Multigene pathway‐based analyses identify nasopharyngeal carcinoma risk associations for cumulative adverse effects of TERT‐CLPTM1L and DNA double‐strand breaks repair

The genetic etiology of nasopharyngeal carcinoma (NPC) and mechanisms for inherited susceptibility remain unclear. To examine genetic risk factors for NPC, we hypothesized that heritable risk is attributable to cumulative effects of multiple common low‐risk variants. With the premise that individual SNPs only confer subtle effects for cancer risk, a multigenic pathway‐based approach was used to systematically examine associations between NPC genetic susceptibility with SNPs in genes in DNA repair pathways and from previously identified cancer genome‐wide association study analyses. This case–control study covers 161 genes/loci and focuses on pathway‐based analyses in 2,349 Hong Kong individuals, allowing stratification according to NPC familial status for meaningful association analysis. Three SNPs (rs401681, rs6774494 and rs3757318) corresponding to TERT/CLPTM1L (OR 95% CI = 0.77, 0.68–0.88), MDS1‐EVI1 (OR 95% CI=0.79 0.69–0.89) and CCDC170 (OR 95% CI = 0.76, 0.66–0.86) conferred modest protective effects individually for NPC risk by the logistic regression analysis after multiple testing adjustment (p_Bonferroni < 0.05). Stratification of NPC according to familial status identified rs2380165 in BLM (OR 95% CI = 1.49, 1.20–1.86, p_Bonferroni < 0.05) association with family history‐positive NPC (FH+ NPC) patients. Multiple SNPs pathway‐based analysis revealed that the combined gene dosage effects for increasing numbers of unfavorable genotypes in TERT‐CLPTM1L and double‐strand break repair (DSBR) conferred elevated risk in FH+ and sporadic NPC patients (ORs per allele, 95% CIs = 1.37, 1.22–1.55, p_Bonferroni = 5.00 × 10^?6; 1.17, 1.09–1.26, p_Bonferroni = 4.58 × 10^?4, respectively, in TERT/NHEJ pathways). Our data suggested cumulative increased NPC risk associations with TERT‐CLPTM1L and DSBR pathways contribute to genetic susceptibility to NPC and have potential translational relevance for patient stratification and therapeutics.     

Genetic variants in pigmentation genes,pigmentary phenotypes,and risk of skin cancer in Caucasians

Human pigmentation is a polygenic quantitative trait with high heritability. Although a large number of single nucleotide polymorphisms (SNPs) have been identified in pigmentation genes, very few SNPs have been examined in relation to human pigmentary phenotypes and skin cancer risk. We evaluated the associations between 15 SNPs in 8 candidate pigmentation genes (TYR, TYRP1, OCA2, SLC24A5, SLC45A2, POMC, ASIP and ATRN) and both pigmentary phenotypes (hair color, skin color and tanning ability) and skin cancer risk in a nested case‐control study of Caucasians within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases and 870 common controls. We found that the TYR Arg402Gln variant was significantly associated with skin color (p‐value = 7.7 × 10^?4) and tanning ability (p‐value = 7.3 × 10^?4); the SLC45A2 Phe374Leu variant was significantly associated with hair color (black to blonde) (p‐value = 2.4 × 10^?7), skin color (p‐value = 1.1 × 10^?7) and tanning ability (p‐value = 2.5 × 10^?4). These associations remained significant after controlling for MC1R variants. No significant associations were found between these polymorphisms and the risk of skin cancer. We observed that the TYRP1 rs1408799 and SLC45A2 1721 C>G were associated with melanoma risk (OR, 0.77; 95% CI, 0.60–0.98 and OR, 0.75; 95% CI, 0.60–0.95, respectively). The TYR Ser192Tyr was associated with SCC risk (OR, 1.23; 95% CI, 1.00–1.50). The TYR haplotype carrying only the Arg402Gln variant allele was significantly associated with SCC risk (OR, 1.35; 95% CI, 1.04–1.74). The OCA2 Arg419Gln and ASIP g.8818 A>G were associated with BCC risk (OR, 1.50; 95% CI, 1.06–2.13 and OR, 0.73; 95% CI, 0.53–1.00, respectively). The haplotype near ASIP (rs4911414[T] and rs1015362[G]) was significantly associated with fair skin color (OR, 2.28; 95% CI, 1.46–3.57) as well as the risks of melanoma (OR, 1.68; 95% CI, 1.18–2.39) and SCC (OR, 1.54; 95% CI, 1.08–2.19). These associations remained similar after adjusting for pigmentary phenotypes and MC1R variants. The statistical power of our study was modest and additional studies are warranted to confirm the associations observed in the present study. Our study provides evidence for the contribution of pigmentation genetic variants, in addition to the MC1R variants, to variation in human pigmentary phenotypes and possibly the development of skin cancer. © 2009 UICC     

