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Epithelial–mesenchymal transition (EMT) is thought to be an important mechanism of cancer cell metastasis. Clinical measurement of EMT markers in primary tumors could improve risk stratification and treatment decisions by identifying patients who potentially have metastatic disease. To evaluate the potential of EMT markers that could be used for risk stratification for patients with colorectal cancer, we conducted a systematic review of studies (N = 30) that measured at least one of a selection of EMT markers in primary tumors and patient outcomes. Fifteen of 30 studies (50%) reported at least one statistically significant result supporting a role for one of the selected EMT markers in identifying patients at risk for worse outcomes. Importantly, however, we identified design inconsistencies that limited inferences and prevented meta-analysis of data. We offer a number of recommendations to make future studies more informative and standardized, including consistent sampling of different parts of the primary tumor, larger sample sizes, and measurement of both protein and RNA expression of a given EMT marker in the same tumors. Strengthening the literature per our recommendations could facilitate translating EMT markers to clinical use. Cancer Epidemiol Biomarkers Prev; 23(7); 1164–75. ©2014 AACR.

This file contains tables showing the association between BMI and each of ER and PR when adjusted for both risk factors and prognostic factors; associations between BMI and each of ER and PR when a consistent BMI reference group of normal weight is used; and risk stratification tables for the prediction of endometrial cancer-specific mortality using dichotomous tumor ER or PR status.

Background: Endometrial tumors arise from a hormonally responsive tissue. Defining subtypes by hormone receptor expression might better inform etiology and prediction of patient outcomes. We evaluated the potential role of tumor estrogen receptor (ER) and progesterone receptor (PR) expression to define endometrial cancer subtypes.Methods: We measured semi-continuous ER and PR protein expression in tissue specimens from 360 endometrial primary tumors from the Nurses' Health Study. To explore the impact of different definitions of marker positivity, we dichotomized ER and PR expression at different cut points in increments of 5% positive cells. Logistic regression was used to estimate associations between endometrial cancer risk factors, such as body mass index, with dichotomous ER or PR status. Reclassification statistics were used to assess whether adding dichotomous ER or PR status to standard prognostic factors of stage, grade, and histologic type would improve endometrial cancer-specific mortality prediction.Results: Compared with not being obese, obesity increased the odds of having an ER-positive tumor at cut points of 0% to 20% [maximum OR, 2.92; 95% confidence interval (CI), 1.34–6.33] as well as the odds of having a PR-positive tumor at cut points of 70% to 90% (maximum OR, 2.53; 95% CI, 1.36–4.68). Adding dichotomous tumor ER or PR status to the panel of standard predictors did not improve both model discrimination and calibration.Conclusions: Obesity may be associated with greater endometrial tumor expression of ER and PR. Adding either marker does not appear to improve mortality prediction beyond the standard predictors.Impact: Body mass index might explain some of the biological variation among endometrial tumors. Cancer Epidemiol Biomarkers Prev; 26(5); 727–35. ©2017 AACR.

PDF file - 98K, This file presents the set of search terms we used as applied to PubMed. It provides information about the structure of the search and how it could be adapted to search for studies of EMT markers and patient outcomes in tumor sites other than colorectal cancer.

This file provides detailed information on immunohistochemistry assay protocols as well as on the analytic handling of missing covariate data.

