Wang, Zhaoming

PURPOSE Recent studies reveal that 5%-18% of children with cancer harbor pathogenic variants in known cancer-predisposing genes. However, DNA damage repair (DDR) genes, which are frequently somatically altered in pediatric tumors, have not been systematically examined as a source of novel cancer-predisposing signals. METHODS To address this gap, we interrogated 189 DDR genes for presence of germline predisposing variants (PV) among 5,993 childhood cancer cases and 14,477 adult noncancer controls (discovery cohort). PV were determined using a tiered approach incorporating ClinVar annotations, InterVar classification, and in silico tools (REVEL, CADD, and MetaSVM). Using logistic and firth regression, we identified genes with PV statistically enriched in the germline of children with tumors and replicated findings among 1,497 additional childhood cancer cases across three independent cohorts. RESULTS Analysis across all cases with cancer revealed enrichment of TP53 PV. Cancer-specific analyses confirmed known associations including germline TP53 PV in adrenocortical carcinoma, high-grade glioma (HGG), and medulloblastoma (MB), PMS2 in HGG and non-Hodgkin lymphoma (NHL), MLH1 in HGG, BRCA2 in NHL, and BARD1 in neuroblastoma. In addition, four novel associations were uncovered, including BRCA1 in ependymoma, SPIDR in HGG, SMC5 in MB, and SMARCAL1 in osteosarcoma (OS). Importantly, the SMARCAL1 :OS association was significant in the discovery (6/230, 2.6%, false discovery rate [FDR] logistic = 0.0189) as well as all three replication cohorts (Childhood Cancer Survivor Study: 8/275, 2.9%; P Fisher < .0001; Cancer Predisposition Syndrome-German Childhood Cancer Registry: 4/135, 3%, P Fisher = .002; Individualized Therapy for Relapsed Malignancies in Childhood: 4/217, 1.8%, P Fisher = .012). The remaining wild-type SMARCAL1 allele was deleted in three of four OS tumors with available data. CONCLUSION Our study confirms the relevance DDR genetic variation in pediatric cancer risk and establishes SMARCAL1 as a novel OS predisposing gene, providing insights into tumor biology and creating opportunities to optimize care for patients with this challenging tumor.

Abstract Obesity has been associated with non‐Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome‐wide association studies of European ancestry ( N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist‐to‐hip ratio (WHR), and waist‐to‐hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.18, 95% confidence interval (95% CI): 1.05–1.33, p = .005]. This finding was consistent with Mendelian randomization analyses, which demonstrated a similar increased risk of DLBCL with higher genetically determined BMI (OR per SD = 1.12, 95% CI: 1.02–1.23, p = .03). No significant associations were observed with other NHL subtypes. Our study demonstrates a positive link between a genetically determined BMI and an increased risk of DLBCL, providing additional support for increased adiposity as a risk factor for DLBCL.

Abstract Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni &lt; 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P &lt; 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

Abstract Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels ( P < 5 × 10 −8 ) were identified as instrumental variables, and assessed using genome‐wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non‐endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non‐endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non‐endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non‐endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age‐at‐diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age‐at‐diagnosis has been explored, genome‐wide association studies (GWAS) have not previously been stratified by age. Potential age‐specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18–53, 54–64, 65+) datasets were analyzed using age‐stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta‐analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54–63 = 1.50x10−9, OR54–63 = 1.28, 95%CI54–63 = 1.18–1.39; p64+ = 2.14x10−11, OR64+ = 1.32, 95%CI64+ = 1.21–1.43] and rs11979158 [p54–63 = 6.13x10−8, OR54–63 = 1.35, 95%CI54–63 = 1.21–1.50; p64+ = 2.18x10−10, OR64+ = 1.42, 95%CI64+ = 1.27–1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18–53 (p18–53 = 9.30 × 10−11, OR18–53 = 1.76, 95%CI18–53 = 1.49–2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of ‘LGG’‐like tumor characteristics in GBM samples in those 18–53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54–63] and 0.8% [64+] (p = 0.0005). Age‐specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18–53 suggests that more younger individuals may present initially with ‘secondary glioblastoma.’

Abstract Objective Genome-wide association studies (GWAS) identify associations of individual SNPs with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants has been shown for many disorders to be a powerful tool in discovering novel networks of susceptibility genes. Design We have conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product (sARTP) method to identify novel gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDA) in 9,040 cases and 12,495 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes identified in PDA-associated gene sets and pathways. Results We identified 14 gene sets and pathways associated with PDA at FDR &lt; 0.05. Five of the strongest signals (P-value ≤ 1.3x10-5 Bonferroni corrected) were in genes from KEGG maturity onset diabetes of the young, Reactome regulation of beta cell development, Biocarta role of epidermal growth factor (EGF) receptor transactivation by G-protein-coupled receptors in cardiac hypertrophy pathway, Nikolsky breast cancer chr17q11-q21 amplicon gene set, and Pujana ATM Pearson correlation coefficient (PCC) network gene set. We identified and validated rs876493 and three correlated SNPs (PGAP3) and rs3124737 (CASP7) as eQTLs in two normal derived pancreas tissue datasets. Conclusion Our agnostic gene set and pathway analysis integrated with functional annotation and eQTL analysis provides novel insight into genes and pathways that may be biologically relevant for risk of PDA. Citation Format: Naomi Walsh, Han Zhang, Paula L. Hyland, Qi Yang, Evelina Mocci, Mingfeng Zhang, Erica J. Childs, Zhaoming Wang, Stephen Chanock, Patricia Hartge, Robert Hoover, Peter Kraft, Donghui Li, Eric J. Jacobs, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Kai Yu, Alison P. Klein, Rachael Z. Stolzenberg-Solomon. Large pathway and gene set analysis of GWAS data identifies novel associations for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 242.

The improvement in survival of childhood cancer observed across the past 50 years has resulted in a growing acknowledgment that simply extending the lifespan of survivors is not enough. It is incumbent on both the cancer research and the clinical care communities to also improve the health span of survivors. It is well established that aging adult survivors of childhood cancer are at increased risk of chronic health conditions, relative to the general population. However, as the first generation of survivors age into their 50s and 60s, it has become increasingly evident that this population is also at risk of early onset of physiologic aging. Geriatric measures have uncovered evidence of reduced strength and speed and increased fatigue, all components of frailty, among survivors with a median age of 33 years, which is similar to adults older than 65 years of age in the general population. Furthermore, frailty in survivors independently increased the risk of morbidity and mortality. Although there has been a paucity of research investigating the underlying biologic mechanisms for advanced physiologic age in survivors, results from geriatric populations suggest five biologically plausible mechanisms that may be potentiated by exposure to cancer therapies: increased cellular senescence, reduced telomere length, epigenetic modifications, somatic mutations, and mitochondrial DNA infidelity. There is now a critical need for research to elucidate the biologic mechanisms of premature aging in survivors of childhood cancer. This research could pave the way for new frontiers in the prevention of these life-changing outcomes.

Objective Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions These data suggest several plausible genetic links between DLBCL and SLE.