Genetic variants in the genes encoding rho GTPases and related regulators predict cutaneous melanoma‐specific survival

Rho GTPases control cell division, motility, adhesion, vesicular trafficking and phagocytosis, which may affect progression and/or prognosis of cancers. Here, we investigated associations between genetic variants of Rho GTPases‐related genes and cutaneous melanoma‐specific survival (CMSS) by re‐analyzing a published melanoma genome‐wide association study (GWAS) and validating the results in another melanoma GWAS. In the single‐locus analysis of 36,018 SNPs in 129 Rho‐related genes, 427 SNPs were significantly associated with CMSS (p < 0.050 and false‐positive report probability <0.2) in the discovery dataset, and five SNPs were replicated in the validation dataset. Among these, four SNPs (i.e ., RHOU rs10916352 G > C, ARHGAP22 rs3851552 T > C, ARHGAP44 rs72635537 C > T and ARHGEF10 rs7826362 A > T) were independently predictive of CMSS (a meta‐analysis derived p = 9.04 × 10^?4, 9.58 × 10^?4, 1.21 × 10^?4 and 8.47 × 10^?4, respectively). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had markedly reduced CMSS in both discovery dataset and validation dataset (p _trend=1.47 × 10^?7 and 3.12 × 10^?5). The model including the NUGs and clinical variables demonstrated a significant improvement in predicting the five‐year CMSS. Moreover, rs10916352C and rs3851552C alleles were significantly associated with an increased mRNA expression levels of RHOU (p = 1.8 × 10^?6) and ARHGAP22 (p = 5.0 × 10^?6), respectively. These results may provide promising prognostic biomarkers for CM personalized management and treatment.     

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.     

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.     

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.     

Genetic variants in one‐carbon metabolism‐related genes contribute to NSCLC prognosis in a Chinese population

BACKGROUND:

One‐carbon metabolism plays a critical role in DNA methylation and DNA synthesis. Variants of genes involved in one‐carbon metabolism may result in aberrant methylation and/or DNA synthesis inhibition, and ultimately modulate the initiation and progression of tumors. In this study, the authors hypothesized that polymorphisms in one‐carbon metabolism‐related genes may contribute to the prognosis of nonsmall cell lung cancer (NSCLC).

METHODS:

The authors screened 57 potentially functional single nucleotide polymorphisms (SNPs) from 11 candidate genes involved in one‐carbon metabolism and genotyped them in a cohort of 568 NSCLC patients by using Illumina Golden Gate platform. The Kaplan‐Meier method with log‐rank test and Cox proportional hazards model were used for survival analyses.

RESULTS:

Variant alleles were significantly associated with favorable survivals of NSCLC for MTR rs3768160 A>G (allelic hazards ratio [HR], 0.78; 95% confidence interval [CI], 0.62‐0.98), MTRR rs2966952 G>A (allelic HR, 0.84; 95% CI, 0.71‐0.99) and DHFR rs1650697 G>A (allelic HR, 0.83; 95% CI, 0.70‐0.99) and with unfavorable prognosis for MTHFD1 rs1950902 G>A with borderline significance (allelic HR, 1.18; 95% CI, 0.99‐1.40). In addition, the combined genotypes of these four SNPs showed a locus‐dosage effect on NSCLC survival (P_trend = 6.9 × 10^?5). In the final multivariate Cox regression model, combined genotypes based on 3 categories may be an independent prognostic factor for NSCLC with adjusted trend HR of 0.78 (95% CI, 0.66‐0.92).

CONCLUSION:

Genetic variants in one‐carbon metabolism pathway may be candidate biomarkers for NSCLC prognosis. Cancer 2010. © 2010 American Cancer Society.     

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 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 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.     

Polymorphic markers associated with severe oxaliplatin-induced, chronic peripheral neuropathy in colon cancer patients

BACKGROUND:

To identify potential genetic markers for severe oxaliplatin‐induced chronic peripheral neuropathy (OXCPN), the authors performed a genome‐wide association analysis of patients with colon cancer who received oxaliplatin‐based chemotherapy.