Nonsynonymous polymorphisms in FAT4 gene are associated with the risk of esophageal cancer in an Eastern Chinese population

FAT4 plays a crucial role in carcinogenesis as a key component of the Hippo signaling pathway. We hypothesized that potential functional polymorphisms in the FAT4 gene may modify the risk of esophageal cancer. To test this hypothesis, we evaluated the association between four nonsynonymous polymorphisms (rs1039808, rs12508222, rs1567047 and rs1014867) in FAT4 and esophageal cancer risk in a case–control study of 2,139 esophageal cancer cases and 2,273 controls in a Chinese population. We found that the T allele of rs1014867 (Pro4972Ser) was significantly associated with a decreased risk of esophageal cancer (odds ratio [OR]=0.77, 95% confidence interval [95% CI]=0.66–0.90; p=1.42 × 10^?3). We also observed a borderline significant association between rs1039808 (Ala807Val) and esophageal cancer risk (OR=0.90, 95% CI=0.82–1.00; p=0.050), which was more prominent in non‐drinkers (OR=0.82, 95% CI=0.71–0.94; p=6.53 × 10^?3). Furthermore, we detected a significant interaction between rs1039808 genotypes and alcohol drinking on esophageal cancer risk (p=0.013). These findings indicate that the nonsynonymous variants rs1014867 (Pro4972Ser) and rs1039808 (Ala807Val) of FAT4 may contribute to esophageal cancer susceptibility.     

Genome‐wide association study and meta‐analysis in Northern European populations replicate multiple colorectal cancer risk loci

Genome‐wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome‐wide association study in 1,701 CRC cases and 14,082 cancer‐free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single‐nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10⁻⁴; OR, 1.14; 95% CI, 1.06–1.23), and it was genome‐wide significant in combined analysis (p = 1.50 × 10⁻⁹; OR, 1.12; 95% CI, 1.08–1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.     

Genetic variation in the TLR and NF‐κB pathways and cervical and vulvar cancer risk: A population‐based case–control study

Genital infection with the oncogenic human papillomavirus is the necessary cause of cervical cancer and of a large fraction of vulvar cancers. The toll‐like receptor and the nuclear factor κB (NF‐κB) signaling pathways have been implicated in inflammation, autoimmune disease and cancer, but whether common nucleotide variation in these pathways is associated with the risk of cervical and vulvar cancers has received little study. Using data from a population‐based case–control study of cervical and vulvar cancers, we genotyped 205 single nucleotide polymorphisms (SNPs) in and around 32 candidate gene regions within these pathways. Gene‐based analyses were used to estimate the associations between individual gene regions and the risk of cervical and vulvar cancers. Odds ratio (OR) and 95% confidence intervals (CI) were calculated to assess the risk of cervical and vulvar cancers for each SNP. p‐Values were adjusted for multiple testing. A total of 876 cervical cancer cases, 517 vulvar cancer cases and 1,100 controls were included in the analysis. The TNF region was significantly associated with the risks of cervical cancer (gene‐based p‐value: 2.0 × 10^?4) and vulvar cancer (gene‐based p‐value: 1.0 × 10^?4). The rare allele (A) of SNP rs2239704 in the 5′ UTR of the LTA gene was significantly associated with increased risks of cervical cancer (OR = 1.31, 95% CI: 1.15–1.50; adjusted p‐value: 0.013) and vulvar cancer (OR = 1.51, 95% CI: 1.30–1.75; adjusted p‐value: 1.9 × 10^?5). These findings add to the evidence of the importance of the immune system in the etiology of cervical and vulvar cancers.     

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.     

