Citations

Abstract Both genetic and epigenetic factors influence the development and progression of epithelial ovarian cancer (EOC). However, there is an incomplete understanding of the interrelationship between these factors and whether they interact to impact disease risk. Given that the development of ovarian cancer is complex, we aimed to identify DNA methylation marks that are candidates for mediating ovarian cancer genetic risk. We used 214 cases and 214 age-matched controls from the Mayo Clinic Ovarian Cancer Study. Pretreatment, blood-derived DNA was profiled for genome-wide methylation (Illumina Infinium HumanMethylation27 BeadArray) and single nucleotide polymorphisms (SNPs, Illumina Infinium HD Human610-Quad BeadArray). We employed a three-step filtering procedure, followed by the Causal Inference Test (CIT), to distinguish CpG sites that mediate genetic risk, from those that are consequential or independently acted on by genotype. Controlling for the estimated distribution of immune cells and other key covariates, we identified 1,993 out of 25,926 (7.7%) CpGs that were significantly differentially methylated between cases and controls (FDR, q < 0.05). The relationship between methylation and case-control status among these 1,993 CpGs was found to be highly consistent with the results of an independent study. Implementation of the CIT test revealed 13 CpG/SNP pairs, comprising 13 unique CpGs and 17 unique SNPs, which represent potential methylation-mediated relationships between genotype and EOC risk. These findings provide additional insight into EOC etiology and may serve as novel biomarkers for EOC susceptibility. Citation Format: Devin C. Koestler, Prabhakar Chalise, Mine S. Cicek, Julie M. Cunningham, Sebastian Armasu, Melissa C. Larson, Jeremy Chien, Matthew Block, Kimberly R. Kalli, Thomas A. Sellers, Ellen L. Goode, Brooke L. Fridley. Integrative genomic analysis identifies epigenetic marks that mediate genetic risk for epithelial ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 260. doi:10.1158/1538-7445.AM2014-260

Abstract Introduction: Current models to predict breast cancer risk do not differentiate risk for estrogen receptor (ER) positive and negative breast cancer (BC), despite growing evidence that these tumors are biologically very different. We hypothesized that women with ER+ BC cancers have different clinical risk factors and histologic findings on prior benign breast biopsies than those with ER- BC. Methods: After IRB approval, we examined associations of age at benign biopsy and histologic features of the benign biopsy with ER status of incident BCs within the Mayo Benign Breast Disease Cohort. Benign biopsy slides were reviewed for extent of lobular involution and degree of epithelial proliferation by a single breast pathologist blinded to BC events. Invasive BCs occurring within 15 years after benign biopsy were classified as ER+ if ER staining was >1%. BC case-only associations with ER status were evaluated using multivariate logistic regression. Full-cohort hazard ratios (HR) and 95% confidence intervals (CI) for risk of ER-specific subtypes were estimated using Cox proportion hazards regression. Results: Among 13,410 women undergoing a benign breast biopsy from 1967-2001, 656 invasive BCs (459 ER+, 106 ER, 106 unknown) occurred within 15 years. Women who developed ER+ and ER- BCs were similar in age at the time of their prior benign breast biopsy (p=0.34). Although benign biopsies in women who later developed ER+ BC were more likely to show complete involution (23% vs 15% for ER- BC), this was not statistically significant (p=0.06). However, the degree of epithelial proliferation was significantly associated with ER status of later BCs (p=0.001), with ER+ BCs more likely than ER- BCs to have had a prior biopsy with atypical hyperplasia (16% vs 8%), and ER+ BCs less likely than ER- BCs to have had a prior biopsy with proliferative disease without atypia (33% vs 52%); this association remained after multivariate adjustment (p=0.003). We further pursued the association of epithelial proliferation with differential risk of ER+ and ER- BC in our overall cohort of 13,410 women (Table 1). Compared to women with non-proliferative disease, women with proliferative disease +/- atypia had ∼2-fold hazard ratios for ER- BC, whereas hazard ratios for ER+ BC were higher in women with atypical hyperplasia (∼4-fold) compared to proliferative disease. Hazard Ratio of ER+ and ER- BC within 15 years of BBD based upon degree of epithelial proliferation at benign biopsyCancer TypeGroupNN EventsHazard Ratio (95% CI)p-valueInvasive ER- ≤15 yearsNP8478421.00 (ref)<0.0001 PD4229542.63 (1.76, 3.93) AH70382.60 (1.22, 5.54) Invasive ER+ ≤15 yearsNP84782321.00 (ref)<0.0001 PD42291511.33 (1.09, 1.64) AH703744.41 (3.39, 5.73) NP=nonproliferative disease, PD=proliferative disease without atypia; AH=atypical hyperplasia Conclusion: ER+ and ER- breast cancers appear to have different features on prior benign breast biopsy, with atypical hyperplasia showing increased risk for both types of breast cancer, but a greater risk for ER+ tumors. Citation Format: Amy C Degnim, Derek C Radisky, Robert A Vierkant, Ryan D Frank, Marlene H Frost, Vernon S Pankratz, Celine M Vachon, Tanya L Hoskin, Julie M Cunningham, Chen Wang, Jean-Pierre Kocher, Teresa M Allers, Joanne L Johnson, Tina J Hieken, Karthik Ghosh, Lynn C Hartmann, Daniel W Visscher. Histologic features of benign breast biopsy tissue and association with ER positive and ER negative breast cancer in the Mayo BBD cohort study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-06.

