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Physiochemical differences between mitochondrial DNA (mtDNA) haplogroups that favor oxidative phosphorylation efficiency during periods of caloric limitation can lead to lifespan lengthening when food calories are less abundant. For example, prior work demonstrated that older female haplogroup H carriers had modestly lengthened lifespans beyond 60 years during the Great Depression, a time of caloric limitation in North America. The objective of the current study is to replicate the prior findings in an independent cohort that includes both sexes and younger ages. By determining and cross-referencing the mtDNA genotypes of a culturally homogeneous population isolate to the lifespans of their ancestors, we found that between 1930 and 1939, haplogroup H compared to haplogroup U carriers had a modestly lengthened lifespan (3 years) past 60 years (hazard ratio 2.35; CI95 1.41–3.90; p-value: 0.0029). The lifespan-lengthening association was apparent in both sexes but only after the age of 60. Our results provide further support for the role of mitochondrial genetics in lengthening human lifespan.

207 Background: The incidence of colorectal cancer (CRC) among individuals younger than age 50 (young-onset CRC; YOCRC) has increased, yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. Some studies suggest that YOCRCs have more aggressive biology. Here, we compare tumor-associated T cell repertoires between patients with YOCRC and average-onset CRC (AOCRC). A robust, focused T cell response is a positive prognostic indicator; therefore, we hypothesized that YOCRCs demonstrate lower T cell abundance and greater T cell diversity than AOCRCs. Methods: The discovery cohort included 242 patients with histologically confirmed Stage I-IV CRC who underwent surgical resection at Cleveland Clinic from 2000 to 2020 and consented to a biorepository. YOCRC was defined as < 50 years at diagnosis (N = 126), and AOCRC as > 60 years (N = 116). DNA was extracted from frozen tumors, and T Cell Receptor (TCR) abundance and clonality were measured using immunoSEQ (Adaptive Biotechnologies). Following quality control, logistic regression models were used to evaluate the associations between TCR repertoire features and age of onset, adjusting for sex, race, tumor location, and stage. Findings were replicated in 152 YOCRC and 1,984 AOCRC cases from the Molecular Epidemiology of Colorectal Cancer Study with adjustment for sex, Jewish ethnicity, tumor location, and stage. Results: YOCRC patients were more likely to have left-sided tumors and be diagnosed at advanced stages in both cohorts. In the discovery cohort, YOCRC tumors had significantly lower TCR clonality (higher T cell diversity) compared to AOCRC tumors in a multivariable model adjusting for sex, race, tumor location and stage (OR: 0.38, 95% Confidence Interval (CI): 0.25-0.56, p < 0.0001). This association was also observed in the replication cohort (OR: 0.74, 95% CI: 0.62-0.89, p = 0.0013). In the replication cohort, further adjustment for microsatellite instability status did not substantially change the association (OR: 0.73, 95% CI: 0.61-0.88 p = 0.0012). When restricting to microsatellite stable tumors, clonality remained statistically significant in both the discovery and replication cohorts. No significant difference in TCR abundance was observed between YOCRC and AOCRC in either cohort. Conclusions: Higher T cell repertoire diversity, indicating a less focused intratumoral T cell response, is more frequently observed in YOCRC. Further studies are warranted to investigate the role of T cell diversity in the etiology and outcomes of YOCRC.

This study explored the impact of social support on suicidal ideation in 169 prisoners with major depressive disorder, accounting for known demographic, criminological, and clinical risk factors. Greater social support was associated with a lower likelihood of the presence of current suicide ideation. This effect remained significant even after adjusting for other significant predictors of suicide ideation including sex, length of sentence served, severity of current depression, and having prior suicide attempts. This study is the first to explore social support and other known risk factors for suicide ideation in a prison population with major depressive disorder. Our findings demonstrate that, even in the presence of significant risk factors for suicidal ideation, social support remained a strong predictor, suggesting the importance of fostering social support in correctional settings.

Diversity in Human Leukocyte Antigen (HLA) genes has been associated with risk of several diseases, including Non-Hodgkin’s lymphoma and ulcerative colitis. Reduced diversity at HLA loci may adversely affect the host’s ability to recognize foreign antigens and tumor neoantigens, and subsequently, increase disease burden. To better understand the role of inherited HLA diversity in colorectal cancer (CRC) risk, we utilized data from a population-based study of 10,347 participants (5,574 CRC cases and 4,773 healthy controls) from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Germline DNA samples were genotyped using genome-wide arrays, and HLA Class I and II four-digit resolution alleles were imputed using SNP2HLA and a reference panel of 5,225 individuals from the Type 1 Diabetes Genetics Consortium. Heterozygosity and homozygosity at each HLA locus and the number of homozygous genotypes at class I loci (A, B, C) and class II loci (DQB1, DRB1, DPB1) were quantified. To examine the joint effect of Class I and Class II loci, we combined the total number of homozygotes for all loci and categorized into 3 groups: heterozygotes at all loci, 1 to 4 homozygotes, or 5 or more homozygotes. Logistic regression was used to estimate the risk of CRC associated with HLA locus homozygosity. Individuals with heterozygous genotypes for all loci served as the reference category, and analyses were adjusted for sex, age, genotyping platform, and global ancestry. Individuals with homozygous genotypes at all 3 Class I genes had an increased risk of CRC when compared to those with heterozygous genotypes at all Class I loci (OR: 1.34; 95% CI: 1.02-1.76, P = 0.033; Ptrend = 0.039). A similar association was observed for Class II loci, with an OR of 1.32 (95% CI: 1.05-1.65, P = 0.015; Ptrend = 0.157). For HLA Class I and II combined, individuals with five or more homozygous genotypes at HLA class I or II loci were at higher risk for developing CRC (OR: 1.84, 95% CI: 1.24-2.73, P = 0.0023; Ptrend = 0.015), when compared to those with all heterozygous genotypes. Our findings support a heterozygote advantage at HLA class I and II loci as a protective factor for CRC. This indicates an important role for HLA genetic variability in the etiology of CRC potentially operating through a mechanism of decreased diversity of tumor neoantigens that can be displayed to the adaptive immune system. Citation Format: Ya-Yu Tsai, Chenxu Qu, Joseph D. Bonner, Rebeca Sanz-Pamplona, Sidney Lindsey, Marilena Melas, Kevin J. McDonnell, Gregory E. Idos, Christopher P. Walker, Kevin K. Tsang, Diane M. Da Silva, Ferran Moratalla, Asaf Maoz, Hedy S. Rennert, W. Martin Kast, Joel K. Greenson, Victor Moreno, Gad Rennert, Stephen B. Gruber, Stephanie L. Schmit. Heterozygote advantage at HLA class I and II loci and colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5874.

