Citations

Abstract Background: Genetic and environmental factors influence colorectal cancer (CRC) risk. Previous studies have provided additional etiologic insight by examining multiplicative gene-environment interactions for individual susceptibility loci. However, individual loci confer only modest risks, which may limit statistical power and clinical significance. A genetic risk score comprising known CRC loci may provide a more comprehensive assessment of risk. Further, there is a paucity of data on the role of additive gene-environment interactions, which may have greater public health implications than multiplicative interactions. We thus evaluated both additive and multiplicative interactions between a genetic risk score and 15 key environmental factors on risk of CRC. Methods: We conducted an analysis of 10,491 CRC cases and 10,725 controls of European ancestry in 7 cohort and 6 case-control studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) or Colon Cancer Family Registry (CCFR). To provide a global measure of genetic predisposition, information across multiple risk variants was combined by calculating a genetic risk score based on 24 polymorphisms near 21 genetic loci identified in previous genome-wide association studies. For the genetic score and environmental factors, the reference category corresponded to that associated with lower CRC risk. We tested for additive interactions by estimating relative excess risk due to interactions (RERIs) using logistic regression; for multiplicative interactions we used an empirical-Bayes approach. Nominal P values ≤ 0.05 were considered statistically significant. Results: After adjustment for age, sex, center, study, principal components, and total energy, as appropriate, we observed super-additive gene-environment interactions for CRC risk between the genetic risk score and body mass index (RERI=0.15; 95% CI: 0.00-0.31), ever smoking (RERI=0.14; 95% CI: 0.00-0.28), pack-years of smoking (RERI=0.23; 95% CI: 0.05-0.41), postmenopausal hormone therapy use (RERI=0.38; 95% CI: 0.17-0.59), and intake of processed meat (RERI=0.23; 95% CI: 0.06-0.40). Of the 15 environmental risk factors, 12 showed RERIs > 0 – suggesting an overall trend toward super-additive interactions for these factors. In addition, we observed evidence of sub-multiplicative interactions for use of aspirin and non-steroidal anti-inflammatory drugs. There were no other statistically significant multiplicative interactions. Conclusions: We observed evidence for super-additive effects of genetic predisposition and environmental risk factors on risk of CRC. Our findings suggest that certain environmental risk factors have stronger effects on absolute risk among individuals with higher genetic risk of CRC. If confirmed in future studies, these results may have implications for targeted prevention strategies. Citation Format: Mengmeng Du, Sonja I. Berndt, Hermann Brenner, Bette J. Caan, Peter T. Campbell, Graham Casey, Andrew Chan, Jenny Chang-Claude, Stephen J. Chanock, Nilanjan Chatterjee, David V. Conti, David Duggan, Jane C. Figueiredo, Steven Gallinger, Jian Gong, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Michael Hoffmeister, John L. Hopper, Li Hsu, Thomas J. Hudson, Carolyn M. Hutter, Eric J. Jacobs, Mark A. Jenkins, Shuo Jiao, Laurence N. Kolonel, Peter Kraft, Loic Le Marchand, Mathieu Lemire, Yi Lin, Noralane M. Lindor, Polly A. Newcomb, John D. Potter, Robert E. Schoen, Fredrick R. Schumacher, Daniela Seminara, Martha L. Slattery, Stephen N. Thibodeau, Cornelia M. Ulrich, Aung Ko Win, Emily White, Brent W. Zanke, Ulrike Peters. Additive and multiplicative gene-environment interactions for colorectal cancer risk. [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 4831. doi:10.1158/1538-7445.AM2013-4831

