virus type 1 (EBV‐1) infection. We carried out a genome‐wide association study (GWAS) of 575,247 autosomal SNPs in 184 NPC patients and 236 healthy controls of Malaysian Chinese ethnicity. Potential association signals were replicated in a separate cohort of 260 NPC patients and 245 healthy controls. We confirmed the association of HLA‐A to NPC with the strongest signal detected in rs3869062 (p = 1.73 × 10^?9). HLA‐A fine mapping revealed associations in the amino acid variants as well as its corresponding SNPs in the antigen peptide binding groove (p_{HLA‐A‐aa‐site‐99} = 3.79 × 10^?8, p_rs1136697 = 3.79 × 10^?8) and T‐cell receptor binding site (p_{HLA‐A‐aa‐site‐145} = 1.41 × 10^?4, p_rs1059520 = 1.41 × 10^?4) of the HLA‐A. We also detected strong association signals in the 5′‐UTR region with predicted active promoter states (p_rs41545520 = 7.91 × 10^?8). SNP rs41545520 is a potential binding site for repressor ATF3, with increased binding affinity for rs41545520‐G correlated with reduced HLA‐A expression. Multivariate logistic regression diminished the effects of HLA‐A amino acid variants and SNPs, indicating a correlation with the effects of HLA‐A*11:01, and to a lesser extent HLA‐A*02:07. We report the strong genetic influence of HLA‐A on NPC susceptibility in the Malaysian Chinese.     

Genetic variants in the platelet‐derived growth factor subunit B gene associated with pancreatic cancer risk

The platelet‐derived growth factor (PDGF) signaling pathway plays important roles in development and progression of human cancers. In our study, we aimed to identify genetic variants of the PDGF pathway genes associated with pancreatic cancer (PC) risk in European populations using three published genome‐wide association study datasets, which consisted of 9,381 cases and 7,719 controls. The expression quantitative trait loci (eQTL) analysis was also performed using data from the 1000 Genomes, TCGA and GTEx projects. As a result, we identified two potential susceptibility loci (rs5757573 and rs6001516) of PDGFB associated with PC risk [odds ratio (OR) = 1.10, 95% confidence interval (CI) = 1.05–1.16, and p = 4.70 × 10^?5 for the rs5757573 C allele and 1.21, 1.11–1.32, and 2.01 × 10^?5 for the rs6001516 T allele]. Haplotype analysis revealed that the C‐T haplotype carriers had a significantly increased risk of PC than those carrying the T‐C haplotype (OR = 1.23, 95% CI = 1.12–1.34, p =5.00 × 10^?6). The multivariate regression model incorporating the number of unfavorable genotypes (NUGs) with age and sex showed that carriers with 1–2 NUGs, particularly among 60–70 age group or males, had an increased risk of PC, compared to those without NUG. Furthermore, the eQTL analysis revealed that both loci were correlated with a decreased mRNA expression level of PDGFB in lymphoblastoid cell lines and pancreatic tumor tissues (p = 0.015 and 0.071, respectively). Our results suggest that genetic variants in PDGFB may play a role in susceptibility to PC. Further population and functional validations of our findings are warranted.     

Identification of novel germline polymorphisms governing capecitabine sensitivity

BACKGROUND:

Capecitabine, an oral 5‐fluorouracil (5‐FU) prodrug, is widely used in the treatment of breast, colorectal, and gastric cancers. To guide the selection of patients with potentially the greatest benefit of experiencing antitumor efficacy, or, alternatively, of developing toxicities, identifying genomic predictors of capecitabine sensitivity could permit its more informed use.

METHODS:

The objective of this study was to perform capecitabine sensitivity genome‐wide association studies (GWAS) using 503 well genotyped human cell lines from individuals representing multiple different world populations. A meta‐analysis that included all ethnic populations then enabled the identification of novel germline determinants (single nucleotide polymorphisms [SNPs]) of capecitabine susceptibility.