10521 Background: Nearly two dozen Fanconi anemia (FA) genes work in concert to mediate critical DNA repair steps. Previous investigations have well described germline pathogenic variation and associated solid tumor cancer predisposition in the highly penetrant (HP)-FA genes, BRCA1 (FANCS), BRCA2 (FANCD1) and PALB2 (FANCN). To date, understanding of pathogenic variation and cancer association among non-HP-FA genes remains incomplete. In this study we investigated the germline mutational landscape of non-HP-FA genes in patients with a personal/family history of a solid tumor. Methods: Unselected, consented patients with a personal/personal history of solid tumor cancer underwent germline testing through a sponsored program of universal access. Testing used a custom panel to detect pathogenic single nucleotide variants, short insertions/deletions and exon-level deletions/duplications of 155 cancer-predisposition genes including 15 non-HP-FA genes [ FANCA, FANCB, FANCC, FAND2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, FANCO (RAD51C), FANCP (SLX4), FANCQ (ERCC4) and FANCU (XRCC2)]. Here we summarize germline pathogenic variant frequency in non-HP-FA genes and describe the mutational landscape across solid tumors. Additionally, we report the clinical actionability (on- and off-label FDA approved drug availability and/or clinical trial eligibility) of identified variants. Results: 5044 patients consented and completed germline genetic testing. 1014/5044 (20.1%) of patients carried a pathogenic variant in a cancer predisposition gene. 116/1014 (11.4%) of germline positive patients carried a pathogenic variant in a non-HP-FA gene. Non-HP-FA genes with highest frequencies included: FANCA (28 patients), FANCM (19 patients), BRIP1 (FANCJ) (19 patents) and FANCC (14 patients). Testing identified germline non-HP-FA pathogenic variants in eighteen different tumor types. The tumor types associated with the highest percentages of associated germline non-HP-FA pathogenic variants included: squamous cell cancers (8.2%), bladder/urothelial cancer (5.0%), breast cancer (3.5%) and ovarian/fallopian tube cancers (3.5%). Moreover, 19 patients carrying a non-HP-FA germline pathogenic variant qualified for an on- or off-label FDA-approved drug; 101 patients achieved clinical trial eligibility by virtue of their non-HP-FA variant. Conclusions: Our study offers a landscape view of germline pathogenic variants in non-HP-FA genes in patients with a history of a solid tumor. Furthermore, this investigation provides a basis for further examination of associations between these germline pathogenic variants and solid tumor cancer predisposition. Finally, importantly, our work underscores the value of expanded germline non-HP-FA gene testing to optimize therapeutic and clinical trial opportunities for cancer patients.

Background Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate‐risk pathogenic variants (PVs). Methods Study participants (N = 1264) were counseled and tested with a 25‐ or 28‐gene panel and completed a 3‐month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA). Results The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non‐Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity. Approximately 28% had a high school education or less, and 23% were non–English‐speaking. The genetic test results were as follows: 7% had a high‐risk PV, 6% had a moderate‐risk PV, 35% had a variant of uncertain significance (VUS), and 52% were negative. Most participants (92%) had a total MICRA score ≤ 38, which corresponded to a mean response of “never,” “rarely,” or only “sometimes” reacting negatively to results. A multivariate analysis found that mean total MICRA scores were significantly higher (more uncertainty/distress) among high‐ and moderate‐risk PV carriers (29.7 and 24.8, respectively) than those with a VUS or negative results (17.4 and 16.1, respectively). Having cancer or less education was associated with a significantly higher total MICRA score; race/ethnicity was not associated with the total MICRA score. High‐ and moderate‐risk PV carriers did not differ significantly from one another in the total MICRA score, uncertainty, distress, or positive experiences. Conclusions In a diverse population undergoing genetic counseling and multigene panel testing for hereditary cancer risk, the psychological response corresponded to test results and showed low distress and uncertainty. Further studies are needed to assess patient understanding and subsequent cancer screening among patients from diverse backgrounds. Lay Summary Multigene panel tests for hereditary cancer have become widespread despite concerns about adverse psychological reactions among carriers of moderate‐risk pathogenic variants (mutations) and among carriers of variants of uncertain significance.This large study of an ethnically and economically diverse cohort of patients undergoing panel testing found that 92% “never,” “rarely,” or only “sometimes” reacted negatively to results.Somewhat higher uncertainty and distress were identified among carriers of high‐ and moderate‐risk pathogenic variants, and lower levels were identified among those with a variant of uncertain significance or a negative result.Although the psychological response corresponded to risk, reactions to testing were favorable, regardless of results., Multigene panel tests for hereditary cancer have become widespread despite concerns that carriers of moderate‐risk pathogenic variants or uncertain variants could have adverse psychological reactions. This large cohort study of patients undergoing panel testing has found that the psychological response is favorable, regardless of genetic test results.

The quantity and quality of immune responses in colorectal cancers (CRC) are widely variable and have important clinical, therapeutic, and prognostic implications. We studied clinical and epidemiologic factors that might influence T-cell quantity and clonality within colorectal adenocarcinomas to better understand the drivers of diverse immune responses. Incident cases of CRC from the Molecular Epidemiology of Colorectal Cancer Study (MECC) were interviewed, and 6,006 cases had complete epidemiologic data. Archived tumor blocks were retrieved from 3,865 (64.4%) cases, and all were reviewed by a single expert pathologist who quantified TILS/hpf. Sufficient tissue for macrodissection and measurement of TCR abundance and clonality using the immunoSEQ assay (Adaptive Biotechnologies) was available and completed for 2,750 cases. Logistic regression, negative binomial regression and linear regression models were used to evaluate potential associations between clinical and epidemiologic variables for: TILS/hpf, TCR abundance, and T-cell clonality. The stage distribution was representative of cancer incidence in the population, and the MSI-H phenotype was observed in 14.2% of cases. Clinical, pathologic, and epidemiologic variables including aspirin, alcohol, diet, hormone use, physical activity, smoking, and statins were assessed in relation to immune measures. Among other findings, >5 years of statins (p Citation Format: Stephen B. Gruber, Joseph D. Bonner, Sidney S. Lindsey, Ya-Yu Tsai, Rebeca Sanz-Pamplona, M. Henar Alonso, Marilena Melas, Hedy S. Rennert, Kevin J. McDonnell, Gregory E. Idos, Christopher P. Walker, W. Martin Kast, Diane Da Silva, Harlan S. Robins, Joel K. Greenson, Victor Moreno, Stephanie L. Schmit, Gad Rennert. Clinical and epidemiologic predictors of clonal immune responses in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2737.