Abstract Definitive radiotherapy combined with chemotherapy is associated with enhanced locoregional control and clinical outcomes in non-small cell lung cancer (NSCLC) patients who are not candidates for surgery. However, radiation-induced pneumonitis and esophagitis are common dose-limiting inflammatory conditions that occur in these patients. These events can compromise the effect of the overall treatment and reduce quality of life in these patients. It is not clear what factors contribute to differences in the development of toxicities among patients with same clinical or dosimetric parameters. In this study, we conducted a large scale pathway-based analysis to identify inflammation-related genetic variants associated with radiation-induced pneumonitis or esophagitis. In the initial discovery phase, 11,930 inflammation-related genetic variants were genotyped in 243 stage I-III NSCLC patients who were treated with definitive radiotherapy at MD Anderson Cancer Center. A fast-track validation was performed for the top candidate SNPs in an additional 212 NSCLC cases following the same criteria. A total of 14 SNPs and 12 SNPs were validated for pneumonitis and esophagitis, respectively. Meta-analysis was used to summarize the results from two phases. The most significant SNPs for esophagitis and pneumonitis mapped to chromosome 18p (OR=9.05, 95%CI=2.68-30.59, P-meta=3.90×10−4) and 14q (OR=4.75, 95%CI=2.17-10.41, P-meta =9.61×10−5), respectively. To explore the potential underlying mechanisms, we analyzed radiation sensitivity and eQTL relationships of the identified SNPs and their host genes in 277 ethnically defined human lymphoblastoid cell lines. Among the 24 host genes for the 26 identified SNPs, three genes (DDX58, GZMB, CDC2) showed significant association with radiation responses in these cell lines (P<0.05). Moreover, a significant eQTL relationship was identified between CDC2 expression and the genotype of the identified CDC2 SNP (P=0.022). Interestingly, this CDC2 SNP is predicted to create a new miRNA binding site. Luciferase reporter assays to test the influence of this SNP on miRNA regulation is currently ongoing. Our results provide evidence that inflammation-related genetic variants contribute to the development of radiation-induced pneumonitis and esophagitis. The results also suggest that gene expression changes through altered miRNA binding may be an underlying mechanism for these events. Citation Format: Xia Pu, Liewei Wang, Michelle AT Hildebrandt, Yuanqing Ye, Joe Y. Chang, Charles Lu, Heath D. Skinner, Nifang Niu, Gregory D. Jenkins, Ritsuko Komaki, John D. Minna, Jack A. Roth, Richard M. Weinshilboum, Xifeng Wu. Inflammation-related genetic variants predict radiation-induced toxicity following definitive radiotherapy for non-small cell lung cancer. [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 3626. doi:10.1158/1538-7445.AM2013-3626

Abstract We have recently reported that in patients with HER2-positive breast cancer, neoadjuvant targeted therapy with lapatinib and trastuzumab to more completely block the HER receptor layer, combined with endocrine therapy (in ER-positive tumors) and without chemotherapy led to a substantial 27% pathologic complete response (pCR) rate in the breast. Activation of downstream signaling pathways may lead to resistance to therapies targeting the HER pathway receptors. Aberrant activation of the PI3K pathway via decreased levels of PTEN and/or the presence of activating PIK3CA mutations has been implicated in resistance to targeted anti-HER2 therapy, but results of clinical trials are all confounded by the co-administration of chemotherapy and are inconsistent. We sought to clarify the role of these variables in predicting pCR, a surrogate for long-term outcome, in patients treated with potent targeted therapy alone in a prospective Phase II neoadjuvant trial in patients with HER2-positive breast cancer. Patients with large tumors (median 6 cm) were given 12 weeks of lapatinib plus trastuzumab followed by surgery (Rimawi et al. JCO, 2013). Serial tissue biopsies were obtained from study participants. For this study, we focused on baseline pre-treatment characteristics. PTEN protein levels were measured by IHC and scored using the H-score. PIK3CA mutations were identified on extracted DNA using multiplex PCR with targeted next generation sequencing (the Ion Torrent 50-gene cancer mutation panel). Of 64 evaluable patients, tissue was available on 59 for PTEN IHC, and sufficient DNA was available on 33 for the mutation panel. PTEN median H-score was 100 (range 0-300). PTEN status when dichotomized by the median was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). Activating PIK3CA mutations were identified in 12 out of 33 tumors (36%; 3 mutations in the helical and 9 in the catalytic domain) and were independent of ER status. None of the patients whose tumors harbored a PIK3CA mutation achieved pCR (p = 0.06). There was no association between PTEN status and PIK3CA mutation suggesting they are independent variables (p = 0.44). When PIK3CA mutations were considered together with PTEN status, there were 31 cases with data on both. The overall pCR rate in this cohort was 16% (lower than pCR rate observed in the overall trial). However, 0/17 cases (0%) with a mutation and/or PTEN low expression (<100 H score) had a pCR compared to 5/14 cases (36%) with PI3KCA wild type and high PTEN levels (p = 0.01). We conclude that PI3K pathway activation downstream of HER2 as a result of either low PTEN or activating PIK3CA mutation results in resistance to the combination of lapatinib and trastuzumab. This is the first report on patient tissue samples from a neoadjuvant trial using the combination of lapatinib and trastuzumab without chemotherapy. If validated in a larger cohort, our findings suggest that patients with HER2 positive tumors and who also harbor aberrant downstream PI3K pathway activation may benefit from the addition of PI3K/Akt/mTOR inhibitors to potent HER2 blockade. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-2.