In research, policy, and practice, continuous variables are often categorized. Statisticians have generally advised against categorization for many reasons, such as loss of information and precision as well as distortion of estimated statistics. Here, a different kind of problem with categorization is considered: the idea that, for a given continuous variable, there is a unique set of cut points that is the objectively correct or best categorization. It is shown that this is unlikely to be the case because categorized variables typically exist in webs of statistical relationships with other variables. The choice of cut points for a categorized variable can influence the values of many statistics relating that variable to others. This essay explores the substantive trade-offs that can arise between different possible cut points to categorize a continuous variable, making it difficult to say that any particular categorization is objectively best. Limitations of different approaches to selecting cut points are discussed. Contextual trade-offs may often be an argument against categorization. At the very least, such trade-offs mean that research inferences, or decisions about policy or practice, that involve categorized variables should be framed and acted upon with flexibility and humility. LAY SUMMARY: In research, policy, and practice, continuous variables are often turned into categorical variables with cut points that define the boundaries between categories. This involves choices about how many categories to create and what cut-point values to use. This commentary shows that different choices about which cut points to use can lead to different sets of trade-offs across multiple statistical relationships between the categorized variable and other variables. These trade-offs mean that no single categorization is objectively best or correct. This context is critical when one is deciding whether and how to categorize a continuous variable.

Objective. Endometrial cancers have historically been classified by histomorphologic appearance, which is subject to interobserver disagreement. As molecular and biomarker testing has become increasingly available, the prognostic significance and accuracy of histomorphologic diagnoses have been questioned. To address these issues for a large, prospective cohort study, we provide the results of a centralized pathology review and biomarker analysis of all incidental endometrial carcinomas occurring between 1976 and 2012 in the Nurses’ Health Study. Methods. Routine histology of all ( n = 360 ) cases was reviewed for histomorphologic diagnosis. Cases were subsequently planted in a tissue microarray to explore expression of a variety of biomarkers (e.g., ER, PR, p53, PTEN, PAX2, AMACR, HNF1β, Napsin A, p16, PAX8, and GATA3). Results. Histologic subtypes included endometrioid (87.2%), serous (5.6%), carcinosarcoma (3.9%), clear cell (1.7%), and mixed type (1.7%). Biomarker results within histologic subtypes were consistent with existing literature: abnormal p53 was frequent in serous cases (74%), and HNF1β (67%), Napsin A (67%), and AMACR (83%) expression was frequent in clear cell carcinomas. Our dataset also allowed for examination of biomarker expression across non-preselected histologies. The results demonstrated that (1) HNF1β was not specific for clear cell carcinoma, (2) TP53 mutations occurred across many histologies, and (3) GATA3 was expressed across multiple histotypes, with 75% of positive cases demonstrating high-grade features. Conclusions. Our findings establish the subtypes of endometrial cancer occurring in the Nurses’ Health Study, corroborate the sensitivity of certain well-established biomarkers, and call into question previously identified associations between certain biomarkers (e.g., HNF1B) and particular histotypes.

Sensitive assays are essential for the accurate identification of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we report a multiplexed assay for the fluorescence-based detection of seroconversion in infected individuals from less than 1 µl of blood, and as early as the day of the first positive nucleic acid test after symptom onset. The assay uses dye-encoded antigen-coated beads to quantify the levels of immunoglobulin G (IgG), IgM and IgA antibodies against four SARS-CoV-2 antigens. A logistic regression model trained using samples collected during the pandemic and samples collected from healthy individuals and patients with respiratory infections before the first outbreak of coronavirus disease 2019 (COVID-19) was 99% accurate in the detection of seroconversion in a blinded validation cohort of samples collected before the pandemic and from patients with COVID-19 five or more days after a positive nasopharyngeal test by PCR with reverse transcription. The high-throughput serological profiling of patients with COVID-19 allows for the interrogation of interactions between antibody isotypes and viral proteins, and should help us to understand the heterogeneity of clinical presentations., A multiplexed fluorescence-based assay detects seroconversion in individuals infected with SARS-CoV-2 from less than 1 µl of blood as early as the day of the first positive nasopharyngeal nucleic acid test after symptom onset.