Immune responses to colorectal cancer (CRC) are important prognostic factors as measured by either tumor infiltrating lymphocytes per high powered field or the presence of Crohn's like lymphoid reaction. New technologies to quantify specific features of immune responses include immunoSeq (Adaptive Biotechnologies), which accurately quantifies T-cell receptor (TCR) abundance and T-cell receptor clonality. Here we measured the independent contributions of TCR abundance and TCR clonality to 5-year CRC-specific survival in the Molecular Epidemiology of Colorectal Cancer (MECC) study. The MECC study consented, interviewed, and followed 6,006 incident cases of CRC diagnosed between March 31, 1998 and July 1, 2017 (median follow-up time = 6.9 years). Archived paraffin blocks were retrieved, and 2,750 cases had sufficient tissue and adequate DNA extraction to perform the immunoSeq assay. Analyses were restricted to 1,625 samples with more than 100 T-cells to permit accurate quantification of TCR abundance and TCR clonality as measured by Simpson Clonality Index. TCR abundance was log2 transformed for analyses, and Simpson Clonality Index was log2-transformed and z-scale normalized separately by assay version. In unadjusted models, dichotomized log2 transformed TCR abundance (Hazard Ratio (HR) = 0.57, 95% confidence interval (CI) 0.47-0.71, p=9.77E-08) and dichotomized TCR clonality (HR = 0.77, 95% CI 0.63-0.94, p=0.01) were each statistically significantly associated with 5-year CRC-specific survival. In a model with adjustment for age, sex, microsatellite instability, stage and assay version, both dichotomized log2 transformed TCR abundance (HR = 0.61, 95% CI, 0.49-0.75, p=3.03E-06), and dichotomized TCR clonality (HR = 0.81, 95% CI, 0.66-0.99, p=0.048) were associated with improved 5-year disease-specific survival. Conclusion: TCR abundance and TCR clonality are independent prognostic indicators in CRC. Citation Format: Joseph Bonner, Sephanie L. Schmit, Sidney S. Lindsey, Ya-Yu Tsai, Rebeca Sanz-Pamplona, M. Henar Alonso, Marilena Melas, Hedy S. Rennert, Kevin J. McDonnell, Gregory Idos, Christopher P. Walker, W. Martin Kast, Diane Da Silva, Harlan S. Robins, Joel K. Greenson, Victor Moreno, Gad Rennert, Stephen B. Gruber. T-cell abundance, clonality and disease specific survival in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 835.

OBJECTIVE This study tested the effectiveness and cost-effectiveness of interpersonal psychotherapy (IPT) for major depressive disorder (MDD) among prisoners. It is the first fully powered randomized trial of any treatment (pharmacological or psychosocial) targeting MDD among incarcerated individuals. METHOD One hundred eighty-one male (n = 117) and female (n = 64) prisoners from prison facilities in 2 states were randomized to group IPT (delivered by master's-level and nonspecialist prison counselors) for MDD plus prison treatment as usual (TAU) or to TAU alone. Participants' average age was 39 (range = 20-61); 20% were African American and 19% were Hispanic. Outcomes assessed at posttreatment and 3-month follow-up included depressive symptoms (primary; assessed using the Hamilton Rating Scale for Depression), suicidality (assessed with the Beck Scale for Suicide Ideation and Beck Hopelessness Scale), in-prison functioning (i.e., enrollment in correctional programs; discipline reports; aggression/victimization; and social support), remission from MDD, and posttraumatic stress disorder symptoms. RESULTS IPT reduced depressive symptoms, hopelessness, and posttraumatic stress disorder symptoms, and increased rates of MDD remission relative to prison TAU alone. Effects on hopelessness were particularly strong. Cost per patient was $2,054 including costs for IPT training and supervision or $575 without these costs. For providers running their second or subsequent IPT group, cost per additional week in remission from MDD (relative to TAU alone) was $524 ($148 excluding training and supervision costs, which would not be needed for established programs). CONCLUSIONS IPT is effective and cost-effective and we recommend its use for MDD among prisoners. It is currently the only treatment for MDD evaluated among incarcerated individuals. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

