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Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer, though mechanisms underlying these effects are incompletely understood. Human organoids are an ideal system to study genomic and epigenomic host-environment interactions. We use human colonic organoids to profile ASA responses on genome-wide gene expression and chromatin accessibility. Human colonic organoids from one individual were cultured and treated in triplicate with 3 mM ASA or vehicle control (DMSO) for 24 h. Gene expression and chromatin accessibility were measured using RNA- and ATAC-sequencing, respectively. Differentially expressed genes were analyzed using DESeq2. Top genes were validated by qPCR. Gene set enrichment was performed by SetRank. Differentially accessible peaks were analyzed using DiffBind and edgeR. Peak annotation and differential transcription factor motifs were determined by HOMER and diffTF. The results showed robust transcriptional responses to ASA with significant enrichment for fatty acid oxidation and peroxisome proliferator-activated receptor (PPAR) signaling that were validated in independent organoid lines. A large number of differentially accessible chromatin regions were found in response to ASA with significant enrichment for Fos, Jun, and Hnf transcription factor motifs. Integrated analysis of epigenomic and genomic treatment responses highlighted gene regions that could mediate ASA’s specific effects in the colon including those involved in chemoprotection and/or toxicity. Assessment of chromatin accessibility and transcriptional responses to ASA yielded new observations about genome-wide effects in the colon facilitated by application of human colonic organoids. This framework can be applied to study colonic ASA responses between individuals and populations in future studies.

Identifying individuals who have Lynch syndrome involves a complex diagnostic workup that includes taking a detailed family history and a combination of various tests such as immunohistochemistry and/or molecular which may be germline and/or somatic. The National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer have come together to publish this practice resource for the evaluation of Lynch syndrome. The purpose of this practice resource was to provide guidance and a testing algorithm for Lynch syndrome as well as recommendations on when to offer testing. This practice resource does not replace a consultation with a genetics professional. This practice resource includes explanations in support of this and a summary of background data. While this practice resource is not intended to serve as a review of Lynch syndrome, it includes a discussion of background information and cites a number of key publications which should be reviewed for a more in-depth understanding. This practice resource is intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses, and other healthcare providers who evaluate patients for Lynch syndrome.

Screening for colorectal cancer (CRC) in Lynch syndrome enables early detection and likely cancer prevention. CRC screening guidelines have evolved from universal to gene-specific recommendations based on lifetime neoplasia risks. Regular screening for Lynch syndrome reduces CRC-related mortality; however, high CRC incidence during regular colonoscopy screening suggests the possibility of nonpolypoid carcinogenesis. Colonoscopy is the primary modality for screening for Lynch syndrome with mixed and emerging data on quality metrics, chromoendoscopy, artificial intelligence, and nonendoscopic modalities. Screening adherence varies across studies. In this review, we present the current state of CRC screening recommendations, outcomes, and modalities in Lynch syndrome.

Purpose: African Americans (AA) have the highest incidence of colorectal cancer compared with other U.S. populations and more proximal colorectal cancers. The objective is to elucidate the basis of these cancer disparities.Experimental design: Of note, 566 AA and 328 non-Hispanic White (NHW) colorectal cancers were ascertained in five Chicago hospitals. Clinical and exposure data were collected. Microsatellite instability (MSI) and BRAF (V600E) and KRAS mutations were tested. Statistical significance of categorical variables was tested by the Fisher exact test or logistic regression and age by the Mann–Whitney U test.Results: Over a 10-year period, the median age at diagnosis significantly decreased for both AAs (68–61; P < 0.01) and NHWs (64.5– 62; P = 0.04); more AA patients were diagnosed before age 50 than NHWs (22% vs. 15%; P = 0.01). AAs had more proximal colorectal cancer than NHWs (49.5% vs. 33.7%; P < 0.01), but overall frequencies of MSI, BRAF and KRAS mutations were not different nor were they different by location in the colon. Proximal colorectal cancers often presented with lymphocytic infiltrate (P < 0.01) and were diagnosed at older ages (P = 0.02). Smoking, drinking, and obesity were less common in this group, but results were not statistically significant.Conclusions: Patients with colorectal cancer have gotten progressively younger. The excess of colorectal cancer in AAs predominantly consists of more proximal, microsatellite stable tumors, commonly presenting lymphocytic infiltrate and less often associated with toxic exposures or a higher BMI. Younger AAs had more distal colorectal cancers than older ones. These data suggest two different mechanisms driving younger age and proximal location of colorectal cancers in AAs. Clin Cancer Res; 20(18); 4962–70. ©2014 AACR.