Low‐risk variants FGFR2, TNRC9 and LSP1 in German familial breast cancer patients

To validate common low‐risk variants predisposing for breast cancer (BC) in a large set of BRCA1/2 negative familial or genetically enriched cases from Germany, we genotyped 1,415 cases and 1,830 healthy women by MALDI‐TOF in 105 candidate SNPs. Significantly higher ORs than previously reported for heterozygous unselected cases were found for the minor allele in FGFR2 (OR = 1.43, 95% CI 1.30‐1.59, p‐value = 1.24 × 10⁻¹²) and for TNRC9 (OR = 1.33, 95% CI 1.19‐1.46, p‐value = 1.54 × 10⁻⁷). Most intriguing, however, were the ORs for homozygous carriers from high‐risk families for FGFR2 (OR = 2.05, 95% CI 1.68–2.51, LSP1 (OR = 0.49, 95% CI 0.28–0.86) and TNRC9 (OR = 1.62, 95% CI 1.27–2.07). Moreover, the additional validation of 99 CGEMS‐SNPs identified putative novel susceptibility alleles within the LSP1 gene (OR = 0.73, 95% CI 0.61–0.87, p‐value = 5.23 × 10⁻⁴⁾. Finally, we provide evidence for the first time that a low‐risk variant located at 6q22.33 (rs6569479) is associated with estrogen receptor negative BC in familial cases (OR = 1.33, 95% CI 1.06–1.66; p‐value = 0.012). Our data confirm the impact of the previously identified susceptibility loci and provide preliminary evidence for novel susceptibility loci in familial BC cases and correlate them to specific histopathological subtypes defined by estrogen receptor status.     

The functional cytotoxic T lymphocyte-associated Protein 4 49G-to-A genetic variant and risk of pancreatic cancer

BACKGROUND:

Antitumor T lymphocytes play an essential part in immune surveillance of cancer cells. Cytotoxic T lymphocyte–associated Protein 4 (CTLA‐4) is a negative regulator of T cell activation and proliferation and therefore influences immune surveillance of carcinogenesis of pancreas. Thus, this study examined the association between functional CTLA‐4 49G‐to‐A (49G>A) single‐nucleotide polymorphism and pancreatic cancer risk.

METHODS:

Genotypes were determined in 368 patients with pancreatic cancer and 926 controls, and odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression.

RESULTS:

A significant increased risk of pancreatic cancer was found to be associated with the CTLA‐4 49G>A single‐nucleotide polymorphism. Compared with noncarriers, the OR of developing pancreatic cancer for CTLA‐4 49 GA or AA carriers was 1.75 (95% CI = 1.34‐2.30, P = 4.83 × 10^?5) or 2.54 (95% CI = 1.67‐3.87, P = 1.36 × 10^?5), respectively. In stratified analyses, the association was more pronounced in GA and AA carriers aged ≤60 years (OR = 3.10, 95% CI = 2.15‐4.47, P_interaction = .002), smokers with GA and AA genotypes (OR = 3.92, 95% CI = 2.39‐6.43, P_interaction = .037), and drinkers with GA and AA genotypes (OR = 4.55, 95% CI = 2.65‐7.82, P_interaction = .042), compared with GG carriers. Moreover, a supermultiplicative interaction between the CTLA‐4 49AA genotype and smoking plus drinking was also evident in intensifying risk of pancreatic cancer (P_interaction = 5.64 × 10^?12).

CONCLUSIONS:

These results suggest that CTLA‐4 49G>A polymorphism is involved in susceptibility to developing pancreatic cancer, alone and in a gene–environment interaction manner. Cancer 2012. © 2012 American Cancer Society.     

A copy number variation in PKD1L2 is associated with colorectal cancer predisposition in korean population

Recently reported genome‐wide association studies have identified more than 20 common low‐penetrance colorectal cancer (CRC) susceptibility loci. Recent studies have reported that copy number variations (CNVs) are considered important human genomic variants related to cancer, while the contribution of CNVs remains unclear. We performed array comparative genomic hybridization (aCGH) in 36 CRC patients and 47 controls. Using breakpoint PCR, we confirmed the breakpoint of the PKD1L2 deletion region. High frequency of PKD1L2 CNV was observed in CRC cases. We validated the association between PKD1L2 variation and CRC risk in 1,874 cases and 2,088 controls (OR = 1.44, 95% CI = 1.04–1.98, p = 0.028). Additionally, PKD1L2 CNV is associated with increased CRC risk in patients younger than 50 years (OR = 2.14, 95% CI 1.39–3.30, p = 5.8 × 10^?4). In subgroup analysis according to body mass index (BMI), we found that the CN loss of PKD1L2 with BMI above or equal to 25 exhibited a significant increase in CRC risk (OR = 2.29, 95% CI 1.29–4.05, p = 0.005). PKD1L2 CNV with BMI above or equal to 25 and age below 50 is associated with a remarkably increased risk of colorectal cancer (OR = 5.24, 95% CI 2.36–11.64, p = 4.8 × 10^?5). Moreover, we found that PKD1L2 variation in obese patients (BMI ≥ 25) was associated with poor survival rate (p = 0.026). Our results suggest that the common PKD1L2 CNV is associated with CRC, and PKD1L2 CNV with high BMI and/or age below 50 exhibited a significant increased risk of CRC. In obese patients, PKD1L2 variation was associated with poor survival.     