e20513 Background: Lung cancer is the leading cause of cancer death in Taiwan. The poor prognosis of lung cancer patients with advanced disease and recent development of precision medicine motivates the investigation of molecular targets. The purpose of the study is to estimate the prevalence of KRAS gene mutations and 15 other gene targets among non-small cell lung cancer (NSCLC) patients in Taiwan. Methods: This retrospective study included 933 NSCLC patients diagnosed between January 1992 and July 2018 at six medical centers in Taiwan, including Taichung Veteran’s General Hospital, Chung San Medical University Hospital, China Medical University Hospital, Kaohsiung Veteran’s General Hospital, Tri-Service General Hospital and National Taiwan University Hospital. Patients ≥18 years, had primary histologically confirmed NSCLC diagnosis at time before any treatment, and availability of archival tumor tissue with >30% tumor cellularity. Mutational Analysis: The Formalin-Fixed Paraffin-Embedded (FFPE) tumor blocks were analyzed for the prevalence of somatic mutations. The entire coding sequence of 16 genes was analyzed by next generation sequencing of macrodissected DNA from FFPE recut slides at a depth of greater than 300x and interrogated for somatic pathogenic variants. RNA was not available; hence this limits sensitivity to detect fusions. Results: The mean age at diagnosis was 62 years, 498/933 (53%) were women, 411/843 (49%) were smokers or former smokers, and 829/933 (89%) of adenocarcinoma histopathology. Stage was available for 723 patients with a distribution of 328/723 (45%) Stage I, 120/723 (17%) Stage II, 210/723 (29%) Stage III, and 65/723 (9%) Stage IV. EGFR mutations were identified in 327/933 (35.1%) and TP53 mutations in 179/933 (19.2%). KRAS mutations were identified in 72/933 (7.7%) patients, with KRAS G12C mutations observed in 23/933 (2.5%), KRAS G12D in 16/933 (1.7%), and KRAS G12V in 14/933 (1.5%) (Table). In addition, co-occurring mutations with KRAS were observed and are highlighted, including 14 TP53, 4 PIK3CA, 2 EGFR, 2 CTNNB1, 1 STK11, 1 BRAF and 1 PTEN. Conclusions: EGFR and TP53 were the most frequent mutations identified among all stage NSCLC in Taiwanese populations, followed by KRAS. KRAS G12C and KRAS G12D, the two most frequent KRAS mutations, were identified in 32% and 22% of the KRAS-mutant tumors. Although the prevalence of any KRAS mutation or KRAS G12C mutation is lower than typically seen in Western countries, it is similar to observations among Asian populations. These findings broaden the understanding of the mutational landscape of NSCLC patients in Taiwan to inform development of new therapeutic approaches. [Table: see text]

e18813 Background: The City of Hope Center for Precision Medicine developed an enterprise-wide platform and precision medicine program to unlock the research potential and clinical value of complex and unique datasets by combining patient data with comprehensive genomic profiling and proprietary analytics. POSEIDON (Precision Oncology Software Environment Interoperable Data Ontologies Network) is a secure, cloud-based Oncology Insights Engine enabling exploration, analysis, visualization, and collaboration on our patient clinico-genomic data along with public data sources. This platform enables investigators to access and visualize data from clinical and multi-omics data and provides an engine that can be utilized for cohort discovery and exploration, preliminary feasibility testing to deriving patient specific insights based on real world data (RWD) and real-world evidence (RWE). Patients are consented through an IRB-approved protocol with active, opt-in participation. Methods: The POSEIDON Common Data Model (PCDM) is a standard, extensible data schema that incorporates patient data to support Precision Medicine. Data are incorporated from disparate data sources and stored in a combined harmonized manner promoting consistency of data and meaning across downstream applications. A multi-step process was created to capture and structure multiple data types into the PCDM. Natural language processing (NLP) tools are deployed to automate and structure valuable data elements from unstructured documents including pathology reports and clinical notes. NLP augmented software tools were developed to assist manual data abstractors to capture more complex terms and disease specific data elements which can include disease progression, progression free survival, and other outcomes. Results: Comprehensive data from 175,000 City of Hope patients are included within this environment for cohort exploration, longitudinal follow-up, outcomes, hypothesis development, and queries for synthetic controls. Data from disease specific-research registries constitute a rich dataset within POSEIDON by disease and tumor type, including lung cancer, colorectal cancer, breast cancer, leukemia, lymphoma and multiple myeloma, among other disease types. Automated genomic workflows were created to gain access to genomic profiling and whole exome sequencing. Genomic data is associated with the clinical data in the PCDM. Automated data flows from the Enterprise Data Warehouse EDW include data that is captured in discrete formats in the EDW and provided for in the PCDM and further enrich the data that flows from the disease registries. Statistically rigorous methods for de-identification are applied for collaborative studies. Conclusions: The City of Hope Center for Precision Medicine and the POSEIDON platform offer an exceptional resource for collaborative RWD & RWE studies.

10603 Background: Clinicians have used strict criteria to determine eligibility for cancer susceptibility (CS) testing and have limited genetic assessment to cancer-related genes. However, half of all CS mutation carriers are missed by criteria-based testing and there may be an unrecognized opportunity to modify care for patients who have rare but actionable genetic disorders as defined by the American College of Medical Genetics (ACMG). With the aim of improving patient outcomes through precision genomics, we initiated an enterprise-wide program to offer somatic and germline sequencing to all patients. Methods: We offer consented patients clinical grade paired somatic & germline WES/ RNA seq and panel germline testing for cancer (156 genes) and ACMG disorders (59 genes). Results are reviewed by a Precision Oncology Tumor Board. Somatic results are returned by the treating team. Germline results are returned by phone (genetic counselor, GC) followed by a clinic visit (GC+MD) for those with pathogenic/likely pathogenic (P/LP) mutations and selected variants of uncertain significant. We evaluated the proportions of patients with somatic findings suggestive of germline conditions and those carrying P/LP mutations in CS and ACMG genes. Results: 1,804 patients enrolled and received somatic sequencing: 52% female; 51% non-Hispanic White/ 20% Hispanic White/ 18% Asian/ 4% Black/ 7% other; median age 64. Review of somatic data suggest that 14% have findings suggestive of germline conditions based on factors such as TMB, MSI, and young age. Of the patients offered germline testing, >95% opted to receive CS/ACMG results. To date, we have sequenced 684 patients for CS and 647 for ACMG. 18% of patients had P/LP mutations in CS genes and 4% had P/LP mutations in ACMG non-cancer genes (Table). Conclusions: Prospective somatic/germline sequencing of unselected cancer patients reveals tumor findings suggestive of germline disorders and identifies patients with CS and non-cancer genetic conditions. These findings highlight the promise of a comprehensive sequencing approach to help guide cancer treatment, management of unrecognized cancer risk and the need for concomitant management of rare disorders such as arrhythmogenic cardiomyopathy and susceptibility to adverse reactions with anesthesia.[Table: see text]