PURPOSE Guidelines recommend all patients with pancreatic ductal adenocarcinoma (PDAC) undergo germline genetic testing (GT). Rates of recommendation and completion of GT among diverse patients with PDAC are not known. The aim was to determine rates of recommendation and completion of point-of-care GT in diverse patients with PDAC. METHODS A retrospective review of patients with PDAC seen at an academic center between April 2019 and December 2020 was performed. Recommendation, completion and results of point-of-care GT, and demographic and clinical factors were recorded. Univariate and multivariate analyses of GT were performed using the chi-square test and logistic regression. RESULTS In total, 579 patients with PDAC were included. The median age at diagnosis was 67 years; 52% were male; 63% were non-Hispanic White (NHW) patients, and 20% were African American (AA) patients. GT was performed in 216 (37%) patients. Of those tested, 47 (22%) had a pathogenic/likely pathogenic variant identified of which 25 (12%) were in PDAC-associated genes. On multivariate analysis, age, NHW race, personal and family cancer history, medical oncology visit, and number of visits were independent predictors of GT completion. AA patients had significantly lower rates of recommendation and completion of GT compared with NHW patients. CONCLUSION Point-of-care GT in patients with PDAC is unacceptably low, especially among AA patients. Testing disparity might be due to lack of provider recommendation more than patient uptake. Lack of testing leads to missed opportunities for potential targeted therapies, improved outcomes, and identification of at-risk family members who could potentially benefit from surveillance.

Germline variants in CDH1 are associated with elevated risks of diffuse gastric cancer and lobular breast cancer. It is uncertain whether there is an increased risk of colorectal neoplasia.This was a retrospective analysis of colonoscopy outcomes in patients with germline CDH1 pathogenic/likely pathogenic variants.Eighty-five patients were included with a mean age of 46.9 years. Initial colonoscopy found adenomatous polyps in 30 patients (35.3%), including advanced adenomas in 9 (10.6%). No colorectal cancers were identified on index or subsequent colonoscopies (when available).CDH1 carriers have colorectal neoplasia identified at similar rates as in the general population. Despite potential difficulties after gastrectomy, colorectal cancer screening remains important in this population.

PURPOSE Strict clinical criteria used by Medicare for germline testing for Lynch syndrome (LS) could lead to missed diagnoses of hereditary cancer syndromes given variable individual and family phenotypes. The aim of this study was to compare rates and spectrum of pathogenic or likely pathogenic (P/LP) variants in LS and other hereditary cancer genes on the basis of meeting Medicare LS testing criteria. METHODS Retrospective review of Medicare beneficiaries who had multigene panel testing with an indication of personal or family history of colorectal cancer (CRC) was performed. Ordering providers determined if Medicare LS criteria were met. The results of genetic testing were compared on the basis of whether or not Medicare testing criteria were met. RESULTS Among 639 Medicare beneficiaries, 495 (77.5%) met testing criteria. Overall rates of P/LP variant identification were similar between those meeting and not meeting testing criteria (18.4% v 11.8%; P = .06). LS was diagnosed more frequently among those meeting testing criteria (10.1% v 4.9%; P = .05). No statistical differences were found in rates of P/LP variant identification for non-LS CRC genes (5.3% v 5.6%; P = .89) or non-CRC genes (4.2% v 2.1%; P = .23). PMS2, MUTYH, and ATM P/LP variants were found at higher rates among those outside of criteria. CONCLUSION Among Medicare beneficiaries undergoing genetic testing for suspected LS, rates of P/LP variants in actionable cancer genes were similar regardless of whether testing criteria were met. Current testing criteria fail to identify individuals with P/LP variants in PMS2 and other actionable cancer genes. Relaxing LS testing criteria could improve identification of individuals with hereditary cancer syndromes among Medicare beneficiaries.

