Citations

Abstract Purpose: Clustering of breast and colorectal cancer has been observed within families in population-based studies giving rise to speculation that there are “breast-colon” cancer susceptibility genes. We performed a genome-wide association study (GWAS) to identify genetic markers associated with a potential breast-colon cancer phenotype. Methods: Cases and controls were ascertained from the Breast and Colon Cancer Family Registries’ (CFR) GWAS subjects. “Breast-colon phenotype” definition was based on 2 or more breast and colon cancer cases diagnosed in first- or second-degree relatives within a family. Cases (n = 985) were women with a history of breast cancer and a family history of colorectal cancer, or persons with colorectal cancer with a family history of breast cancer. Unrelated controls (n = 1769) were frequency matched to cases for age and gender. Following standard quality control measures, 6,220,060 directly measured and imputed single nucleotide polymorphisms (SNPs) were included in the discovery set. SNPs associated at p<1×10−5 were analyzed in a replication dataset of cases (n = 293) and controls (n = 2103) from the Genetics and Epidemiology of Colorectal Cancer Consortium. Results: In a regression model that included gender, age, CFR center and 6 principal components, the top association in the discovery set was in the chromosome 8q22.3 region overlying the BAALC gene (top SNP rs12548629, P = 3.63×10−7). In the replication dataset, of 341 SNPs tested, the top signal was found in multiple correlated SNPs overlying the ROBO1 gene on chromosome 3p12 (rs7429100, P = 2.8×10−3), however, the signal on chromosome 8, the BAALC gene did not replicate. In the discovery set, P values for the SNPs overlaying ROBO1 gene ranged from 2.2×10−5 to 9.7×10−5 (rs7429100, P = 3.9×10−5). The combined meta-analysis showed strongest association at the ROBO1 gene (rs7429100, Pfixed effects 1.84×10−6, Pheterogeneity >0.05 for testing for heterogeneity between the overall discovery set and the replication set). ROBO1 (roundabout, axon guidance receptor, homolog 1) is a transmembrane receptor of the immunoglobulin family and is differentially expressed in human cancers, with a possible role as a tumor suppressor gene. Low ROBO1 expression has been shown to be an adverse prognostic factor for invasive ductal breast cancer and may also play a role in pathogenesis of colorectal cancer. BAALC (brain and acute leukemia, cytoplasmic) is predominantly expressed by neural and blood cells and is largely implicated in acute leukemia. Conclusion: In this exploratory analysis, to elucidate genes/regions associated with pleiotropic effect for breast and colorectal cancer risk we identified germline variation in the region of ROBO1 and BAALC. Validation in a larger dataset and functional characterization of the loci is warranted to elucidate mechanisms by which these genes/SNPs may contribute to the development of breast and colorectal cancer. Citation Format: Mala Pande, Aron Joon, Sanjay Shete, Abenaa M. Brewster, Cathy Eng, Wei V. Chen, Habibul Ahsan, Irene L. Andrulis, Esther M. John, Yi Lin, Polly A. Newcomb, Noralane M. Lindor, Christopher I. Amos, John Hopper, Patrick M. Lynch. Risk loci for a breast-colon cancer phenotype: results from a genome-wide association study. [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 2782. doi:10.1158/1538-7445.AM2015-2782

Carriers of germline mutations in DNA mismatch repair (MMR) genes are at increased risk of several cancers including colorectal and gynecologic cancers (Lynch syndrome). There is no substantial evidence that these mutations are associated with an increased risk of cervical cancer. A total of 369 families with at least one carrier of a mutation in a MMR gene (133 MLH1, 174 MSH2, 35 MSH6 and 27 PMS2) were ascertained via population cancer registries or via family cancer clinics in Australia, New Zealand, Canada, and USA. Personal and family histories of cancer were obtained from participant interviews. Modified segregation analysis was used to estimate the hazard ratio (incidence rates for carriers relative to those for the general population), and age‐specific cumulative risks of cervical cancer for carriers. A total of 65 cases of cervical cancer were reported (including 10 verified by pathology reports). The estimated incidence was 5.6 fold (95% CI: 2.3–13.8; p = 0.001) higher for carriers than for the general population with a corresponding cumulative risk to 80 years of 4.5% (95% CI: 1.9–10.7%) compared with 0.8% for the general population. The mean age at diagnosis was 43.1 years (95% CI: 40.0–46.2), 3.9 years younger than the reported USA population mean of 47.0 years (p = 0.02). Women with MMR gene mutations were found to have an increased risk of cervical cancer. Due to limited pathology verification we cannot be certain that a proportion of these cases were not lower uterine segment endometrial cancers involving the endocervix, a recognized cancer of Lynch syndrome.

Background and aim Although Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any. Methods The primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria. Results 112 subjects were randomised: 60 men and 52 women at a mean age of 38 years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6 months, the mean % change in adenoma count over the 6 months of trial was −13.0% for CXB+DFMO and −1.0% for CXB (p=0.69). Mean % change in adenoma burden was −40% (CXB+DFMO) vs −27% (CXB) (p=0.13). Video-based global polyp change was −0.80 for CXB+DFMO vs −0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02). Conclusions CXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves. Trial registration number ClinicalTrials.gov number N01-CN95040.

