Cross-cancer pleiotropic analysis of endometrial cancer: PAGE and E2C2 consortia

Setiawan, Veronica Wendy; Schumacher, Fredrick; Prescott, Jennifer; Haessler, Jeffrey; Malinowski, Jennifer; Wentzensen, Nicolas; Yang, Hannah; Chanock, Stephen J.; Brinton, Louise A.; Hartge, Patricia; Lissowska, Jolanta; Park, S. Lani; Cheng, Iona; Bush, William S.; Crawford, Dana C.; Ursin, Giske; Horn‐Ross, Pamela L.; Bernstein, Leslie; Lu, Lingeng; Risch, Harvey A.; Yu, Herbert; Sakoda, Lori C.; Doherty, Jennifer A.; Chen, Chu; Jackson, Rebecca D.; Coté, Michele L.; Kocarnik, Jonathan; Peters, Ulrike; Kraft, Peter; Vivo, Immaculata De; Haiman, Christopher A.; Kooperberg, Charles; Marchand, Loı̈c Le

doi:10.1093/carcin/bgu107

Cited by 18 publications

(17 citation statements)

References 43 publications

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“…9–11 Germline TET2 variants are associated with an increased risk of prostate 12,13 and endometrial 7 cancers, and melanoma. 8 Thus, germline and somatic alterations implicate TET2 as a cancer gene in MPDs and epithelial cancers.…”

Section: Introductionmentioning

confidence: 99%

TET2 binds the androgen receptor and loss is associated with prostate cancer

Nickerson

Das

et al. 2016

Oncogene

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Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumor genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumors in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5–15% of myeloid, kidney, colon and prostate cancers. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We performed fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identified six new risk variants in introns 1 and 2. Oligonucleotides containing two risk variants were bound by the transcription factor octamer-binding protein 1 (Oct1/POU2F1) and TET2 and Oct1 expression were positively correlated in prostate tumors. TET2 is expressed in normal prostate tissue and reduced in a subset of tumors from the Cancer Genome Atlas (TCGA). Small interfering RNA (siRNA)-mediated TET2 knockdown (KD) increases LNCaP cell proliferation, migration, and wound healing, verifying loss drives a cancer phenotype. Endogenous TET2 bound the androgen receptor (AR) and AR-coactivator proteins in LNCaP cell extracts, and TET2 KD increases prostate-specific antigen (KLK3/PSA) expression. Published data reveal TET2 binding sites and hydroxymethylcytosine (hmC) proximal to KLK3. A gene co-expression network identified using TCGA prostate tumor RNA-sequencing identifies co-regulated cancer genes associated with 2-oxoglutarate (2-OG) and succinate metabolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated BAP1, and citric acid cycle enzymes IDH1/2, SDHA/B, and FH. The co-expression signature is conserved across 31 TCGA cancers suggesting a putative role for TET2 as an energy sensor (of 2-OG) that modifies aspects of androgen-AR signaling. Decreased TET2 mRNA expression in TCGA PCa tumors is strongly associated with reduced patient survival indicating reduced expression in tumors maybe an informative biomarker of disease progression and perhaps metastatic disease.

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Section: Introductionmentioning

confidence: 99%

TET2 binds the androgen receptor and loss is associated with prostate cancer

Nickerson

Das

et al. 2016

Oncogene

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“…To our knowledge, this is the first study to investigate pleiotropic associations of cancer GWAS loci on risks of EA and BE. Although our study sample size is moderate, the combined number of EA and BE cases is larger than that of most previous studies on cancer pleiotropy (4, 7-9). For SNPs with MAF of 0.3 (the average MAF of all tested SNPs), we had 80% statistical power to detect an OR of 1.21 per minor allele for analyses on EA/BE combined, with a Bonferroni-corrected type I error rate of 5%.…”

Section: Discussionmentioning

confidence: 88%

“…Studies investigating pleiotropic effects of GWAS-identified risk variants have revealed additional risk loci for endometrial, colorectal, and pancreatic cancer, but not for estrogen-receptor (ER)-negative breast cancer (ER-positive cancers were not investigated), prostate cancer, or non-Hodgkin lymphoma (4, 7-9). Some studies, including those of non-Hodgkin lymphoma, endometrial cancer, and colorectal cancer, investigated cancer GWAS hits while studies of pancreatic cancer, prostate cancer, and ER-negative breast cancer investigated cancer and non-cancer GWAS-hits (4, 7-9).…”

Section: Discussionmentioning

confidence: 99%

“…Some studies, including those of non-Hodgkin lymphoma, endometrial cancer, and colorectal cancer, investigated cancer GWAS hits while studies of pancreatic cancer, prostate cancer, and ER-negative breast cancer investigated cancer and non-cancer GWAS-hits (4, 7-9). Our investigation based on cancer GWAS SNPs is not supportive of shared genetic susceptibility between EA/BE and other cancer sites.…”

Section: Discussionmentioning

confidence: 99%

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Pleiotropic Analysis of Cancer Risk Loci on Esophageal Adenocarcinoma Risk

Lee

Stram

et al. 2015

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus (BE). Methods We examined the associations between risks of EA and BE and 387 single nucleotide polymorphisms (SNPs) that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 BE) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. Results After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or BE. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. Conclusions Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or BE. Impact To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and BE.

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“…This genome-wide pleiotropy scan approach has previously yielded novel associations for risk of pancreatic adenocarcinoma [11] and endometrial [12] and colorectal cancer [13]. The hypothesized pleiotropic effects (when a genetic locus is associated with multiple phenotypes or phenotypic traits) [14] are especially meaningful in cancer.…”

Section: Introductionmentioning

confidence: 99%

A Genome-wide Pleiotropy Scan for Prostate Cancer Risk

Panagiotou¹,

Travis²,

Campa³

et al. 2015

European Urology

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Background No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS). Objective To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer. Design, setting, and participants SNPs implicated in any phenotype other than prostate cancer (p ≤ 10−7) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24 534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Outcome measurements and statistical analysis Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated. Results and limitations A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p = 1.6 × 10-6), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95%CI 1.16–1.27; p = 3.22 × 10−18). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86–0.94; p = 2.5 × 10−6). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12,95% CI 1.06–1.19; p = 4.67 × 10−5); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL. Conclusions We did not identify new SNPs for aggressive prostate cancer. However, rs16844874 may provide preliminary genetic evidence on the role of the glycine pathway in prostate cancer etiology. Patient summary We evaluated whether genetic variants associated with several traits are linked to the risk of aggressive prostate cancer. No new such variants were identified.

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Cross-cancer pleiotropic analysis of endometrial cancer: PAGE and E2C2 consortia

Cited by 18 publications

References 43 publications

TET2 binds the androgen receptor and loss is associated with prostate cancer

TET2 binds the androgen receptor and loss is associated with prostate cancer

Pleiotropic Analysis of Cancer Risk Loci on Esophageal Adenocarcinoma Risk

A Genome-wide Pleiotropy Scan for Prostate Cancer Risk

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