OBJECTIVES Because of high historical no-show rates and poor bowel preparation quality in our unit, we sought to evaluate whether text message navigation for patients scheduled for colonoscopy would reduce no-show rates and improve bowel preparation quality compared with usual care. METHODS We performed a randomized controlled quality improvement study from April to August 2019 in an urban academic endoscopy unit. All patients scheduled for colonoscopy were randomly assigned to a control group that received usual care (paper instructions/nursing precalls) or to the intervention group that received usual care plus the text message program [short message service (SMS)]. The program provided timed-release instructions on dietary modifications and bowel preparation before colonoscopy. The primary outcome was no-shows. Secondary outcomes were no-show/same-day cancellations, no-show/cancellations within 7 days of the procedure, and bowel preparation quality. RESULTS A total of 1625 patients were randomized (SMS=833, control=792). No-show rates were significantly lower in the SMS group compared with the control group (8% vs. 14%; P

The incidence of colorectal cancer (CRC) and cancer-related mortality has increased in patients

Because ADAM17 promotes colonic tumorigenesis, we investigated potential miRNAs regulating ADAM17; and examined effects of diet and tumorigenesis on these miRNAs. We also examined pre-miRNA processing and tumour suppressor roles of several of these miRNAs in experimental colon cancer. Using TargetScan, miR-145, miR-148a, and miR-152 were predicted to regulate ADAM17. miR-143 was also investigated as miR-143 and miR-145 are co-transcribed and associated with decreased tumour growth. HCT116 colon cancer cells (CCC) were co-transfected with predicted ADAM17-regulating miRNAs and luciferase reporters controlled by ADAM17-3’UTR. Separately, pre-miR-143 processing by colonic cells was measured. miRNAs were quantified by RT-PCR. Tumours were induced with AOM/DSS in WT and transgenic mice (Tg) expressing pre-miR-143/miR-145 under villin promoter. HCT116 transfection with miR-145, −148a or −152, but not scrambled miRNA inhibited ADAM17 expression and luciferase activity. The latter was suppressed by mutations in ADAM17-3’UTR. Lysates from colonocytes, but not CCC, processed pre-miR-143 and mixing experiments suggested CCC lacked a competency factor. Colonic miR-143, miR-145, miR-148a, and miR-152 were downregulated in tumours and more moderately by feeding mice a Western diet. Tg mice were resistant to DSS colitis and had significantly lower cancer incidence and tumour multiplicity. Tg expression blocked up-regulation of putative targets of miR-143 and miR-145, including ADAM17, K-Ras, XPO5, and SET. miR-145, miR-148a, and miR-152 directly suppress colonocyte ADAM17 and are down-regulated in colon cancer. This is the first direct demonstration of tumour suppressor roles for miR-143 and miR-145 in an in vivo model of colonic tumorigenesis.

Contains fulltext : 225261.pdf (Publisher’s version ) (Closed access) Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.

PURPOSE Prior estimates of breast cancer risk in women with Lynch syndrome (LS) range from population risk to 18-fold increased risk with reported differences by gene. Here, breast cancer rates were determined in a large cohort of women with pathogenic variants (PVs) in a mismatch repair (MMR) gene detected through multigene panel testing and compared with rates in the US population and women undergoing panel testing. METHODS MMR gene PV carriers were identified among women tested for suspicion of LS or hereditary breast and ovarian cancer (HBOC) who met inclusion criteria. Standardized incidence ratios (SIRs) and 95% CIs of breast cancer were calculated compared with age-matched incidence in the general US female population and with women negative for PVs stratified by the test indication. RESULTS In total, 0.8% of women (30,362 of 441,966 women) carried MMR gene PVs. PVs in PMS2 (37.5%) and MSH6 (29.3%) were more common than in MLH1 (13.7%) and MSH2/EPCAM (19.4%). Women with PVs in PMS2 and MSH6 were tested more frequently for HBOC, whereas those with PVs in MLH1 and MSH2/EPCAM were tested more frequently for LS. Breast cancer rates in women with LS were lower than those in the general female population (SIR, 0.88; 95% CI, 0.81 to 0.96) and did not differ compared with women with negative panel testing for HBOC (SIR, 0.90; 95% CI, 0.82 to 0.99) or LS (SIR, 1.02; 95% CI, 0.78 to 1.30). CONCLUSION In this large cohort of women with LS identified through panel testing, there was no evidence for increased risk of breast cancer compared with the general US population or women undergoing panel testing. These findings support average-risk breast cancer screening in women with LS.