The protective role of polymorphism MKK4-1304 T>G in nasopharyngeal carcinoma is modulated by Epstein-Barr virus' infection status

MKK4 is a candidate tumor suppressor, which acts as a critical mediator of Epstein-Barr Virus (EBV)-induced c-Jun N-terminal kinase (JNK) activation. Functional polymorphism MKK4 -1304T>G has been showed to be protective in colorectal cancer or lung cancer. We hypothesized that genetic variants in the MKK4 promoter were associated with the risk of nasopharyngeal carcinoma (NPC). Two common polymorphisms in MKK4, -1304T>G and -1044A>T were genotyped in two independent case-control panels of Eastern and Southern Chinese populations, totally containing 1237 NPC and 1328 controls. We found that compared to the most common -1304TT genotype, carriers of variant genotypes (-1304TG+GG) were associated with a significantly reduced risk for NPC in total subjects (adjusted OR = 0.78; 95%CI = 0.67-0.94). Further stratification analysis showed that the protective effect was more pronounced in EBV negative status (adjusted OR = 0.51; 95%CI = 0.41-0.68) but restrained in those with EBV infection (adjusted OR = 1.05; 95%CI = 0.88-1.26), and that the -1304GG variant genotypes interacted with EBV negative status on reducing cancer risk (p = 0.011). However, no significant association was observed between the -1044A>T polymorphism and risk of NPC. Our data suggest that the protective role of genetic variant MKK4 -1304T>G is restrained in NPC with EBV infection. These findings implicate the role of EBV and MKK4 -1304 T>G interaction as a causative factor for the NPC.     

Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low‐density lipoprotein (LDL), and high‐density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP‐CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10⁻⁴). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92–1.18, p = 0.49), 0.94 (95% CI: 0.84–1.05, p = 0.27), and 0.98 (95% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3‐hydoxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR ) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.     

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.     

Possible association between polymorphisms of human vascular endothelial growth factor A gene and susceptibility to glioma in a Chinese population

Vascular endothelial growth factor A (VEGFA), one of the most predominant mediators of pathologic angiogenesis, plays a critical role in glioma carcinogenesis and development via promoting tumor growth. We hypothesized that VEGFA polymorphisms may influence glioma risk. We recently genotyped 9 VEGFA single‐nucleotide polymorphisms (SNPs) in 766 glioma patients and 824 cancer‐free controls selected from a Chinese population. We evaluated the glioma risk conferred by individual SNPs, haplotypes as well as cumulative SNP effect. In the single‐locus analysis, we found that rs2010963 (G+405C, G‐634C) [odds ratio (OR) = 1.29; 95% confidence interval (CI) = 1.04–1.58; GC/CC vs. GG] and rs3025030 (OR = 2.21; 95% CI = 1.18–4.14; CC vs. GG/GC) were associated with increased risk for glioma, and rs3024994 (OR = 0.66; 95% CI = 0.47–0.94; CT/TT vs. CC) was associated with reduced glioma risk, albeit insignificant after Bonferroni correction for multiple comparisons. The haplotype‐based analysis revealed that AGG in block 1 and ATT, ACT in block 2 were associated with 20–40% reductions in glioma risk. The inverse association of haplotype AGG containing rs2010963G remained significant after correction for multiple testing (p = 0.002, p_corrected = 0.022). The aforementioned 3 SNPs revealed a significant cumulative risk effect; the increased risk for glioma was 1.38‐fold for each additional adverse genotype he or she carries (p_trend = 8.4 × 10^?5). Our findings suggested that VEGFA variants may be involved in glioma risk. Larger studies with ethnically diverse populations are warranted to confirm the results reported in this investigation.     

