Issa, Jean‐Pierre J.

Abstract Introduction Epigenetic changes are reversible features of the genome that regulate gene transcription and protein expression on several levels including DNA methylation, histone modification or miRNA expression. We investigated the association between inherited variation in genes of key epigenetic processes and risk of multiple cancers within the GAME-ON consortium. Methods We performed a pathway based meta-analysis using genotypes from more than 50,000 cases of breast, lung, prostate, ovarian and colorectal cancer cases and more than 60,000 controls from various genome wide association studies participating in the GAME-ON consortium to estimate associations with cancer risk. Using the 1000GenomeProject database, we selected 505,702 genotyped and imputed single nucleotide polymorphisms in 551 genes (flanking region +/- 250kb) related to DNA methylation, histone modification or chromatin remodeling based on GO and GeneCard databases. In order to allow variants to be associated with only a subset of traits we used subset based meta-analysis. False-discovery rate (FDR) corrected p-values (q-values) lower than 0.05 were considered significant. Results and Discussion 582 SNPs were significantly associated with risk of at least one cancer. We identified nine major regions that showed significant associations with more than one cancer type. Among the most interesting regions was the region around PHC3 (3q36), which showed associations with prostate and colorectal cancer and clear cell ovarian carcinomas. PHC3 is involved in chromatin remodeling and plays a role in epithelial neoplasms. Significant Odds ratios (ORs) ranged from 0.80 to 1.31. The number of risk and protective alleles in this region was similarly distributed (19 and 18, respectively). One of the strongest associations was observed for rs76925190 (intronic in PRKC1), which increased the risk of colorectal and prostate cancer (q-value 4.28*10-10). Variants in this region were previously associated with prostate cancer. Polymorphisms in the region (19q13) around BABAM1 (RISC and BRCA1 A complex member 1), were associated with lung, breast, ovarian and prostate cancer. BABAM1 is associated with the BRCA1-complex. Its function in histone modification and DNA repair emphasizes its importance in carcinogenesis. Significant ORs ranged from 0.88 to 1.14 with similar distribution of risk and protective alleles in this region (19 and 17, respectively). The strongest association was observed for rs4808076 (intronic in ANKLE1), which increased the risk of squamous lung, serous ovarian and ER- -breast cancer (q-value 2.40*10-6). Variants in this region were previously associated with risk of breast and ovarian cancer. Conclusions This study emphasizes the importance of variants in genes of epigenetic processes on cancer risk and further provides insights into novel, pleiotropic epigenetic mechanisms of cancer development. Citation Format: Dominique Scherer, Reka Toth, Linda Kelemen, Angela Risch, Aditi Hazra, Jean Pierre Issa, Victor Moreno, Rosalind A. Eeles, John Quackenbush, Ellen L. Goode, Shuji Ogino, Rayjean Hung, Cornelia M. Ulrich. Genetic variants in epigenetic pathways and risk of multiple cancer types in the GAME-ON consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4612. doi:10.1158/1538-7445.AM2015-4612

Abstract SGI-110 is a novel second generation HMA, formulated as a low volume SQ injection. It is designed as a dinucleotide incorporating decitabine and guanosine, to prolong in vivo exposure and potentially improve efficacy of its active component, decitabine by protecting decitabine from rapid deamination by cytidine deaminase. Preclinically, SGI-110 demonstrated potent activity in-vivo using different routes of administration. A randomized Phase 1-2 FIH PK/PD-guided, dose-escalation study is being conducted in subjects with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage of the study is to determine the safety and tolerability of SGI-110 and to establish the MTD and the biologically effective dose (BED). Subjects are randomized to one of two SQ regimens (daily x5 or once weekly x3, both given in 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage of the study will be a randomized Phase 2 dose expansion, once the BED and MTD have been determined. Currently, 5 dose-cohorts have been fully enrolled, (n= 55) at doses ranging from 3mg/m2 to 60 mg/m2 daily x5, and 6mg/m2 to 90 mg/m2 weekly x3 but are not yet fully evaluable. PK guidance has allowed rapid dose escalation, and PD assessment of global hypomethylation has been correlated with increased dose and exposure levels. Apart from manageable local injection site pain, SGI-110 has been well tolerated. Other AE's were neutropenia, thrombocytopenia, or anemia. There have been 3 remissions in relapsed AML subjects: 1 CR with weekly (60mg/m2) and 1 PR and 1 CR with daily (36 and 60 mg/m2 respectively). The PK profile showed efficient conversion of SGI-110 to decitabine achieving exposures in the therapeutic range as predicted from the SGI-110 rational design, characterized by decitabine AUC in therapeutic range (cohorts 4-5), lower Cmax, and longer effective half life, as compared to historical data based on molar equivalent doses of IV decitabine. Dose-dependent hypomethylation induction in the first 5 cohorts was observed. The subject who achieved a CR had the highest degree of hypomethylation induction of all subjects tested to date, and also the highest decitabine AUC in the cohort. Updated efficacy, safety, PK, and PD data of both regimens will be presented. SGI-110 is safe and well tolerated to date; biologically effective and therapeutic dose levels have been achieved with little toxicity so far with both regimens. Preliminary efficacy (PR+CR) has been observed in relapsed AML subjects. The PK profile showed efficient conversion of SGI-110 to decitabine with achievable therapeutic exposures, longer apparent half life, and lower Cmax than predicted equivalent decitabine doses given IV. Global Hypomethylating effects were observed at all dose levels, evaluated to date with both regimens. The results justify the progress of the study to the second dose-expansion Phase 2 stage after establishing the BED and MTD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-214. doi:1538-7445.AM2012-LB-214