Organoids have immense potential as ex vivo disease models for drug discovery and personalized drug screening. Dynamic changes in individual organoid morphology, number, and size can indicate important drug responses, however these metrics are difficult and labor-intensive to obtain for high-throughput image datasets. Here, we present OrganoID, a robust image analysis platform that automatically recognizes, labels, and tracks single organoids, pixel-by-pixel, in brightfield and phase-contrast microscopy experiments. The platform was trained on images of pancreatic cancer organoids and validated on separate images of pancreatic, lung, colon, and adenoid cystic carcinoma organoids, which showed excellent agreement with manual measurements of organoid count (96%) and size (95%) without any parameter adjustments. Single-organoid tracking accuracy remained above 89% over a four-day time-lapse microscopy study. Automated single-organoid morphology analysis of a chemotherapy dose-response experiment identified decreased organoid circularity as an important morphological feature reflecting drug response. OrganoID enables straightforward, detailed, and accurate image analysis to accelerate the use of organoids in high-throughput, data-intensive biomedical applications.

PURPOSE OF REVIEW The goal of this review is to help providers recognize, diagnose and manage gastrointestinal (GI) polyposis syndromes. RECENT FINDINGS Intestinal polyps include a number of histological sub-types such as adenomas, serrated, hamartomas among others. Over a quarter of individuals undergoing screening colonoscopy are expected to have colonic adenomas. Although it is not uncommon for adults to have a few GI polyps in their lifetime, some individuals are found to have multiple polyps of varying histology throughout the GI tract. In these individuals, depending on polyp histology, number, location and size as well as extra-intestinal features and/or family history, a polyposis syndrome should be considered with appropriate testing and management. SUMMARY Diagnosis and management of polyposis syndromes has evolved with advent of multigene panel testing and new data on optimal surveillance strategies. Evidence-based recommendations and current practice guidelines for polyposis syndromes are reviewed here. Areas of uncertainty and future research are also highlighted.

Gut epithelial morphogenesis is maintained by intestinal stem cells. Here, we report that depletion of N

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Many colorectal cancers (CRCs) that exhibit microsatellite instability (MSI) are not explained by MLH1 promoter methylation or germline mutations in mismatch repair (MMR) genes, which cause Lynch syndrome (LS). Instead, these Lynch-like syndrome (LLS) patients have somatic mutations in MMR genes. However, many of these patients are young and have relatives with cancer, suggesting a hereditary entity. We performed germline sequence analysis in LLS patients and determined their tumor's mutational profiles using FFPE DNA. Six hundred fifty-four consecutive CRC patients were screened for suspected Lynch syndrome using MSI and absence of MLH1 methylation. Suspected LS cases were exome sequenced to identify germline and somatic mutations. Single nucleotide variants were used to characterize mutational signatures. We identified 23 suspected LS cases. Germline sequence analysis of 16 available samples identified 5 cases with LS mutations and 11 cases without LS mutations, LLS. Most LLS tumors had a combination of somatic MMR gene mutation and loss of heterozygosity. LLS patients were relatively young and had excess first-degree relatives with cancer. Four of the 11 LLS patients had rare likely pathogenic variants in genes that maintain genome integrity. Moreover, tumors from this group had a distinct mutational signature compared to tumors from LLS patients lacking germline mutations in these genes. In summary, more than a third of the LLS patients studied had germline mutations in genes that maintain genome integrity and their tumors had a distinct mutational signature. The possibility of hereditary factors in LLS warrants further studies so counseling can be properly informed.

Contains fulltext : 215586.pdf (Publisher’s version ) (Open Access) Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vgamma4(+)/Vdelta1(+) intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vgamma4(+)/Vdelta1(+) IELs was accompanied by the expansion of gluten-sensitive, interferon-gamma-producing Vdelta1(+) IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vgamma4(+)/Vdelta1(+) subset among TCRgammadelta(+) IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRgammadelta(+) IEL compartment in CeD. VIDEO ABSTRACT.