Introduction Recent studies indicate low rates of follow-up colonoscopy after abnormal fecal immunochemical testing (FIT) within safety net health systems. A patient navigation (PN) program is an evidence-based strategy that has been shown to improve colonoscopy completion in private and public healthcare settings. The aim of this study was to evaluate the effectiveness of a PN program to encourage follow-up colonoscopy after abnormal FIT within a large safety net hospital system. Methods We established an enterprisewide PN program at 5 tertiary care hospitals within the Los Angeles County Department of Health Services system in 2018. The PN assisted adult patients aged 50-75 years with an abnormal FIT to a follow-up colonoscopy within 6 months. PN activities included initiating referral for and scheduling of colonoscopy, performing reminder phone calls to patient for their upcoming colonoscopy, and following up with patients who did not attend their colonoscopy. We assess the effectiveness of the PN intervention by comparing follow-up colonoscopy rates with a period before the intervention. Results There were 2,531 patients with abnormal FIT results (n = 1,214 in 2017 and n = 1,317 in 2018). A majority were women (55% in 2017 vs 52% in 2018) with a mean age of 60 ± 6.2 years. From a previous mean of 163 days without PN in 2017, the mean time from abnormal FIT to colonoscopy with PN improved to 113 days in 2018. The frequency of colonoscopy completion with PN increased from 40.6% (n = 493) in 2017 to 46% (n = 600) in 2018. Discussion After the introduction of the PN program, there was a significant increase in patients undergoing follow-up colonoscopy after abnormal FIT and patients were more likely to undergo colonoscopy within the recommended 6 months.

e14006 Background: Next generation sequencing (NGS) allows for reliable, comprehensive and cost-effective identification of clinically actionable genetic and genomic alterations. The increasing adoption of NGS in clinical oncology has increased our ability to identify germline alterations predisposing to cancer development as well as somatic changes enabling prescription of individualized cancer treatment and enhanced clinical trial participation. Here we summarize implementation of an NGS-based precision medicine initiative involving oncology patients from a single institution cancer center. Methods: IRB-approved NGS matched whole exome (WES) germline and solid tumor somatic tumor sequencing together with somatic tumor RNA sequencing (RNA-seq) were performed using germline DNA extracted from peripheral blood lymphocytes and nucleic acids for tumor DNA and RNA sequencing obtained from formalin-fixed, paraffin-embedded tumor specimens. Results of sequencing and analyses were presented to a multi-disciplinary tumor board to establish recommendations for management of germline pathogenic variation, therapeutic drug matching, clinical trials eligibility and molecularly informed patient prognosis. Results: A total of 1,005 patients completed sequencing. Germline and somatic WES exceeded 100X and 250X mean target coverage, respectively; somatic RNA-seq exceeded 200 million mean reads. Patients ranged in age from 17 to 90 years. The study cohort comprised comparable numbers of female (51%) and male (49%) patients. Ethnicities and races were broadly represented with 22% of participants identifying as Hispanic, 14% as Asian, 4% as Black, 55% as Non-Hispanic White and 5% as other. The most common solid tumor histological classification was colorectal (18%), followed by breast (16%), prostate (7%), head and neck (7%), sarcoma (7%), ovarian (5%), melanoma (4%) and lung (3%). Bioinformatic analyses and precision medicine tumor board review established that 12% of patients harbored a germline pathogenic variant and 43% carried clinically actionable genetic/genomic alterations; a majority of patients met molecular requirements for participation in a clinical trial. Conclusions: This study confirms the feasibility and utility of clinical NGS and precision medicine tumor board review in clinical oncology to identify germline genetic pathology, deliver personalized cancer therapeutics, increase clinical trial enrollment and clarify diagnosis and prognosis.

1592 Background: The germline variant APC I1307K is one of the most commonly identified pathogenic variants on germline genetic testing panels. The purpose of the Molecular Epidemiology of Colorectal Cancer study was to quantify the risk of colorectal cancer among carriers, characterize the clinical, pathologic, and molecular features of colorectal cancers arising in patients with APC I1307K, and to describe the overall and disease-specific survival of carriers with colorectal cancer. Here, the final results of the Molecular Epidemiology of Colorectal Cancer Study are reported with respect to APC I1307K. Methods: We consented 6,006 incident, pathologically confirmed cases of colorectal adenocarcinoma and 5,023 age, sex, and ethnicity matched controls without colorectal cancer between March 31, 1998 and July 1, 2017 within a geographically defined area of Northern Israel. Comprehensive, in-person epidemiologic interviews were conducted for cases and controls, with uniform histopathologic review, detailed molecular analysis, medical record review and clinical follow-up for up to 21 years. Results: The demographic and clinical features of incident colorectal cancer cases matched the population distribution of colorectal cancer in Israel. APC I1307K was identified in 429 (7.1%) of cases and 201 (4.0%) of controls. The estimated relative risk of colorectal cancer among carriers was 1.89 (95% confidence interval, 1.59 - 2.24), p < 0.0001. The prevalence and odds ratios differed by ethnic group. Homozygous carriers were at especially high risk, with an odds ratio of 3.90 (95% confidence interval 1.11–13.71). APC I1307K carriers were significantly less likely to have microsatellite instable tumors (p = 0.04). Overall survival of APC I1307K carriers was not significantly different than survival of non-carriers, after adjustment for age, stage, sex, ethnicity, and microsatellite instability. Conclusions: APC I1307K is an actionable germline mutation that confers meaningful lifetime risk of colorectal cancer in heterozygous and homozygous carriers. APC I1307K is not an independent prognostic factor for overall survival or disease specific survival and is not associated with the MSI phenotype. Cumulative lifetime risk estimates inform genetic counseling and provide data for policies regarding the timing and frequency of screening and other preventive strategies.

Our study sought to estimate the association between race, gender, comorbidity and body mass index (BMI) on the incidence of hospital-acquired pressure ulcer (PU) from a population-based retrospective cohort comprising 242 745 unique patient hospital discharges in two fiscal years from July 2009 to June 2010 from 15 general and tertiary care hospitals. Cases were patients with a single inpatient encounter that led to an incident PU. Controls were patients without a PU at any encounter during the two fiscal years with the earliest admission retained for analysis. Logistic regression models quantified the association of potential risk factors for PU incidence. Spline functions captured the non-linear effects of age and comorbidity. Overall 2·68% of patients experienced an incident PU during their inpatient stay. Unadjusted analyses revealed statistically significant associations by age, gender, race, comorbidity, BMI, admitted for a surgical procedure, source of admission and fiscal year, but differences by gender and race did not persist in adjusted analyses. Interactions between age, comorbidity and BMI contributed significantly to the likelihood of PU incidence. Patients who were older, with multiple comorbidities and admitted for a surgical diagnosis-related groups (DRG) were at greater risk of experiencing a PU during their stay.

