Citations

ObjectiveMutations in Charcot–Marie–Tooth disease (CMT) genes are the cause of rare familial forms of polyneuropathy. Whether allelic variability in CMT genes is also associated with common forms of polyneuropathy—considered “acquired” in medical parlance—is unknown. Chemotherapy‐induced peripheral neuropathy (CIPN) occurs commonly in cancer patients and is individually unpredictable. We used CIPN as a clinical model to investigate the association of non‐CMT polyneuropathy with CMT genes.MethodsA total of 269 neurologically asymptomatic cancer patients were enrolled in the clinical trial Alliance N08C1 to receive the neurotoxic drug paclitaxel, while undergoing prospective assessments for polyneuropathy. Forty‐nine CMT genes were analyzed by targeted massively parallel sequencing of genomic DNA from patient blood.ResultsA total of 119 (of 269) patients were identified from the 2 ends of the polyneuropathy phenotype distribution: patients that were most and least susceptible to paclitaxel polyneuropathy. The CMT gene PRX was found to be deleteriously mutated in patients who were susceptible to CIPN but not in controls (p = 8 × 10−3). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p = 5 × 10−4). Three nonsynonymous recurrent single nucleotide variants contributed to the ARHGEF10 signal: rs9657362, rs2294039, and rs17683288. Of these, rs9657362 had the strongest effect (odds ratio = 4.8, p = 4 × 10−4).InterpretationThe results reveal an association of CMT gene allelic variability with susceptibility to CIPN. The findings raise the possibility that other acquired polyneuropathies may also be codetermined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT. Ann Neurol 2014;76:727–737

Abstract Tumor infiltrating regulatory T cells (Tregs) appear to play a role in survival in a number of solid tumors, including ovarian cancer. We assessed genetic variation via tag SNPs (N=749) in 25 Treg associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. SNPs were selected based on r2 ≥ 0.8, MAF ≥ 0.05, 5 kb upstream and downstream from the gene. We had SNP and outcome data for ovarian cancer from 10,084 combined ovarian cancer cases, including 5,248 high grade serous, 1,452 endometrioid, 661 mucinous, and 795 clear cell cases of European descent across multiple studies from the Ovarian Cancer Association Consortium (OCAC). Cox proportional hazards regression modeling was used to estimate per-allele hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with overall survival, adjusting for age at diagnosis, population substructure PCs, study site, histology (for the all case analysis), tumor stage, tumor grade and oral contraceptive use. The strongest associations were found for endometrioid histologic subtype and IL2RA SNPs (maximum r2=0.67) rs11256497 [HR=1.42, 95% CI: 1.22-1.64; p=5.7 x 10−6], rs791587 [HR=1.36, 95% CI: 1.17-1.57; p=6.2 x 10−5], rs2476491 [HR=1.40, 95% CI: 1.19-1.64; p=5.6 x 10−5], and rs10795763 [HR=1.35, 95% CI: 1.17-1.57; p=7.9 x 10−5], as well as clear cell ovarian cancer and CTLA4 SNP rs231775 [HR=0.67, 95% CI: 0.54-0.82; p=9.3 x 10−5]. No other associations were observed at p<1 x 10−4. Overall, this study provided evidence that variation in genes related to Tregs, particularly IL2RA and CTLA4, influence ovarian cancer survival. Citation Format: Bridget Charbonneau, Keith Knutson, Robert A. Vierkant, Julie M. Cunningham, Zachary C. Fogarty, Kimberly R. Kalli, Matthew J. Maurer, Ann L. Oberg, Brooke L. Fridley, Claudia C. Preston, Paul D.P. Pharoah, Susan J. Ramus, Catherine M. Phelan, Kunle Odunsi, Kirsten Moysich, Ellen L. Goode. Polymorphisms in regulatory T cell related genes and ovarian cancer survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4844. doi:10.1158/1538-7445.AM2013-4844

Abstract Background. Transmembrane transport (GO:0055085) is the process whereby a solute/hormone/ion/iron is transported from one side of a membrane to the other. Disruption of these processes leads to defects in homeostasis which contributes to cancer risk. We hypothesized that germline single nucleotide polymorphisms (SNPs) in the cellular transport genes are associated with EOC risk and histopathology subtype. Methods. We genotyped 305 SNPs from 120 cellular transport related genes in 14,525 cases and 23,448 controls of European ancestry, 387 African, and 2,388 Asian ancestries from 43 studies in the Ovarian Cancer Association Consortium (OCAC). A custom Illumina iSelect designed for the Collaborative Oncological Gene-environment Study (COGS) was used. For women of European ancestry, both invasive cancers combined and the four main histological subtypes (serous (n=8,369), mucinous (n=943), endometroid (n=2,067) and clear cell (n=1,024) carcinoma) were analyzed, while for women of African and Asian ancestry only the serous subtype was analyzed adjusting for study site and first 5 principal components. Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. We fitted a log-additive genetic model. Results. In women of European ancestry, the strongest evidence of an association for all invasive EOCs was the iron transport gene, HEPH rs17216603 (OR=0.85, 95%CI=0.78-0.93, P=2.8x10−4), which was also the most significant association for serous histological subtype (OR=0.81, 95%CI=0.73-0.91, P=2.0x10−4). For endometrioid EOC, the strongest association was observed in the glucuronidation gene, UGT1A5 rs11563251 (OR=0.82, 95%CI=0.73-0.92, P=6.6x10−4). For clear cell and mucinous EOC, the thyroid hormone transport protein, SERPINA7 rs1804495 showed the strongest associations (OR=1.06, 95%CI=1.06-1.38, P=0.0041) and (OR=0.85, 95%CI=0.73-0.98, P=0.0407), respectively. For women of African ancestry, the strongest association for serous EOC was the glutathione conjugation gene, MGST rs6488840 (OR=0.55, 95%CI=0.37-0.82, P=0.0035). This SNP was not significant in women of European or Asian ancestry. In women of Asian ancestry, the HEPH rs17216603 (OR=1.45, 95%CI=1.15-1.83, P=0.0019) demonstrated the strongest association, although the directionality of risk was reversed compared to European women. Conclusions. Our results suggest that variation in transmembrane transport genes may influence EOC risk and histopathologic subtype in women of European, African and Asian ancestries, highlighting the differences in the disease etiology across populations. Additional epidemiological and functional studies are warranted to elucidate translational and clinical utility of these associations. Citation Format: Ganna Chornokur, Jonathan Tyrer, Hui-Yi Lin, Gang Han, Xiaotao Qu, Chen Zhihua, Ya-Yu Tsai, Ellen L. Goode, Julie M. Cunningham, Edwin Iversen, Susan J. Ramus, Andrew Berchuk, Joellen M. Schildkraut, Alvaro Monteiro, Simon A. Gayther, Steven A. Narod, Paul Pharoah, Thomas A. Sellers, Catherine M. Phelan. Variation in transmembrane transport genes influence epithelial ovarian cancer risk and histopathologic subtype. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3644. doi:10.1158/1538-7445.AM2013-3644