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p

Objectives Previous research has reported associations between social relationships and carcinogenesis. Inflammation is a potential mediator of these associations. To clarify these links for one tumor site, we examined associations between social relationships, circulating inflammation markers, and breast cancer incidence. Materials and Methods Among 132,262 participants from the prospective Women’s Health Initiative, we used linear and logistic regression to evaluate associations between social relationship characteristics (social support, social strain, social network size) and inflammation markers of C-reactive protein (CRP) and white blood cell count (WBC). Cox regression was used to evaluate associations between inflammation markers and breast cancer incidence, as well as associations between social relationship characteristics and breast cancer incidence with and without adjustment for inflammation markers. Results Larger social networks were associated with lower continuous CRP (beta = −0.22, 95% CI -0.36, −0.08) and WBC (beta = −0.23, 95% CI -0.31, −0.16). Greater social strain was associated with higher continuous CRP (beta = 0.24, 95% CI 0.14, 0.33) and WBC (beta = 0.09, 95% CI 0.04, 0.14). When WBC was dichotomized at 10,000 cells/uL, high WBC was associated with greater hazards of in situ breast cancer (HR = 1.65, 95% CI 1.17, 2.33) but not invasive breast cancer. Social relationship characteristics were not associated with incidence of invasive or in situ breast cancer. Conclusion Larger social networks were associated with lower inflammation and greater social strain was associated with higher inflammation. Higher inflammation might be associated with development of in situ breast cancer, but this appeared to be due to factors other than social relationships.

Developing a system of molecular subtyping for endometrial tumors might improve insight into disease etiology and clinical prediction of patient outcomes. High body mass index (BMI) has been implicated in development of endometrial cancer through hormonal pathways and might influence tumor expression of biomarkers involved in BMI-sensitive pathways. We evaluated whether endometrial tumor expression of 7 markers from BMI-sensitive pathways of insulin resistance could effectively characterize molecular subtypes: Adiponectin Receptor 1, Adiponectin Receptor 2, Leptin Receptor, Insulin Receptor (beta subunit), Insulin Receptor Substrate 1, Insulin-Like Growth Factor 1 Receptor, and Insulin-Like Growth Factor 2 Receptor. Using endometrial carcinoma tissue specimens from a case-only prospective sample of 360 women from the Nurses’ Health Study, we scored categorical immunohistochemical measurements of protein expression for each marker. Logistic regression was used to estimate associations between endometrial cancer risk factors, especially BMI, and tumor marker expression. Proportional hazards modeling was performed to estimate associations between marker expression and time to all-cause mortality as well as time to endometrial cancer-specific mortality. No association was observed between BMI and tumor expression of any marker. No marker was associated with time to either all-cause mortality or endometrial cancer-specific mortality in models with or without standard clinical predictors of patient mortality (tumor stage, grade, and histologic type). It did not appear that any of the markers evaluated here could be used effectively to define molecular subtypes of endometrial cancer.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P

Background Metastases play a role in about 90% of cancer deaths. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells might provide diagnostic information about the likelihood that cancer cells have detached from the primary tumor. Used together with established diagnostic tests of detachment—lymph node evaluation and radiologic imaging—EMT marker measurements might improve the ability of clinicians to assess the patient’s risk of metastatic disease. Translation of EMT markers to clinical use has been hampered by a lack of valid analyses of clinically-informative parameters. Here, we demonstrate a rigorous approach to estimating the sensitivity, specificity, and prediction increment of an EMT marker to assess cancer cell detachment from primary tumors. Methods We illustrate the approach using immunohistochemical measurements of the EMT marker E-cadherin in a set of colorectal primary tumors from a population-based prospective cohort in North Carolina. Bayesian latent class analysis was used to estimate sensitivity and specificity in a setting of multiple imperfect diagnostic tests and no gold standard. Risk reclassification analysis was used to assess the extent to which addition of the marker to the panel of established diagnostic tests would improve mortality prediction. We explored how changing the latent class conditional dependence assumptions and definition of marker positivity would impact the results. Results All diagnostic accuracy and prediction increment statistics varied with the choice of cut point to define marker positivity. When comparing different definitions of marker positivity to each other, numerous trade-offs were observed in terms of sensitivity, specificity, predictive discrimination, and prediction model calibration. We then discussed several implementation considerations and the plausibility of analytic assumptions. Conclusions The approaches presented here can be extended to any EMT marker, to most forms of cancer, and to different kinds of EMT marker measurements, such as RNA or gene methylation data. These methods provide valid, clinically-informative assessment of whether and how to use a given EMT marker to refine tumor staging and consequent treatment decisions. Electronic supplementary material The online version of this article (10.1186/s12885-017-3964-3) contains supplementary material, which is available to authorized users.