An intron 4 VNTR polymorphism of the endothelial nitric oxide synthase gene is associated with early‐onset colorectal cancer

Endothelial‐derived nitric oxide, which is produced by endothelial nitric oxide synthase (eNOS), may play an important role in colorectal carcinogenesis. However, the putative contribution of common eNOS genetic polymorphisms to colorectal cancer risk remains unknown. We genotyped 3 polymorphisms of eNOS (T‐786C, G894T, and intron4b/a) in 727 colorectal adenocarcinoma cases and 736 age‐ and sex‐matched healthy controls in Taiwan. Genotypes of the T‐786C and G894T polymorphisms were determined by fluorescence polarization assays and the 27‐bp variable number of tandem repeat (VNTR) polymorphism in intron 4 (intron4b/a) was analyzed by PCR. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Among younger participants (≤60 yrs), the intron4a variant genotype was associated with a significantly increased risk of colorectal cancer, compared with the intron4bb genotype (OR = 1.60, 95% CI = 1.04–2.46). In addition, those young individuals bearing a greater number of high‐risk genotypes (OR > 1, i.e., CT+TT for T‐786C, ba+aa for intron4b/a, and GG for G894T) of eNOS had a higher colorectal cancer risk (p_trend = 0.039). Compared with younger individuals without any putative high‐risk genotypes, those with 3 high‐risk genotypes had a significantly greater cancer risk (OR = 1.89, 95% CI = 1.04–3.43). Our results suggest that the eNOS intron4b/a polymorphism may contribute to early‐onset colorectal cancer risk in the Taiwanese population. © 2008 Wiley‐Liss, Inc.     

Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early‐onset fluoropyrimidine toxicity

We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early‐onset fluoropyrimidine (FP) toxicity, in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129–5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP‐based chemotherapy. Associations of DPYD variants and haplotypes with hematologic, gastrointestinal, infectious, and dermatologic toxicity in therapy cycles 1–2 and resulting FP‐dose interventions (dose reduction, therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity‐related therapy delay or cessation were retrospectively examined for risk variants. The association of c.1129–5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.1129–5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% CI = 2.30–6.09, p = 2 × 10^?5) for severe toxicity (grades 3–5). Of 31 risk variant carriers (c.1129–5923C>G/hapB3, c.1679T>G, c.1905+1G>A or c.2846A>T), 11 (all with c.1129–5923C>G/hapB3) experienced severe toxicity (15% of 72 cases, RR = 2.73, 95% CI = 1.61–4.63, p = 5 × 10^?6), and 16 carriers (55%) required FP‐dose interventions. Seven of the 15 (47%) retrospective cases carried a risk variant. The c.1129–5923C>G/hapB3 variant is a major contributor to severe early‐onset FP toxicity in Caucasian patients. This variant may substantially improve the identification of patients at risk of FP toxicity compared to established DPYD risk variants (c.1905+1G>A, c.1679T>G and c.2846A>T). Pre‐therapeutic DPYD testing may prevent 20–30% of life‐threatening or lethal episodes of FP toxicity in Caucasian patients.     

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.     

Advanced colonic neoplasia in the first degree relatives of colon cancer patients: A colonoscopy‐based study

We aimed to determine the risk of advanced neoplasms among a cohort of asymptomatic first degree relatives (FDRs) of patients with sporadic colorectal cancer (CRC) compared with matched controls. Data for patients with a diagnosis of CRC made between September 2013 and August 2014 were obtained from a population‐based cancer registry system in Tehran. Screening colonoscopies were done for 342 FDRs and the findings were compared to those from 342 age‐ and gender‐matched healthy controls without a family history of CRC. We reported the association as conditional Odds Ratio (OR) using Mantel Hazel and Logistic regression. The prevalence of advanced neoplasia was 13.2% among FDRs and 3.8% in controls (matched OR [mOR], 4.0, 95% confidence interval [CI], 2.1 – 7.6; p < 0.001). In FDRs aged 40–49 years, the prevalence of advanced neoplasia was significantly higher than in their matched controls (mOR, 6.8, 95% CI, 1.5–31.4; p = 0.01). Family history of CRC in at least one FDR was the strongest predictor of advanced neoplasia (adjusted OR, 4.0, 95% CI: 2.1–7.6; p < 0.001). The age of the index case at diagnosis did not predict the presence of advanced colonic neoplasms in their FDRs. Our study indicates a high risk of advanced neoplasia in FDRs of CRC cases, where only eight colonoscopies are needed to detect one advanced neoplasia. Our data suggest that all FDRs, regardless of the age of CRC diagnosis in their index case, should be considered for a targeted early screening.     