Previous studies identified a cluster of individuals with an autosomal recessive form of deafness that reside in a small region of mid-Michigan. We hypothesized that affected members from this community descend from a defined founder population. Using public records and personal interviews, we constructed a genealogical database that includes the affected individuals and their extended families as descendants of 461 settlers who emigrated from the Eifel region of Germany between 1836 and 1875. The genealogical database represents a 13-generation pedigree that includes 27,747 descendants of these settlers. Among these descendants, 13,784 are presumed living. Many of the extant descendants reside in a 90-square-mile area, and 52% were born to parents who share at least one common ancestor. Among those born to related parents, the median kinship coefficient is 3.7 × 10(-3). While the pedigree contains 2,510 founders, 344 of the 461 settlers accounted for 67% of the genome in the extant population. These data suggest that we identified a new population isolate in North America and that, as demonstrated for congenital hearing loss, this rural mid-Michigan community is a new resource to discover heritable factors that contribute to common health-related conditions.

The Study to Explore Early Development (SEED), a multisite investigation addressing knowledge gaps in autism phenotype and etiology, aims to: (1) characterize the autism behavioral phenotype and associated developmental, medical, and behavioral conditions and (2) investigate genetic and environmental risks with emphasis on immunologic, hormonal, gastrointestinal, and sociodemographic characteristics. SEED uses a case–control design with population-based ascertainment of children aged 2–5 years with an autism spectrum disorder (ASD) and children in two control groups—one from the general population and one with non-ASD developmental problems. Data from parent-completed questionnaires, interviews, clinical evaluations, biospecimen sampling, and medical record abstraction focus on the prenatal and early postnatal periods. SEED is a valuable resource for testing hypotheses regarding ASD characteristics and causes.

Identification of microsatellite unstable (MSI-H) colorectal cancers (CRCs) is important not only for the identification of hereditary nonpolyposis colorectal cancer syndrome but also because MSI-H CRCs have a better prognosis and may respond differently to 5-fluorouracil-based chemotherapy. We present 2 nearly equivalent logistic regression models for clinical use that predict microsatellite instability based on the review of 1649 CRCs from patients of all ages collected in a population-based case control study in northern Israel. One hundred ninety-eight of these 1649 tumors demonstrated a high degree of microsatellite instability (12%). Multivariate analysis found that2 tumor-infiltrating lymphocyte (TIL) cells per high-powered field, the lack of dirty necrosis, the presence of a Crohn-like reaction, right-sided location, any mucinous differentiation (mucinous or focally mucinous) and well or poor differentiation, and age less than 50 were all independent predictors of MSI-H. We developed 2 logistic regression models that differ only by the statistical approach used to analyze the number of TIL cells per high-powered field, where the slightly more accurate (and complex) model uses the log of the total number of TIL cells. The simpler clinical model uses a cut-off of 2TIL cells per high-powered field. The accuracy of both models is high, with an 85.4% versus 85.0% probability of correctly classifying tumors as MSI-H. By employing the simpler model, pathologists can predict the likelihood of microsatellite instability by compiling the MSI probability score (Table 4 and Fig. 1) from simple histologic and clinical data available during sign-out. Our model shows that approximately 43% of CRCs have a MSI probability score of 1 or less and hence have little likelihood (3%) of being MSI-H. Although this model is not perfect in predicting microsatellite instability, its use could improve the efficiency of expensive diagnostic testing.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and effective lipid-lowering agents. Statins inhibit the growth of colon-cancer cell lines, and secondary analyses of some, but not all, clinical trials suggest that they reduce the risk of colorectal cancer.The Molecular Epidemiology of Colorectal Cancer study is a population-based case-control study of patients who received a diagnosis of colorectal cancer in northern Israel between 1998 and 2004 and controls matched according to age, sex, clinic, and ethnic group. We used a structured interview to determine the use of statins in the two groups and verified self-reported statin use by examining prescription records in a subgroup of patients for whom prescription records were available.In analyses including 1953 patients with colorectal cancer and 2015 controls, the use of statins for at least five years (vs. the nonuse of statins) was associated with a significantly reduced relative risk of colorectal cancer (odds ratio, 0.50; 95 percent confidence interval, 0.40 to 0.63). This association remained significant after adjustment for the use or nonuse of aspirin or other nonsteroidal antiinflammatory drugs; the presence or absence of physical activity, hypercholesterolemia, and a family history of colorectal cancer; ethnic group; and level of vegetable consumption (odds ratio, 0.53; 95 percent confidence interval, 0.38 to 0.74). The use of fibric-acid derivatives was not associated with a significantly reduced risk of colorectal cancer (odds ratio, 1.08; 95 percent confidence interval, 0.59 to 2.01). Self-reported statin use was confirmed for 276 of the 286 participants (96.5 percent) who reported using statins and whose records were available.The use of statins was associated with a 47 percent relative reduction in the risk of colorectal cancer after adjustment for other known risk factors. Because the absolute risk reduction is likely low, further investigation of the overall benefits of statins in preventing colorectal cancer is warranted.

Overexpression of the epidermal growth factor (EGF) pathway has been implicated in melanoma pathogenesis, and a recent case-control study identified a single nucleotide polymorphism (G to A) in the EGF gene where the G allele was associated with increased EGF expression and an increased risk of melanoma. To further evaluate this association, we conducted a case-control analysis from the Genes, Environment, and Melanoma study at the University of Michigan site using two different study designs. Incident cases of histopathologically confirmed first primary melanoma that were diagnosed between January 1, 2000 and December 31, 2000 from the University of Michigan Melanoma Clinic (n = 330) were compared with the following two different sources of nonmelanoma controls: spouse/friend controls (n = 84) and healthy volunteer controls from a case-control study of psoriasis (n = 148). Using a second analytic design, comparisons between multiple primary melanoma cases (n = 62) and single primary melanoma cases (n = 330) were also evaluated to estimate odds ratios (ORs). Genotyping for the single nucleotide substitution (G to A) at position 61 in the 5′ untranslated region of the EGF gene was performed from genomic DNA, and epidemiological risk factors were assessed through a telephone interview. When EGF genotypes were compared between incident primary melanoma cases and the nonmelanoma controls, the risk associated with the homozygous G/G genotype was not statistically significantly associated with an increased risk for incident primary melanoma compared with the homozygous A/A genotype [OR, 1.09; 95% confidence interval (CI); 0.65–1.85]. No strong associations with EGF G/G genotype were observed in comparisons of multiple primary and single primary melanoma cases (OR, 0.66; 95% CI; 0.25–1.73). Case subjects with tumors ≥3.5 mm compared with those