RESULTS:

First, an intrapopulation GWAS of Caucasian individuals identified reference SNP 4702484 (rs4702484) (within adenylate cyclase 2 [ADCY2]) at a level reaching genome‐wide significance (P = 5.2 × 10^?8). This SNP is located upstream of the 5 methyltetrahydrofolate‐homocysteine methyltransferase reductase (MTRR) gene, and it is known that the enzyme for MTRR is involved in the methionine‐folate biosynthesis and metabolism pathway, which is the primary target of 5‐FU‐related compounds, although the authors were unable to identify a direct relation between rs4702484 and MTRR expression in a tested subset of cells. In the meta‐analysis, 4 SNPs comprised the top hits, which, again, included rs4702484 and 3 additional SNPs (rs8101143, rs576523, and rs361433) that approached genome‐wide significance (P values from 1.9 × 10^?7 to 8.8 × 10^?7). The meta‐analysis also identified 1 missense variant (rs11722476; serine to asparagine) within switch/sucrose nonfermentable‐related, matrix‐associated, actin‐dependent regulator of chromatin (SMARCAD1), a novel gene for association with capecitabine/5‐FU susceptibility.

CONCLUSIONS:

Toward the goal of individualizing cancer chemotherapy, the current study identified novel SNPs and genes associated with capecitabine sensitivity that are potentially informative and testable in any patient regardless of ethnicity. Cancer 2011. © 2011 American Cancer Society.     

Genetic variants in ABCG1 are associated with survival of nonsmall‐cell lung cancer patients

Cell membrane transporters and metabolic enzymes play a crucial role in the transportation of a wide variety of substrates that maintain homeostasis in biological processes. We explored associations between genetic variants in these genes and survival of nonsmall‐cell lung cancer (NSCLC) patients by reanalyzing two datasets from published genome‐wide association studies (GWASs). In the discovery by using the GWAS dataset of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we evaluated associations of 1,245 single‐nucleotide polymorphisms (SNPs) in genes of four transporter families and two metabolic enzyme families with survival of 1,185 NSCLC patients. We then performed a replication analysis in the Harvard University Lung Cancer study (LCS) with 984 NSCLC patients. Multivariate Cox proportional hazards regression and false discovery rate (FDR) corrections were performed to evaluate the associations. We identified that 21 genotyped SNPs in eight gene regions were significantly associated with survival with FDR ≤0.1 in the discovery dataset. Subsequently, we confirmed six SNPs, which were putative functional, in ABCG1 of the ATP‐binding cassette transporter family in the replication dataset. In the pooled analysis, two tagging (at r² > 0.8 for linkage disequilibrium with other replicated SNPs)/functional SNPs were independently associated with survival: rs225388 G > A [adjusted hazards ratio (HR) = 1.12, 95% confidence interval (CI) = 1.03–1.20, P_trend = 4.6 × 10^?3] and rs225390 A > G (adjusted HR = 1.16, 95% CI = 1.07–1.25, P_trend = 3.8 × 10^?4). Our results indicated that genetic variants of ABCG1 may be predictors of survival of NSCLC patients.     

A comprehensive genome‐wide analysis of melanoma Breslow thickness identifies interaction between CDC42 and SCIN genetic variants

Breslow thickness (BT) is a major prognostic factor of cutaneous melanoma (CM), the most fatal skin cancer. The genetic component of BT has only been explored by candidate gene studies with inconsistent results. Our objective was to uncover the genetic factors underlying BT using an hypothesis‐free genome‐wide approach. Our analysis strategy integrated a genome‐wide association study (GWAS) of single nucleotide polymorphisms (SNPs) for BT followed by pathway analysis of GWAS outcomes using the gene‐set enrichment analysis (GSEA) method and epistasis analysis within BT‐associated pathways. This strategy was applied to two large CM datasets with Hapmap3‐imputed SNP data: the French MELARISK study for discovery (966 cases) and the MD Anderson Cancer Center study (1,546 cases) for replication. While no marginal effect of individual SNPs was revealed through GWAS, three pathways, defined by gene ontology (GO) categories were significantly enriched in genes associated with BT (false discovery rate ≤5% in both studies): hormone activity, cytokine activity and myeloid cell differentiation. Epistasis analysis, within each significant GO, identified a statistically significant interaction between CDC42 and SCIN SNPs (p_meta‐int =2.2 × 10^?6, which met the overall multiple‐testing corrected threshold of 2.5 × 10^?6). These two SNPs (and proxies) are strongly associated with CDC42 and SCIN gene expression levels and map to regulatory elements in skin cells. This interaction has important biological relevance since CDC42 and SCIN proteins have opposite effects in actin cytoskeleton organization and dynamics, a key mechanism underlying melanoma cell migration and invasion.     