METHODS:

This was a prospective study in which DNA was purified in peripheral blood from patients with colon cancer who received oxaliplatin. The primary endpoint was the development of severe (grade 2 lasting for >7 days or grade 3) OXCPN. For the discovery set, genotyping was done for 96 patients who received adjuvant fluorouracil and oxaliplatin using the a genome‐wide human single‐nucleotide polymorphism (SNP) array. An association between polymorphisms and severe OXCPN was investigated. At the same time, 247 patients who received oxaliplatin‐based, first‐line chemotherapy for advanced disease were enrolled as a validation set.

RESULTS:

Among the 32 genotyped candidate SNPs selected from the discovery set, 9 SNPs in 8 genes (tachykinin, precursor 1[TAC1]; forkhead box C1 [FOXC1]; integrin, alpha 1 [ITGA1]; acylphosphatase 2, muscle type [ACYP2]; deleted in lymphocytic leukemia, 7 [DLEU7]; B‐cell translocation gene 4 [BTG4]; calcium/calmodulin‐dependent protein kinase II inhibitor 1 [CAMK2N1]; and phenylalanyl‐tRNA synthase 2 [FARS2]) had nominal replication (P < .05). The most significant association was observed at reference SNP number (rs)10486003 in TAC1 (P = 4.84 × 10^?7) in combined data from 2 sets. Five SNPs (rs10486003, rs2338, rs830884, rs843748, and rs797519) were significant in a multiple regression analysis (P < .05). Overall prediction accuracy calculated by the regression model was 72.8% (95% confidence interval, 65.8%‐79.9%) in the model development and 75.9% (95% confidence interval, 66.9%‐84.9%) in the model evaluation.

CONCLUSIONS:

The current results indicated that a genome‐wide pharmacogenomic approach is useful for identifying novel polymorphism predictors of severe OXCPN that may be used in personalized chemotherapy. Cancer 2011;. © 2011 American Cancer Society.     

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.     

Costs associated with complications are lower with capecitabine than with 5‐fluorouracil in patients with colorectal cancer

BACKGROUND:

Capecitabine, an oral alternative to 5‐fluorouracil (5‐FU) in patients with colorectal cancer (CRC), has equal clinical efficacy and a favorable safety profile; however, its use may be limited because of unit cost concerns. In this study, the authors measured the cost of chemotherapy‐related complications during treatment with capecitabine‐ and 5‐FU–based regimens.

METHODS:

Patients with CRC who received at least 1 administration of capecitabine or 5‐FU during 2004 and 2005 were identified from the Thomson MarketScan research databases. Monthly frequency and cost for 23 complications were recorded. Logistic regression was used to predict complication probability. General linear models were used to predict monthly complication cost and total monthly expenditure.

RESULTS:

In total, 4973 patients with CRC met the inclusion criteria for this analysis. Although the most frequently observed complications were the same between capecitabine and 5‐FU (nausea and vomiting, infection, anemia, neutropenia, diarrhea), each was observed with greater frequency in 5‐FU–based regimens. The mean predicted monthly complication cost was significantly higher (by 136%) with 5‐FU monotherapy than with capecitabine monotherapy (difference, $601; 95% confidence interval [95% CI], $469‐$737). In addition, the mean predicted monthly complication cost for 5‐FU+oxaliplatin was higher than the cost with capecitabine plus oxaliplatin (difference, $1165; 95% CI, $892‐$1595). When acquisition, administration, and complication costs were taken into consideration, there were no significant differences in the total cost between capecitabine regimens and 5‐FU regimens.

CONCLUSIONS:

Capecitabine compared well with 5‐FU–based therapy in patients with CRC and was associated with lower complication rates and associated costs. Cancer 2009. © 2009 American Cancer Society.     

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.     