// Evan L. Busch 1, 2, 3 , Jason L. Hornick 4 , Renato Umeton 5 , Adem Albayrak 5 , Neal I. Lindeman 4 , Laura E. MacConaill 4 , Elizabeth P. Garcia 4 , Matthew Ducar 4 and Timothy R. Rebbeck 2, 3 1 Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA 2 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA 4 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA 5 Department of Informatics, Dana-Farber Cancer Institute, Boston, MA 02215, USA Correspondence to: Evan L. Busch, email: nhebu@channing.harvard.edu Keywords: metastasis, carcinomas, epithelial-mesenchymal transition, mutation, detachment Received: June 27, 2017 Accepted: September 01, 2017 Published: September 21, 2017 ABSTRACT Metastases are involved in most cancer deaths. Evidence has suggested that cancer cell detachment from primary tumors might occur largely via the mechanism of epithelial-mesenchymal transition (EMT) activated by epigenetic events, but data addressing other possible triggers of detachment, particularly genetic mutations, have been limited. Using the Profile study of cancer genomics at Dana-Farber Cancer Institute, we examined somatic mutations in the EMT genes CDH1 in 5,106 primary carcinomas and CTNNB1 in 7,578 primary carcinomas across 13 anatomic sites: urinary bladder, breast, colon/rectum, endometrium, esophagus, kidney, lung, ovary, pancreas, prostate, skin (non-melanoma), stomach, and thyroid. For each gene and anatomic site, we calculated the prevalence of primary carcinomas with at least one mutation. Across all anatomic sites, 4% of carcinomas had at least one CDH1 mutation and 4% of carcinomas had at least one CTNNB1 mutation. By anatomic site, the observed prevalence of carcinomas with at least one mutation was less than 5% at 10 sites for CDH1 and 12 sites for CTNNB1 . Tumor stage data were available for a subset of breast, colorectal, lung, and prostate tumors. Among patients from this subset who were diagnosed with regional or distant disease, only 4% had a CDH1 mutation and 1% had a CTNNB1 mutation in the primary tumor. The low mutation prevalences, especially among those with diagnoses of regional or distant disease, suggest that somatic mutations in CDH1 and CTNNB1 are unlikely to explain a substantial proportion of cancer cell detachment from primary carcinomas originating at most anatomic sites.

Background: Endometrial tumors arise from a hormonally responsive tissue. Defining subtypes by hormone receptor expression might better inform etiology and prediction of patient outcomes. We evaluated the potential role of tumor estrogen receptor (ER) and progesterone receptor (PR) expression to define endometrial cancer subtypes. Methods: We measured semi-continuous ER and PR protein expression in tissue specimens from 360 endometrial primary tumors from the Nurses' Health Study. To explore the impact of different definitions of marker positivity, we dichotomized ER and PR expression at different cut points in increments of 5% positive cells. Logistic regression was used to estimate associations between endometrial cancer risk factors, such as body mass index, with dichotomous ER or PR status. Reclassification statistics were used to assess whether adding dichotomous ER or PR status to standard prognostic factors of stage, grade, and histologic type would improve endometrial cancer-specific mortality prediction. Results: Compared with not being obese, obesity increased the odds of having an ER-positive tumor at cut points of 0% to 20% [maximum OR, 2.92; 95% confidence interval (CI), 1.34–6.33] as well as the odds of having a PR-positive tumor at cut points of 70% to 90% (maximum OR, 2.53; 95% CI, 1.36–4.68). Adding dichotomous tumor ER or PR status to the panel of standard predictors did not improve both model discrimination and calibration. Conclusions: Obesity may be associated with greater endometrial tumor expression of ER and PR. Adding either marker does not appear to improve mortality prediction beyond the standard predictors. Impact: Body mass index might explain some of the biological variation among endometrial tumors. Cancer Epidemiol Biomarkers Prev; 26(5); 727–35. ©2017 AACR.