A polymorphism in miR‐1262 regulatory region confers the risk of lung cancer in Chinese population

It has been proposed that the majority of disease‐associated loci identified by genome‐wide association studies (GWAS) are enriched in non‐coding regions, such as the promoter, enhancer or non‐coding RNA genes. Thus, we performed a two‐stage case‐control study to systematically evaluate the association of genetic variants in miRNA regulatory regions (promoter and enhancer) with lung cancer risk in 7,763 subjects (discovery stage: 2,331 cases and 3,077 controls; validation stage: 1,065 cases and 1,290 controls). As a result, we identified that rs12740674 (C > T) in miR‐1262 enhancer was significantly associated with the increased risk of lung cancer (additive model in discovery stage: adjusted OR = 1.31, 95%CI = 1.13–1.53, p = 3.846 × 10^?4 in Nanjing GWAS; adjusted OR = 1.20, 95%CI = 1.00–1.44, p = 0.041 in Beijing GWAS; validation stage: adjusted OR = 1.20, 95%CI = 1.03–1.41, p = 0.024). In meta‐analysis, the p value for the association between rs12740674 and lung cancer risk reached 6.204 × 10^?6 (adjusted OR = 1.24, 95%CI = 1.13–1.36). Using 3DSNP database, The Cancer Genome Atlas (TCGA) data and functional assays, we observed that the risk T allele of rs12740674 reduced the expression level of miR‐1262 in lung tissue through chromosomal looping, and overexpression of miR‐1262 inhibited lung cancer cell proliferation probably through targeting the expression levels of ULK1 and RAB3D . Our findings confirmed the important role that genetic variants of noncoding sequence play in lung cancer susceptibility and indicated that rs12740674 in miR‐1262 may be biologically relevant to lung carcinogenesis.     

Evaluation of genetic variants in association with colorectal cancer risk and survival in Asians

Genome‐wide association studies (GWAS) have identified over 40 genetic loci associated with colorectal cancer (CRC) risk. The association of single nucleotide polymorphisms (SNPs) at these loci with CRC risk and survival has not been adequately evaluated in East Asians. GWAS‐identified CRC risk variants were used to construct weighted genetic risk scores (GRSs). We evaluated these GRSs in association with CRC risk in 3,303 CRC cases and 3,553 controls using logistic regression models. Associations with overall and CRC‐specific survival were assessed in 731 CRC patients using Cox regression models. The association between the GRSs (overall and Asian‐specific) and CRC risk was approximately twofold (highest vs . lowest quintile), and the shape of the dose–response was linear (p _trend = 1.24 × 10^?13 and 3.02 × 10^?14 for overall GRS and Asian‐specific GRS, respectively). The association of the GRS with CRC risk was stronger among those with a family history of CRC (p _interaction = 0.007). Asian‐specific GRS using previously reported survival SNPs increased risk for mortality and the shape of the dose–response was linear for CRC‐specific and all‐cause mortality (p _trend = 0.01 and 0.006, respectively). Furthermore, the minor alleles of rs6983267 and rs1957636 were associated with worse CRC‐specific and overall survival. We show that GRSs constructed using GWAS‐identified common variants are strongly associated with CRC risk in Asians. We confirm previous findings for the possible association between some SNPs with survival, and provide evidence for two additional CRC risk variants that may be related to CRC survival.     