Cumulative evidence for relationships between multiple variants in the VTI1A and TCF7L2 genes and cancer incidence

Genetic studies have linked the VTI1A‐TCF7L2 region with risk of multiple cancers. However, findings from these studies were generally inconclusive. We aimed to provide a synopsis of current understanding of associations between variants in the VTI1A‐TCF7L2 region and cancer susceptibility. We conducted a comprehensive research synopsis and meta‐analysis to evaluate associations between 17 variants in this region and risk of seven cancers using data from 32 eligible articles totaling 224,656 cancer cases and 324,845 controls. We graded cumulative evidence of significant associations using Venice criteria and false‐positive report probability tests. We also conducted analyses to evaluate potential function of these variants using data from the Encyclopedia of DNA Elements (ENCODE) Project. Eight variants showed a nominally significant association with risk of individual cancer (p < 0.05). Cumulative epidemiological evidence of an association was graded as strong for rs7903146 [odds ratio (OR) = 1.05, p = 4.13 × 10^?5] and rs7904519 (OR = 1.07, p = 2.02 × 10^?14) in breast cancer, rs11196172 (OR = 1.11, p = 2.22 × 10^?16), rs12241008 (OR = 1.13, p = 1.36 × 10^?10) and rs10506868 (OR = 1.10, p = 3.98 × 10^?9) in colorectal cancer, rs7086803 in lung cancer (OR = 1.30, p = 3.54 × 10^?18) and rs11196067 (OR = 1.18, p = 3.59 × 10^?13) in glioma, moderate for rs12255372 (OR = 1.12, p = 2.52 × 10^?4) in breast cancer and weak for rs7903146 (OR = 1.11, p = 0.007) in colorectal cancer. Data from ENCODE suggested that seven variants with strong evidence and other correlated variants might fall within putative functional regions. Collectively, our study provides summary evidence that common variants in the VTI1A and TCF7L2 genes are associated with risk of breast, colorectal, lung cancer and glioma and highlights the significant role of the VTI1A‐TCF7L2 region in the pathogenesis of human cancers.     

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.     

Aberrant immunoarchitecture distinguishes hyperplastic germinal centres in pattern 1 angioimmunoblastic T‐cell lymphoma from reactive follicles

We compare 30 biopsies each of Pattern 1 angioimmunoblastic T‐cell lymphoma (AITL1) and reactive lymphoid hyperplasia (RLH) by immunohistology, in‐situ hybridization for Epstein‐Barr virus‐encoded RNA and T‐cell receptor‐γ (TRG)‐clonality. AITL1 cases, more often than RLH controls, were older [median ages 61 (range 23–79) vs 46 (range 11–59) years, p < 10^‐4], non‐Chinese [16/30 (53%) vs 8/28 (29%), p = 0.035], presented nodally [29/30 (97%) vs 23/30 (77%), p = 0.024], showed: pan‐T cell antigen attenuation [25/29 (86%) vs 5/21 (24%), p = 1.0 × 10^‐5], CD4 predominance [25/28 (89%) vs 12/23 (52%), p = 3.4 × 10^‐3], interfollicular lymphoid CD10‐positivity [16/30 (53%) vs 1/29 (3%), p = 1.5 × 10^‐5], TRG clonality [16/28 (57%) vs 1/20 (5%), p = 1.4 × 10^‐4], higher maximum number of Epstein‐Barr virus‐encoded RNA + nuclei per 0.5‐mm high‐power field [median 6 (range 0–70) vs 1 (range 0–40), p = 0.012] and interfollicular Ki‐67 proliferation fraction [median 40% (range 10–80%) vs 20% (range 5–40), p < 10^‐4], whereas their germinal centres (GCs) more often showed attenuation of CD10 [30/30 (100%) vs 11/29 (38%), p = 5.3 × 10^‐8] and CD57 [18/25 (72%) vs 4/22 (18%), p = 2.4 × 10^‐4] (respectively). GC‐predominant PD‐1 and ICOS immunoreactivity were more often seen in RLH [20/22 and 9/19 controls (91% and 47%)] than AITL1 [9/25 and 3/19 cases (36% and 16%), p = 1.0 × 10^‐4 and 0.033, respectively]. Significant independent predictors against AITL1 were: solid GC CD10 immunoreactivity {p = 0.023, odds ratio (OR) for AITL1 0.01 [95% confidence interval (CI): 0.0002–0.529]}; lower interfollicular proliferation fraction [p = 0.047, OR for AITL1 1.1 (95% CI: 1.001–1.209) per % rise in Ki‐67]; younger presenting age [p = 0.028, OR for AITL1 1.136 (95% CI: 1.014–1.272) per year older]. Hence, GCs and perifollicular zones in AITL1 are distinct from those in RLH. Copyright © 2013 John Wiley & Sons, Ltd.