Abstract Human chromosome 13q14 is one of the hotspots of chromosomal deletion in prostate cancer, multiple myeloma, and chronic lymphocytic leukemia. Chromosome Condensation 1-like (CHC1L) is an uncharacterized gene in this region. CHC1L is found within the smallest common region of loss of heterozygosity in prostate cancer, and its decreased expression is linked to pathogenesis and progression of both prostate cancer and multiple myeloma. In the present study, we describe the generation and characterization of Chc1L gene knockout mice. Knockout mice develop normally and display an exaggerated proliferative response to LPS stimulation of cultured bone marrow and spleen cells at ten weeks of age. At approximately two years of age, both homozygous and heterozygous mice have markedly increased incidence of tumorigenesis, 80% and 56% respectively, compared to wild-type mice, 26%. The tumors are distributed most commonly to the spleen, mesenteric lymph nodes, liver and small intestine. The morphologic and immunophenotypic features of the tumor cells are consistent with those of tissue histiocytes, and most Chc1L knockout and heterozygote mice succumb to either Histiocytic Sarcoma or Histiocyte-Associated Lymphoma. These data provide the first direct evidence that Chc1L is a tumor suppressor gene involved in suppression of histiocyte-rich neoplasms. Citation Format: David Spillane, Ding Yan Wang, Changxin Shi, Youdong Wang, Anthony Gramolini, Keith Stewart, Susan Newbigging, Mingyao Liu, Xiao-Yan Wen. Chc1L is a tumor suppressor involved in development of histiocyte-rich neoplasms. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C41.

ScopeWe reevaluated previously reported associations between variants in pathways of one‐carbon (1‐C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10−5) and rs828054 (OR = 1.06; p = 1 × 10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1‐C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction = 0.03–0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP‐by‐folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Abstract Background: Because of the faltering sensitivity and/or specificity, urine-based assays currently have a limited role in the management of patients with bladder cancer. The aim of this study was to externally validate our previously reported protein biomarker panel from multiple sites in the United States and Europe. Methods: This multicenter external validation study included a total of 320 subjects (bladder cancer = 183). The 10 biomarkers (IL8, MMP9, MMP10, SERPINA1, VEGFA, ANG, CA9, APOE, SDC1, and SERPINE1) were measured using commercial ELISA assays in an external laboratory. The diagnostic performance of the biomarker panel was assessed using receiver operator curves (ROC) and descriptive statistical values. Results: Utilizing the combination of all 10 biomarkers, the area under the ROC for the diagnostic panel was noted to be 0.847 (95% confidence interval, 0.796–0.899), outperforming any single biomarker. The multiplex assay at optimal cutoff value achieved an overall sensitivity of 0.79, specificity of 0.79, positive prediction value of 0.73, and negative prediction value of 0.84 for bladder cancer classification. Sensitivity values of the diagnostic panel for high-grade bladder cancer, low-grade bladder cancer, muscle invasive bladder cancer, and non-muscle invasive bladder cancer were 0.81, 0.90, 0.95, and 0.77, respectively. Conclusions: Urinary levels of the biomarker panel enabled discrimination of patients with bladder cancer and controls, and the levels of biomarker subsets were associated with advancing tumor grade and stage. Impact: If proven to be reliable, urinary diagnostic biomarker assays can detect bladder cancer in a timely manner such that the patient can expect improvements in overall survival and quality of life. Cancer Epidemiol Biomarkers Prev; 23(9); 1804–12. ©2014 AACR.