Interaction analysis between germline susceptibility loci and somatic alterations in lung cancer

Emerging evidence indicates that germline variations may interact with somatic events in carcinogenesis. However, the germline–somatic interaction in lung cancer remains largely unknown. We investigated whether lung cancer driver genes (CDGs) were more likely to locate within cancer susceptibility regions. Pathway analysis was performed to identify common pathways underlying CDGs and cancer susceptibility genes (CSGs). Next, we analyzed the associations between lung cancer risk SNPs and somatic alterations, including mutations and copy number alterations, in the level of genes, pathways, and overall burden of alterations. Enrichment analysis showed that lung CDGs are more likely to locate within cancer susceptibility regions (p = 8.40 × 10^?3). Both of lung CSGs and CDGs showed significant enrichment in pathways such as cell cycle and p53 signaling pathway. Gene‐based analysis showed that rs36600 (22q12.2) was associated with somatic mutations within ARID1A (OR = 2.45, 95%CI: 1.47–4.08, p = 5.78 × 10^?4). Pathway‐based analysis of somatic truncation mutations identified rs2395185 and rs3817963 at 6p22.1 was associated with cell cycle pathway (OR = 1.56, p = 3.61 × 10^?4 for rs2395185; OR = 1.58, p = 4.15 × 10^?4 for rs3817963), and rs3817963 was also associated with MAPK signaling pathway (OR = 1.54, p = 8.58 × 10^?4). Further analysis associated rs2395185 at 6p22.1 (HLA class II genes) with increased APOBEC3A expression (p = 9.50 × 10^?3) and elevated APOBEC mutagenesis (p = 3.58 × 10^?3). These results indicate germline–somatic interactions in lung tumorigenesis, and help to uncover the molecular mechanisms underlying lung cancer risk SNPs.     

Association of expression quantitative trait loci for long noncoding RNAs with lung cancer risk in Asians

Identification of long noncoding RNA (lncRNA) expression quantitative trait loci (lncR‐eQTL) that associated with lung cancer can provide insights into regulatory mechanisms of lncRNA, and help reveal the role of lncRNA in lung cancer. A two‐stage case‐control design was implemented in this study. We first selected the lncRNAs that differently expressed based on the Cancer Genome Atlas (TCGA) project (75 normal and 708 tumor tissues) and identified eQTLs for selected lncRNAs based on data of 278 normal lung tissues from the the genotype‐tissue expression database. Then we selected lncR‐eQTLs that associated with lung cancer based on two lung cancer GWAS datasets (7127 cases and 6818 controls). Promising lncR‐eQTLs were further replicated in an additional population (1056 cases and 1053 controls). Functional annotations of the identified lncR‐eQTLs and related lncRNAs were finally performed by using multiple public databases. Our eQTL analysis finally detected three lncRNA‐eQTLs, rs793544 in 3q13.12 (odds ratio [OR] = 1.15; confidence interval [CI]:1.09‐1.22; P = 2.30 × 10^?6), rs7234707 in 18p11.31 (OR = 1.1; CI:1.05‐1.15; P = 9.01 × 10^?5) and rs1600249 in 8p23.1 (OR = 1.1; CI:1.05‐1.16; P = 1.27 × 10^?4), that were consistently associated with the risk of lung cancer. These findings indicate that lncR‐eQTLs may serve as novel susceptibility markers for lung cancer.     