Abstract Introduction: Peripheral blood leukocyte (PBL) telomere length is associated with colon cancer (CC) risk, but the relationship of PBL telomere length to survival in CC patients receiving chemotherapy is unknown. Methods: We measured relative telomere length (RTL) by qPCR of PBL DNA from 2,748 cases (53% male, 85% white, median age 58 yrs) in the North American Phase III Intergroup Trial N0147 that compared disease-free survival (DFS) among completely resected Stage III CC treated with mFOLFOX6 +/- cetuximab. Tumor markers were assessed, and 12% were BRAF mutant; 35% Kras mutant, and 12% deficient mismatch repair (dMMR). Linear and non-linear prognostic associations of PBL RTL to the primary endpoint of DFS were assessed by Cox models. Optimal categories of RTL were developed using cumulative martingale residual plots, designated from shortest to longest RTL (Table 1). Results: Never smokers had longer PBL RTL (p = 0.0006) than past or current smokers. Those with diabetes mellitus (DM) had longer PBL RTL than those without DM (p = 0.0165). PBL RTL was not associated with any tumor markers (MMR status; p = 0.7174; BRAF mutant vs wild-type (wt); p =0.4039; Kras mutant vs wt; p= 0.1149). PBL RTL was significantly associated with DFS in a non-linear form (p = 0.0389). Cases in the longer RTL category had more favorable DFS than those with shorter or longest RTL, (Table), which remained after adjusting for age, sex , T/N stage, grade, tumor markers, and treatment (p = 0.0230). We observed no significant interaction (p = 0.1490) between RTL categories and treatment. Conclusion: We observed a non-linear association between RTL and DFS in stage III CC, suggesting that an optimal range telomere length can influence tumor behavior in CC patients. Future studies of telomere maintenance mechanisms may help to explain the association of RTL with improved DFS. RTL is associated with smoking and DM in CC cases but further studies are needed to determine if either tobacco use or DM affect survival from CC by modulating PBL telomere length. Citation Format: Nivedita Basu, Ruth A. Johnson, Qian Shi, Garth D. Nelson, Julie M. Cunningham, Richard M. Goldberg, Frank A. Sinicrope, Daniel J. Sargent, Steven R. Alberts, Gloria M. Petersen, Stephen N. Thibodeau, Halcyon G. Skinner, Kristin Litzelman, Songwon Seo, Russell J. Vanderboom, Ronald E. Gangnon, Corinne D. Engelman, David N. Rider, Lisa A. Boardman. Telomeres and survival in stage III colon cancers: Findings from NCCTG N0147 (Alliance) study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5102. doi:10.1158/1538-7445.AM2014-5102

Abstract Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P < 10−5). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk. Cancer Res; 75(12); 2457–67. ©2015 AACR.

Key PointsThe NF-κB subunits p52 and RelB increase IRF4 promoter activity and expression in PTCL cells. A positive feedback loop involving CD30, NF-κB, and IRF4 drives PTCL cell proliferation and can be blocked by NF-κB inhibitors.

Opioids are a well-established treatment option for chronic pain. However, opioid therapy is associated with many side effects, including opioid induced hyperalgesia (OIH). This article reviews studies which have evaluated OIH in chronic pain patients on opioids.

Abstract Purpose: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. Experimental Design: We used unpublished survival time data for 2,242 patients from two case–control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. Results: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%–31%] for non-carriers, 25% (95% CI, 22%–28%) for BRCA1 carriers, and 35% (95% CI, 30%–41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer–specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers. Clin Cancer Res; 21(3); 652–7. ©2014 AACR.

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