Objectives To describe the use of complementary and alternative medicines (CAMs) among men with a family history of prostate cancer and to evaluate the relationship between selected sociodemographic and behavioral characteristics and the use of CAMs. Methods Unaffected brothers of men diagnosed with prostate cancer were asked to participate in a short computer-assisted telephone interview. The survey focused primarily on the use of different vitamins, herbal supplements, and medications, some of which are marketed for prostate health or prostate cancer prevention. Results A total of 111 men completed the survey, representing 66% of eligible study subjects. Of the 111 men, 61 (55%) reported currently taking some form of CAM, with 30% taking a vitamin or supplement purported to have prostate-specific benefits. The prevalence of CAM use generally increased with increasing age; however, men who were younger than their affected brother at the time of the diagnosis of prostate cancer were more likely to use CAMs than were older brothers. Conclusions Most men with a family history of prostate cancer take vitamins and supplements, some of which are believed to prevent future cancer occurrence. The results of this study and others provide some insight into the determinants of potentially beneficial health behaviors in high-risk individuals.

Background Mutations in BRCA1 and/or BRCA2 (BRCA1/2) profoundly increase the risks of breast and ovarian cancers, but it is unclear whether mutations in these genes increase the risk of colorectal cancer. We investigated BRCA1/2 founder mutations and a family history of breast cancer as potential risk factors for colorectal cancer. Methods In the population-based Molecular Epidemiology of Colorectal Cancer study in northern Israel, 1422 case patients with incident colorectal cancer, diagnosed between March 31, 1998, and December 31, 2002, and 1566 control subjects without colorectal cancer were genotyped for the BRCA1 187delAG, BRCA1 5385insC, and BRCA2 6174delT founder mutations. Genotypes and interview data from all case patients and control subjects and from only those of Ashkenazi Jewish descent (1002 case patients and 1038 control subjects) were used to calculate odds ratios [ORs] from logistic regression. Results Twenty-four (2.4%) case patients and 20 (1.9%) control subjects carried one of the three mutations (OR = 1.24, 95% confidence interval [CI] = 0.68 to 2.26). A family history of breast cancer in a female relative was not associated with an increased risk of colorectal cancer, even after adjustment for the presence of a BRCA founder mutation (OR = 1.03, 95% CI = 0.75 to 1.41). Conclusions Although weak associations cannot be excluded, Ashkenazi BRCA founder mutations do not confer a strongly elevated risk of colorectal cancer. Similarly, a family history of breast cancer does not appear to be a strong risk factor for colorectal cancer in this population.

The phenotypic markers of colorectal carcinomas with microsatellite instability have been widely studied and include mucinous or poor differentiation, prominent host response, a circumscribed growth pattern, histologic heterogeneity, and right-sided location. As part of a population-based case-control study of colorectal cancer in northern Israel, we reviewed the pathology and microsatellite status of 528 consecutively diagnosed colorectal cancers. Phenotypic analysis was performed by one pathologist (J.K.G.) and included assessment of grade, mucinous histology (50%, or focal), histologic heterogeneity, growth pattern, necrosis, and host response. Microsatellite status was determined on microdissected portions of formalin-fixed, paraffin-embedded tissue using a panel of 5 NCI consensus primers. Fifty-two of 528 colorectal carcinomas were microsatellite unstable (9.85%). Multivariate analysis found that2 tumor infiltrating lymphocytes per high power field (p0.0001), the lack of dirty necrosis (p = 0.0054), a Crohn's-like host response (p = 0.0064), right-sided location (p = 0.032), well or poor differentiation (p = 0.037), and any mucinous differentiation (p = 0.039) were independent predictors of microsatellite instability. Tumor infiltrating lymphocytes were the single best histologic predictor of microsatellite instability. The absence of dirty necrosis and the presence of well-differentiated tumors and tumors with only focal mucinous differentiation were also important markers for microsatellite instability that have not been emphasized previously. The combination of2 tumor infiltrating lymphocytes per high power field and/or any mucinous differentiation and/or the absence of dirty necrosis identified all MSI-H tumors in this study.

Our study sought to estimate the association between race, gender, comorbidity and body mass index (BMI) on the incidence of hospital‐acquired pressure ulcer (PU) from a population‐based retrospective cohort comprising 242 745 unique patient hospital discharges in two fiscal years from July 2009 to June 2010 from 15 general and tertiary care hospitals. Cases were patients with a single inpatient encounter that led to an incident PU. Controls were patients without a PU at any encounter during the two fiscal years with the earliest admission retained for analysis. Logistic regression models quantified the association of potential risk factors for PU incidence. Spline functions captured the non‐linear effects of age and comorbidity. Overall 2·68% of patients experienced an incident PU during their inpatient stay. Unadjusted analyses revealed statistically significant associations by age, gender, race, comorbidity, BMI, admitted for a surgical procedure, source of admission and fiscal year, but differences by gender and race did not persist in adjusted analyses. Interactions between age, comorbidity and BMI contributed significantly to the likelihood of PU incidence. Patients who were older, with multiple comorbidities and admitted for a surgical diagnosis‐related groups (DRG) were at greater risk of experiencing a PU during their stay.

Radiologic data are increasingly important in clinical care guidelines for neurologic disorders and in the conduct of clinical trials assessing novel therapies. The infrastructure and expertise for neuroradiologic evaluations remain scarce in resource-limited settings, but where available, MRI and CT capacity can offer new insights into common, globally devastating diseases. In vivo data for frequently fatal tropical conditions such as cerebral malaria have been largely limited to autopsy studies, which only provide information on nonsurvivors at a single point in time. New imaging facilities in sub-Saharan African offer opportunities for expanded research on tropical neurologic disorders.1 However, data management challenges hamper the research utility of radiologic evaluations.