Pathogenic sequence variants (PSV) in

Differences in tumor characteristics might partially account for mortality disparities between African American (AA) and European American (EA) colorectal cancer patients. We evaluated effect modification by race for exposure and patient-outcomes associations with colorectal tumor methylation among 218 AA and 267 EA colorectal cancer cases from the population-based North Carolina Colon Cancer Study. Tumor methylation was assessed in CACNA1G, MLH1, NEUROG1, RUNX3, and SOCS1. We used logistic regression to assess whether associations between several lifestyle factors—intake of fruits, vegetables, folate, and non-steroidal anti-inflammatory drugs—and tumor methylation were modified by race. Proportional hazards models were used to evaluate whether race modified associations between tumor methylation and time to all-cause mortality. Greater fruit consumption was associated with greater odds of high NEUROG1 methylation among EA at methylation cut points of 15–35% (maximum OR 3.44, 95% CI 1.66, 7.13) but not among AA. Higher folate intake was associated with lower odds of high CACNA1G methylation among EAs but not AAs. Tumor methylation was not associated with all-cause mortality for either group. Race might modify associations between lifestyle factors and colorectal tumor methylation, but in this sample did not appear to modify associations between tumor methylation and all-cause mortality.

Sulfonylureas, a commonly-used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In eleven ethnically diverse cohorts that included 71 857 European, African American, and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT, and QRS intervals. In ancestry-specific meta-analyses, 8 novel pharmacogenomic loci met the threshold for genome-wide significance (P < 5 x 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Functional health literacy is essential for the self-management of chronic diseases and preventive health behaviors. Patients with cancer who have a low level of health literacy may be at greater risk for poor care and poor outcomes.We assessed health literacy using the Short Test of Functional Health Literacy in Adults in 347 participants with colorectal cancer who were nested within a prospective observational study of system, health care provider, and participant characteristics influencing cancer outcomes.Having adequate health literacy increased the likelihood that participants with stage 3/4 disease received chemotherapy (odds ratio, 3.29; 95% confidence interval, 1.23-8.80) but had no effect on cancer stage at diagnosis or vital status at last observation during postenrollment follow-up. No difference was seen in health literacy status regarding participant beliefs and preferences about chemotherapy among those with stage 3/4 disease, nor in participant roles in deciding whether to receive chemotherapy.Patients with lower levels of health literacy were less likely to receive chemotherapy compared with participants with higher levels of health literacy. Therefore, clear communication related to key health care decisions may lead to fewer disparities due to a patient's level of health literacy.