Key PointsWe identified CRBN-binding proteins and confirmed recent work implicating the Ikaros transcription factors as important members. Low IZKF1 levels predict lack of IMiD responsiveness and shorter OS; IZKF1 expression is a potential predictive biomarker for clinic application.

Objectives: To evaluate outcomes among cancer patients with preexisting coronary artery disease and cardiac stenting who subsequently underwent thoracic radiotherapy (RT). Methods: From 1998 to 2012, 147 patients received percutaneous coronary intervention (PCI) and then curative external beam RT (>30 Gy, except for Hodgkin lymphoma patients) involving the heart and the lungs. Heart-specific and lung-specific dosimetric parameters were correlated to overall survival (OS) and cardiac-specific survival by Cox variate methods. Results: The mean interval between PCI and cancer diagnosis was 1.8 years (range, 0.1 to 14.2 y). Hypertension was present in 105 patients (71%), and hyperlipidemia in 82 (56%). At the time of analysis, 69 patients (47%) were alive, 3 (2%) died of cardiac causes, and 53 (36%) died of cancer. In multivariate analyses, OS since PCI was related to cancer type (P=0.004). Decreased OS since cancer diagnosis was related to older age (P<0.001) and increased percentage of targeted volume or organ receiving 20 Gy or more for lung (P<0.001), even after controlling for sex, cancer type, and stage. However, for non–cancer-specific survival and major adverse cardiac event-free survival, older age and underlying cardiopulmonary comorbidities dominated (rather than heart and lung dosimetric parameters) in predicting worse outcome for these patients with preexisting coronary artery disease who later underwent RT. Conclusions: Cancer type, older age, and preexisting cardiopulmonary comorbidities and risk factors most significantly predicted clinical outcome and survival for these patients with existing coronary stents who subsequently received thoracic RT. Dosimetric detrimental effects were not significant in our study.

BACKGROUNDWith the advent of limits to resident duty hours and the size of teaching services, many academic institutions have introduced nonteaching services, often triaging perceived better teaching cases to the resident services.OBJECTIVETo compare resident versus faculty perceptions of ideal cases for teaching services and compare these perceptions with actual triage decisions made by faculty who assigned patients to either teaching or nonteaching services.DESIGNResidents and hospitalist faculty were surveyed about their perceptions of ideal and actual teaching admissions, first with qualitative, open‐ended questions and then with quantitative, specific questions generated from responses to the first survey. Characteristics of patients admitted to teaching and nonteaching services were analyzed retrospectively and compared with resident and faculty perceptions.RESULTSResidents and faculty agreed that rare cases, patients with unique physical findings, and a variety of pathology were ideal for teaching services and that social admissions, benefactors, and patients with chronic or functional pain were not. Residents believed that traditional (“bread and butter”) medicine cases were under‐represented on the teaching services. Although residents perceived that they received a disproportionate number of older patients, outside transfers, patients with chronic pain, and patients with cancer, the only statistically significant difference was in patient age, with the teaching service actually receiving younger patients (66.7 vs 69.3 years; P = 0.008).CONCLUSIONSResidents and faculty have similar views about ideal teaching cases, but a triage system based on perceived educational merit creates the possibility of resident misperceptions about their case mix, even if patients are distributed relatively equitably. Journal of Hospital Medicine 2014;9:508–514. © 2014 Society of Hospital Medicine