Association of breast cancer risk loci with breast cancer survival

The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited genetic variation might affect the disease prognosis and response to treatment. Several lines of evidence suggest that alleles influencing breast cancer risk might also be associated with breast cancer survival. We examined the associations between 35 breast cancer susceptibility loci and the disease over‐all survival (OS) in 10,255 breast cancer patients from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) of which 1,379 died, including 754 of breast cancer. We also conducted a meta‐analysis of almost 35,000 patients and 5,000 deaths, combining results from BPC3 and the Breast Cancer Association Consortium (BCAC) and performed in silico analyses of SNPs with significant associations. In BPC3, the C allele of LSP1‐rs3817198 was significantly associated with improved OS (HR_per‐allele=0.70; 95% CI: 0.58–0.85; p_trend = 2.84 × 10^?4; HR_{heterozygotes} = 0.71; 95% CI: 0.55–0.92; HR_homozygotes = 0.48; 95% CI: 0.31–0.76; p_2DF = 1.45 × 10^?3). In silico, the C allele of LSP1‐rs3817198 was predicted to increase expression of the tumor suppressor cyclin‐dependent kinase inhibitor 1C (CDKN1C). In the meta‐analysis, TNRC9‐rs3803662 was significantly associated with increased death hazard (HR_META =1.09; 95% CI: 1.04–1.15; p_trend = 6.6 × 10^?4; HR_{heterozygotes} = 0.96 95% CI: 0.90–1.03; HR_homozygotes = 1.21; 95% CI: 1.09–1.35; p_2DF=1.25 × 10^?4). In conclusion, we show that there is little overlap between the breast cancer risk single nucleotide polymorphisms (SNPs) identified so far and the SNPs associated with breast cancer prognosis, with the possible exceptions of LSP1‐rs3817198 and TNRC9‐rs3803662.     

Association study of genetic variation in DNA repair pathway genes and risk of basal cell carcinoma

DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair‐related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single‐nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome‐wide association meta‐analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified three SNPs (rs2805831 upstream of XPA : OR = 0.93, P = 1.35 × 10^?6; rs659857 in exon of MUS81 : OR = 1.06, P = 3.09 × 10^?6 and rs57343616 in 3′ UTR of NABP2 : OR = 1.11, P = 6.47 × 10^?6) as significantly associated with BCC risk in meta‐analysis, and all of them were nominally significant in both data sets. Furthermore, rs659857 [T] was significantly associated with decreased expression of MUS81 mRNA in the expression quantitative trait locus (eQTL) analysis. Our findings suggest that the inherited common variation in three DNA repair genes—XPA , MUS81 and NABP2 —may be involved in the development of BCC. To our knowledge, our study is the first report thoroughly examining the effects of SNPs across DNA repair pathway genes on BCC risk based on a genome‐wide association meta‐analysis.     

Genome‐wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients

Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi‐institutional genome‐wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time‐to‐event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random‐effects meta‐analysis. The strongest association after meta‐analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR = 1.76; 95% CI 1.41–2.18, p = 4.84 × 10^?7). After imputation across this region, the combined analysis identified two SNPs that reached genome‐wide significance. The strongest single association was with rs55933544 (HR = 1.9; 95% CI 1.5–2.4; p = 1.3 × 10^?8), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus.     

Genes involved in the WNT and vesicular trafficking pathways are associated with melanoma predisposition

Multifactorial predisposition to melanoma includes genes involved in pigmentation, immunity and DNA repair. Nonetheless, missing heritability in melanoma is still important. We studied the role of 335 candidate SNPs in melanoma susceptibility by using a dedicated chip and investigating 110 genes involved in different pathways. A discovery set was comprised of 1069 melanoma patients and 925 controls from France. Data were replicated using validation phases II (1085 cases and 801 controls from Spain) and III (1808 cases and 1894 controls from Germany and a second set of Spanish samples). In addition, an exome sequencing study was performed in three high‐risk French melanoma families. Nineteen SNPs in 17 genes were initially associated with melanoma in the French population. Six SNPs were replicated in phase II, including two new SNPs in the WNT3 (rs199524) and VPS41 (rs11773094) genes. The role of VPS41 and WNT3 was confirmed in a meta‐analysis (3940 melanoma cases and 3620 controls) with two‐side p values of 0.002, (OR = 0.86) and 4.07 × 10^?10 (OR = 0.80), respectively. Exome sequencing revealed a non‐synonymous VPS41 variant in one family that was shown to be strongly associated with familial melanoma (OR = 4.46, p = 0.001) in an independent sample of 178 melanoma families. WNT3 belongs to WNT pathway known to play a crucial role in melanoma, whereas VPS41 regulates vesicular trafficking and is thought to play a role in pigmentation. Our work identified two new pathways involved in melanoma predisposition. These results may be useful in the future for identifying individuals highly predisposed to melanoma.