Background Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals. Methods and results We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, p interaction =3.9e −9 ) and rs9830388 in UBE2E2 (β=25.2, p interaction =1.7e −8 ). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, p interaction =2.55e −8 ). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (p interaction >0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries. Conclusions Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, plays a vital role in the regulation of metabolism, stress responses, and genome stability. However, the role of SIRT1 in the multi-step process leading to transformation and/or tumorigenesis, as either a tumor suppressor or tumor promoter, is complex and may be dependent upon the context in which SIRT1 activity is altered, and the role of SIRT1 in tumor metabolism is unknown. Here, we demonstrate that SIRT1 dose-dependently regulates cellular glutamine metabolism and apoptosis, which in turn differentially impact cell proliferation and cancer development. Heterozygous deletion of Sirt1 induces c-Myc expression, enhancing glutamine metabolism and subsequent proliferation, autophagy, stress resistance, and cancer formation. In contrast, homozygous deletion of Sirt1 triggers cellular apoptotic pathways, increases cell death, diminishes autophagy, and reduces cancer formation. Consistent with the observed dose dependence in cells, intestine-specific Sirt1 heterozygous mice have enhanced intestinal tumor formation, whereas intestine-specific Sirt1 homozygous knockout mice have reduced development of colon cancer. Furthermore, SIRT1 reduction, but not deletion, is associated with human colorectal tumors, and colorectal cancer patients with low protein expression of SIRT1 have a poor prognosis. Taken together, our findings indicate that the dose-dependent regulation of tumor metabolism and possibly apoptosis by SIRT1 mechanistically contribute to the observed dual roles of SIRT1 in tumorigenesis. Our study highlights the importance of maintenance of a suitable SIRT1 dosage for metabolic and tissue homeostasis, which will have important implications in SIRT1-small-molecule-activator/inhibitor-based therapeutic strategies for cancers.

Fat transfer is an increasingly popular method for refining postmastectomy breast reconstructions. However, concern persists that fat transfer may promote disease recurrence. Adipocytes are derived from adipose-derived stem cells and express adipocytokines that can facilitate active breast cancer cells in laboratory models. The authors sought to evaluate the association between fat transfer to the reconstructed breast and cancer recurrence in patients diagnosed with local or regional invasive breast cancers.A multicenter, case-cohort study was performed. Eligible patients from four centers (Memorial Sloan Kettering, M. D. Anderson Cancer Center, Alvin J. Siteman Cancer Center, and the University of Chicago) were identified by each site's institutional tumor registry or cancer data warehouse. Eligibility criteria were as follows: mastectomy with immediate breast reconstruction between 2006 and 2011, age older than 21 years, female sex, and incident diagnosis of invasive ductal carcinoma (stage I, II, or III). Cases consisted of all recurrences during the study period, and controls consisted of a 30 percent random sample of the study population. Cox proportional hazards regression was used to evaluate for association between fat transfer and time to recurrence in bivariate and multivariate models.The time to disease recurrence unadjusted hazard ratio for fat transfer was 0.99 (95 percent CI, 0.56 to 1.7). After adjustment for age, body mass index, stage, HER2/Neu receptor status, and estrogen receptor status, the hazard ratio was 0.97 (95 percent CI, 0.54 to 1.8).In this population of breast cancer patients who had mastectomy with immediate reconstruction, fat transfer was not associated with a higher risk of cancer recurrence.Therapeutic, III.

BACKGROUND Depletion of gut-associated lymphocytes by HIV infection facilitates microbial translocation, which may contribute to non-Hodgkin lymphoma (NHL) risk via chronic immune activation and B-cell hyperstimulation. METHOD We therefore examined associations of four microbial translocation markers with subsequent NHL risk in a case-control study nested within four prospective cohort studies of HIV-infected individuals. Prediagnostic blood specimens for 56 NHL cases and 190 controls matched for age, sex, race, specimen type, cohort, and CD4 T-cell count were tested for the endotoxin lipopolysaccharide (LPS), antiendotoxin core antibody (EndoCab), LPS-binding protein (LBP), and soluble CD14 (sCD14). RESULTS Elevated levels of sCD14 were associated with significantly increased NHL risk [odds ratio (OR) 2.72 (95% confidence interval [95% CI] 1.29-5.76)]. In subgroup analyses, elevated LPS levels were also associated with significantly increased NHL risk [OR 3.24 (95% CI 1.10-9.53)]. EndoCab and LBP levels were not associated with NHL risk. CONCLUSION The association of sCD14 and LPS with NHL risk supports an etiologic role for gut microbial translocation in lymphomagenesis among HIV-infected individuals. Additional studies with larger sample sizes are needed to confirm these observations.