Because nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit tumor growthin vitro, we investigated the association between NSAIDs and melanoma to determine if there was epidemiologic evidence of a chemopreventive effect from these medications. Three hundred twenty-seven subjects with incident melanoma and 119 melanoma-free controls completed a structured interview assessing melanoma risk factors. The unadjusted odds ratio (OR) for use of nonaspirin NSAIDs was 0.58 (95% CI 0.31–1.11), in a comparison of subjects with melanoma to controls. After adjustment for melanoma risk factors, the OR was 0.71 (95% CI 0.23–2.02). Aspirin users had an unadjusted OR of 0.85 (95% CI 0.45–1.69) and an adjusted OR of 1.45 (95% CI 0.44–4.74). In this pilot study, we found no evidence of a significant association between analgesic use and melanoma risk when potential confounders are assessed. Based on conflicting reports in the literature, meta-analysis may be appropriate.

Variations in genetic mutations in pancreatic carcinoma between different populations have not been studied extensively, especially in developing countries where pancreatic cancer is rare. We studied the molecular pathology of 44 pancreatic carcinomas from patients residing in a heavily polluted region in the Nile River delta and compared the findings with tumors from 44 United States (US) patients. We evaluated K-ras mutations in codon 12, p53 mutations in exons 5–8, and Gadd45a mutations in exons 1 and 4. Overall, rates of K-ras, p53 and Gadd45 mutations were not statistically different in tumors of patients from Egypt and the US (67.4 vs. 63.4%; 27.3 vs. 36.4% and 9.1 vs. 4.5%, respectively). However, there were distinct differences in the specific types of K-ras and p53 mutations between the 2 groups. In K-ras ,G fi T transversion mutation was more frequent in the tumors from Egypt than from the US (58.6 vs. 26.9%), whereas G fi C transversion was detected in 26.9% of US tumors but none from Egypt (p 5 0.003). We also found a trend toward differences in the p53 exons in which mutations occurred, with higher frequency of exon 5 mutation and lower frequency of exon 6 mutation in Egyptian tumors. Logistic regression showed that K-ras G fi T transversion mutations and p53 exon 6 mutations were predicted by the country of residence of the patients. Our study identifies that there are differences in the types of mutations found in tumors from pancreatic carcinoma patients in Egypt and the US, and suggests that environmental factors may explain these differences. ' 2006 Wiley-Liss, Inc.

The kin-cohort design has been proposed as an alternative to traditional case-control and cohort measures to evaluate inherited susceptibility to cancer in population-based studies. Here, we used this design to evaluate inherited susceptibility to prostate cancer associated with APC I1307K using data from the Molecular Epidemiology of Colorectal Cancer study. Two techniques were used to compare the incidence of prostate cancer in APC I1307K carriers. First, we compared the incidence of prostate cancer in relatives of mutation carriers and noncarriers using standard techniques for survival analysis. Second, we used the marginal maximum likelihood method for kin-cohort analysis to infer the genotypes in the relatives. We also evaluated APC I1307K in 75 Ashkenazi Jewish individuals with prostate cancer from 27 families enrolled in the University of Michigan Prostate Cancer Genetic Study. We observed a slightly increased risk of prostate cancer in relatives of APC I1307K carriers, however, this difference was not statistically significant (hazard ratio, 1.6; 95% confidence intervals, 0.7-3.4). Similar conclusions were drawn using both techniques for kin-cohort analysis. APC I1307K was found in 7.4% of families genotyped, which is slightly higher than the allele prevalence reported in Ashkenazi Jews in the general population. In addition, we did not observe loss of heterozygosity at APC or a somatic mutation near APC I1307K using microdissected tumor DNA from mutation carriers enrolled in the Prostate Cancer Genetic Study. Overall, the evidence for an association between APC I1307K and prostate cancer is not compelling. APC I1307K is unlikely to play a clinically meaningful role in susceptibility to prostate cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(3):468–73)

ContextIn 1895, Aldred Scott Warthin, MD, PhD, initiated one of the most thoroughly documented and longest cancer family histories ever recorded. The unusually high incidence and segregation of cancers of the colon, rectum, stomach, and endometrium in Dr Warthin’s family G was later followed up by his colleagues, most recently by Henry Lynch, MD. Described today as a Lynch syndrome family, family G was last documented in 1971, prior to the modern era of molecular diagnostics.ObjectiveTo update family G.Design, Setting, and ParticipantsHistorical prospective cohort study of family G members from 1895 to 2000.Main Outcome MeasuresThe primary outcomes were the frequencies and types of cancers, ages at diagnosis, and presence of the T to G transversion at the splice acceptor site of exon 4 of the mutS homolog 2, colon cancer, nonpolyposis type 1 (E coli) (MSH2) gene in family G members. A secondary analysis compared cancer-specific incidence rates in family G with published national and regional cancer incidence rates through the standardized incidence ratio (SIR).ResultsFamily G now has 929 known descendants of the original progenitor first reported in 1913. Cancers of the colon and rectum (SIR, 3.20; 95% confidence interval [CI], 2.39-4.19) and endometrium (SIR, 3.51; 95% CI, 1.92-5.89) continue to predominate in family G. Five of 40 tested members of family G carry the MSH2 T to G mutation; as a result, 15 of their living relatives are at increased risk of developing 1 or more colorectal or Lynch syndrome–associated cancers. In contrast, 97 living members of family G can now be excluded as mutation carriers.ConclusionWithin the last decade, molecular diagnostic testing has transformed the care of family G and other Lynch syndrome families in which a pathogenic mutation has been identified.

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906G→C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P=.042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P=.033). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%–3% of colorectal cancer in those whose age at diagnosis is

1027 Background: Non-steroidal anti-inflammatory medications (NSAIDs) have been shown to inhibit tumor growth in melanoma cell lines and mouse models of melanoma. We investigated the association be...

1 Background: 3-hydroxy-2-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors are effective lipid-lowering agents that also inhibit the growth of colon cancer cell lines and were noted to be a...

Genomic instability is a hallmark of cancer and is featured prominently in Bloom syndrome. Bloom syndrome, the prototype of somatic mutational disorders, is a rare autosomal recessive disorder characterized by a profound predisposition to cancer. Bloom syndrome is caused by inactivating, germline