Abstract Background: Cigarette smoking (smoking), hormone therapy (MHT), and folate intake (folate) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. Expression of estrogen receptor β (ESR2) has been associated with colorectal cancer stage and survival. Methods: In this prospective cohort study, we examined smoking, MHT, and folate-associated colorectal cancer risks by ESR2 protein expression level among participants in the Iowa Women's Health Study (IWHS). Self-reported exposure variables were assessed at baseline. Archived, paraffin-embedded colorectal cancer tissue specimens were collected and evaluated for ESR2 protein expression by IHC. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between smoking, MHT, or folate and ESR2-defined colorectal cancer subtypes. Results: Informative environmental exposure and protein expression data were available for 491 incident colorectal cancer cases. Positive associations between ESR2-low and -high tumors and several smoking-related variables were noted, most prominently with average number of cigarettes per day (RR, 4.24; 95% CI, 1.81–9.91 for ESR2-low and RR, 2.15; 95% CI, 1.05–4.41 for ESR2-high for ≥40 cigarettes compared with nonsmokers). For MHT, a statistically significant association with ESR2-low tumors was observed with longer duration of exposure (RR, 0.54; 95% CI, 0.26–1.13 for >5 years compared with never use). No associations were found for folate. Conclusions: In this study, smoking and MHT were associated with ESR2 expression patterns. Impact: These data support possible heterogeneous effects from smoking and MHT on ERβ-related pathways of colorectal carcinogenesis in older women. Cancer Epidemiol Biomarkers Prev; 24(4); 713–9. ©2015 AACR.

Diastolic mitral valve regurgitation is a rare phenomenon described in patients with atrioventricular conduction abnormalities, severe left ventricular systolic or diastolic dysfunction with regional wall motion dyssynchrony, or severe acute aortic valve regurgitation. The presence of diastolic mitral valve regurgitation in acute aortic regurgitation due to endocarditis suggests critical severity requiring urgent surgical valve replacement. We describe a case of diastolic mitral regurgitation in the setting of complex native mitral-aortic valve endocarditis in a patient in normal sinus rhythm and review the etiologic mechanisms of this phenomenon, echocardiographic assessment, and therapeutic implications for hemodynamic management.

Objective: The purpose of our study was to compare the clinical utility of administering 2 recommended developmental screening instruments, the Infant Developmental Inventory (IDI) and the Ages and Stages Questionnaire (ASQ), at 9-month well-child visits in paper format. Methods: Outcomes of the 2 screens, including correct completion and interpretation by clinician, time of visit, and screen outcome were compared. Results: Out of 33 children administered the ASQ and with documented scores, 12 (36.4%) did not receive passing scores, while 5 (12.2%) of the 41 children administered the IDI did not receive passing scores ( P = .014). Out of 41 IDI screens, 12 (29.3%) were completed incorrectly, while there were no ASQ screens completed incorrectly ( P < .001) by caregivers. Conclusion: In our pilot study, the ASQ is more often completed correctly by caregivers and identifies more children at risk for delay as compared with the IDI. Additional larger scale studies are needed to evaluate the usefulness of developmental screening tools when used within primary care practice.

Abstract Background: Hormone therapy (HT) may prevent colorectal cancer (CRC), but the molecular mechanisms have not been fully defined. Expression of estrogen receptor beta (ERβ) has been associated with CRC stage and survival and may influence HT-related prevention pathways. In this prospective cohort study, we examined HT-associated CRC risk by ERβ protein expression levels in the population-based Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). Exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 CRC cases, diagnosed through 12/31/2002, for molecular epidemiology studies. HT was categorized as never, former, and current and with durations of &lt;=5 years or &gt;5 years. ERβ protein expression was determined by immunohistochemistry on tissue microarrays. For each tumor core, both staining intensity (0-3) and proportion of cells stained (0-5) were scored. These two scores were added to determine negative (0), low (1-5) or high (6-8) ERβ protein expression levels. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: Complete HT and ERβ data were available from 484 CRC cases. Associations between HT and CRC subtypes defined by ERβ expression level are shown in the Table. Conclusions: Data from the IWHS cohort suggest that current and longer-duration HT exposure favorably influence the risk for ERβ-neg or ERβ-low CRC cases to a greater degree than ERβ-high CRC cases. Further investigation is required to confirm these observations, and to clarify the underlying mechanisms. ERβ Neg or Low ERβ High Hormone Therapy Person years Events, N RR* (95% CI) Events, N RR* (95% CI) Never 341377 128 1.00 (Ref.) 196 1.00 (Ref.) Ever 212696 62 0.74 (0.54,1.03) 98 0.82 (0.63,1.07) Former 151535 48 0.79 (0.56,1.12) 67 0.73 (0.54,0.99) Current 61161 14 0.60 (0.33,1.09) 31 1.11 (0.74,1.64) P-trend 0.05 0.52 Duration &lt; = 5yrs 148704 47 0.84 (0.59,1.19) 68 0.80 (0.60,1.08) &gt;5yrs 60064 14 0.5 (0.26,0.93) 28 0.89 (0.59,1.34) P-trend 0.03 0.25 Citation Format: Lori S. Tillmans, Robert A. Vierkant, Alice H. Wang, Charles F. Lynch, Kristin E. Anderson, Amy J. French, Robert W. Haile, John D. Potter, Susan L. Slager, Thomas C. Smyrk, Stephen N. Thibodeau, James R. Cerhan, Paul J. Limburg. Hormone therapy and incident colorectal cancer risk by ER beta protein expression level in a population-based cohort of older women. [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 3652. doi:10.1158/1538-7445.AM2013-3652