Thyroid cancer GWAS identifies 10q26.12 and 6q14.1 as novel susceptibility loci and reveals genetic heterogeneity among populations

Thyroid cancer is the most heritable cancer of all those not displaying typical Mendelian inheritance. However, most of the genetic factors that would explain the high heritability remain unknown. Our aim was to identify additional common genetic variants associated with susceptibility to this disease. In order to do so, we performed a genome‐wide association study in a series of 398 cases and 502 controls from Spain, followed by a replication in four well‐defined Southern European case‐control collections contributing a total of 1,422 cases and 1,908 controls. The association between the variation at the 9q22 locus near FOXE1 and thyroid cancer risk was consistent across all series, with several SNPs identified (rs7028661: OR = 1.64, p = 1.0 × 10^?22, rs7037324: OR = 1.54, p = 1.2 × 10^?17). Moreover, the rare alleles of three SNPs (rs2997312, rs10788123 and rs1254167) at 10q26.12 showed suggestive evidence of association with higher risk of the disease (OR = 1.35, p = 1.2 × 10^?04, OR = 1.26, p = 5.2 × 10^?04 and OR = 1.38, p = 5.9 × 10^?05, respectively). Finally, the rare allele of rs4075570 at 6q14.1 conferred protection in the series studied (OR = 0.82, p = 2.0 × 10^?04). This study suggests that heterogeneity in genetic susceptibility between populations is a key feature to take into account when exploring genetic risk factors related to this disease.     

Genome wide association study identifies a novel putative mammographic density locus at 1q12‐q21

Mammographic density (MD) is an intermediate phenotype for breast cancer. Previous studies have identified genetic variants associated with MD; however, much of the genetic contribution to MD is unexplained. We conducted a two‐stage genome‐wide association analysis among the participants in the “Determinants of Density in Mammographies in Spain” study, together with a replication analysis in women from the Australian MD Twins and Sisters Study. Our discovery set covered a total of 3,351 Caucasian women aged 45 to 68 years, recruited from Spanish breast cancer screening centres. MD was blindly assessed by a single reader using Boyd's scale. A two‐stage approach was employed, including a feature selection phase exploring 575,374 SNPs in 239 pairs of women with extreme phenotypes and a verification stage for the 183 selected SNPs in the remaining sample (2,873 women). Replication was conducted in 1,786 women aged 40 to 70 years old recruited via the Australian Twin Registry, where MD were measured using Cumulus‐3.0, assessing 14 SNPs with a p value <0.10 in stage 2. Finally, two genetic variants in high linkage disequilibrium with our best hit were studied using the whole Spanish sample. Evidence of association with MD was found for variant rs11205277 (OR = 0.74; 95% CI = 0.67–0.81; p = 1.33 × 10^?10). In replication analysis, only a marginal association between this SNP and absolute dense area was found. There were also evidence of association between MD and SNPs in high linkage disequilibrium with rs11205277, rs11205303 in gene MTMR11 (OR = 0.73; 95% CI = 0.66–0.80; p = 2.64 × 10^?11) and rs67807996 in gene OTUD7B (OR = 0.72; 95% CI = 0.66–0.80; p = 2.03 × 10^?11). Our findings provide additional evidence on common genetic variations that may contribute to MD.     

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.     

Novel colon cancer susceptibility variants identified from a genome‐wide association study in African Americans

Genome‐wide association studies (GWAS) in ethnic/racial minority populations can help to fine‐map previously identified risk regions or discover new risk loci because of the genetic diversity in these populations. We conducted a GWAS of colorectal cancer (CRC) in 6,597 African Americans (1,894 cases and 4,703 controls) (Stage 1) and followed up the most promising markers in a replication set of 2,041 participants of African descent (891 cases and 1,150 controls) (Stage 2). We identified a novel variant, rs56848936 in the gene SYMPK at 19q13.3, associated with colon cancer risk (odds ratio 0.61 for the risk allele G, p = 2.4 × 10^?8). The frequency of the G allele was 0.06 in African Americans, compared to <0.01 in Europeans, Asians and Amerindians in the 1000 Genomes project. In addition, a variant previously identified through fine‐mapping in this GWAS in the region 19q13.1, rs7252505, was confirmed to be more strongly associated with CRC in the African American replication set than the variant originally reported in Europeans (rs10411210). The association between rs7252505 and CRC was of borderline significance (p = 0.05) in a Hispanic population GWAS with 1,611 CRC cases and 4,330 controls. With the three datasets combined, the odds ratio was 0.84 for the risk allele A (95% confidence interval 0.79–0.89, p = 3.7 × 10^?8). This study further highlights the importance of conducting GWAS studies in diverse ancestry populations.