Most cancer deaths are due to metastases. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells could be helpful to assess patient risk of metastatic disease, even among those otherwise diagnosed with local disease. Previous studies of EMT markers and patient outcomes used inconsistent methods and did not compare the clinical impact of different expression cut points for the same marker. Using digital image analysis, we measured the EMT markers Snail and E-cadherin in primary tumor specimens from 190 subjects in tissue microarrays from a population-based prospective cohort of colorectal cancer patients and estimated their associations with time-to-death. After measuring continuous marker expression data, we performed a systematic search for the cut point for each marker with the best model fit between dichotomous marker expression and time-to-death. We also assessed the potential clinical impact of different cut points for the same marker. After dichotomizing expression status at the statistically-optimal cut point, we found that Snail expression was not associated with time-to-death. When measured as a weighted average of tumor cores, low E-cadherin expression was associated with a greater risk of dying within 5 years of surgery than high expression (risk difference = 33 %, 95 % confidence interval 3–62 %). Identifying a clinically-optimal cut point for an EMT marker requires trade-offs between strength and precision of the association with patient outcomes, as well as consideration of the number of patients whose treatments might change based on using the marker at a given cut point.

Endometrial carcinoma (EC), a malignancy that arises from the epithelial lining of the uterus, is heterogeneous at histologic and molecular levels. Risk factors and outcomes also differ by type. Though prior studies characterized the genomic landscape of endometrial carcinoma, few integrated histologic, clinical, and prospectively collected epidemiologic data into the analysis. We collected formalin-fixed paraffin embedded tumor tissue from women enrolled in the Nurses’ Health Study who were diagnosed with EC between 1976 and 2012. We targeted 50 cancer related genes for high-throughput sequencing to identify genetic variants in 37 ECs and correlate findings with immunohistochemical, histologic, and epidemiologic data. Case selection was designed to include maximal power to discover genetic changes associated with p53 immunohistochemical status and clinical stage of disease at diagnosis. Mutations most frequently occurred in TP53 (57%), PTEN (46%), and PIK3CA (38%). TP53 mutations were seen in 83% of ECs that immunostained positive for mutant p53, with the most frequent TP53 mutations occurring in R248. Well-differentiated endometrioid tumors had elevated frequencies of PTEN and PIK3CA mutations compared to less differentiated tumors (p < 0.05). The mutation profiles of these samples are consistent with previous studies, supporting the viability of archival paraffin-embedded tissue in mutation detection. This study’s interdisciplinary approach to tumor characterization may help inform future development of personalized models for EC. Citation Format: Maxine Chen, Marta Crous-Bou, Michael J. Downing, Evan L. Busch, Kimberley Glass, Jennifer Prescott, George L. Mutter, Immaculata De Vivo. Mutation analysis of endometrial cancer in a population-based study by targeted next-generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1291. doi:10.1158/1538-7445.AM2017-1291

Epithelial–mesenchymal transition (EMT) is thought to be an important mechanism of cancer cell metastasis. Clinical measurement of EMT markers in primary tumors could improve risk stratification and treatment decisions by identifying patients who potentially have metastatic disease. To evaluate the potential of EMT markers that could be used for risk stratification for patients with colorectal cancer, we conducted a systematic review of studies (N = 30) that measured at least one of a selection of EMT markers in primary tumors and patient outcomes. Fifteen of 30 studies (50%) reported at least one statistically significant result supporting a role for one of the selected EMT markers in identifying patients at risk for worse outcomes. Importantly, however, we identified design inconsistencies that limited inferences and prevented meta-analysis of data. We offer a number of recommendations to make future studies more informative and standardized, including consistent sampling of different parts of the primary tumor, larger sample sizes, and measurement of both protein and RNA expression of a given EMT marker in the same tumors. Strengthening the literature per our recommendations could facilitate translating EMT markers to clinical use. Cancer Epidemiol Biomarkers Prev; 23(7); 1164–75. ©2014 AACR.