Hereditary factors play a role in the development of colorectal cancer (CRC). Identification of germline predisposition can have implications on treatment and cancer prevention. This study aimed to determine the prevalence of pathogenic germline variants (PGVs) in CRC patients using a universal testing approach, association with clinical outcomes, and the uptake of family variant testing.We performed a prospective multisite study of germline sequencing using a more than 80-gene next-generation sequencing platform among CRC patients (not selected for age or family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020.Of 361 patients, the median age was 57 years (SD, 12.4 y), 43.5% were female, 82% were white, and 38.2% had stage IV disease. PGVs were found in 15.5% (n = 56) of patients, including 44 in moderate- and high-penetrance cancer susceptibility genes. Thirty-four (9.4%) patients had incremental clinically actionable findings that would not have been detected by practice guideline criteria or a CRC-specific gene panel. Only younger age at diagnosis was associated with the presence of PGVs (odds ratio, 1.99; 95% CI, 1.12-3.56). After a median follow-up period of 20.7 months, no differences in overall survival were seen between those with or without a PGV (P = .2). Eleven percent of patients had modifications in their treatment based on genetic findings. Family cascade testing was low (16%).Universal multigene panel testing in CRC was associated with a modest, but significant, detection of heritable mutations over guideline-based testing. One in 10 patients had changes in their management based on test results. Uptake of cascade family testing was low, which is a concerning observation that warrants further study.

Active vitamin D, 1α,25(OH)2D3, is a nuclear hormone with roles in colonic homeostasis and carcinogenesis; yet, mechanisms underlying these effects are incompletely understood. Human organoids are an ideal system to study genomic and epigenomic host-environment interactions. Here, we use human colonic organoids to measure 1α,25(OH)2D3 responses on genome-wide gene expression and chromatin accessibility over time. Human colonic organoids were cultured and treated in triplicate with 100 nM 1α,25(OH)2D3 or vehicle control for 4 h and 18 h for chromatin accessibility, and 6 h and 24 h for gene expression. ATAC- and RNA-sequencing were performed. Differentially accessible peaks were analyzed using DiffBind and edgeR; differentially expressed genes were analyzed using DESeq2. Motif enrichment was determined using HOMER. At 6 h and 24 h, 2,870 and 2,721 differentially expressed genes, respectively (false discovery rate, FDR < 5%), were identified with overall stronger responses with 1α,25(OH)2D3. Similarly, 1α,25(OH)2D3 treatment led to stronger chromatin accessibility especially at 4 h. The vitamin D receptor (VDR) motif was strongly enriched among accessible chromatin peaks with 1α,25(OH)2D3 treatment accounting for 30.5% and 11% of target sequences at 4 h and 18 h, respectively (FDR < 1%). A number of genes such as CYP24A1, FGF19, MYC, FOS, and TGFBR2 showed significant transcriptional and chromatin accessibility responses to 1α,25(OH)2D3 treatment with accessible chromatin located distant from promoters for some gene regions. Assessment of chromatin accessibility and transcriptional responses to 1α,25(OH)2D3 yielded new observations about vitamin D genome-wide effects in the colon facilitated by application of human colonic organoids. This framework can be applied to study host-environment interactions between individuals and populations in the future.

Multigene panel tests for hereditary cancer syndromes are increasingly utilized in the care of colorectal cancer (CRC) and polyposis patients. However, widespread availability of panels raises a number of questions including which patients should undergo testing, which genes should be included on panels, and the settings in which panels should be ordered and interpreted. To address this knowledge gap, key questions regarding the major issues encountered in clinical evaluation of hereditary CRC and polyposis were designed by the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position Statement Committee and leadership. A literature search was conducted to address these questions. Recommendations were based on the best available evidence and expert opinion. This position statement addresses which genes should be included on a multigene panel for a patient with a suspected hereditary CRC or polyposis syndrome, proposes updated genetic testing criteria, discusses testing approaches for patients with mismatch repair proficient or deficient CRC, and outlines the essential elements for ordering and disclosing multigene panel test results. We acknowledge that critical gaps in access, insurance coverage, resources, and education remain barriers to high-quality, equitable care for individuals and their families at increased risk of hereditary CRC.

Background Evidence suggests that early-onset gastric cancers are distinct from traditional gastric cancers; however, detailed genomic and morphologic characterization of these cancers has not been performed. Methods Genomic analysis was performed for 81 patients with gastric cancer who were 50 years old or younger; pathology slides were available for 53 of these patients, and they were re-reviewed to perform a morphologic-molecular correlation analysis. The results were compared with corresponding cBioPortal data and The Cancer Genome Atlas (TCGA) analysis, which represent traditional gastric cancers. The TP53 molecular signature was established to determine the pattern of somatic mutational damage. Variants of potential germline origin were also identified from next-generation sequencing data. Results A higher rate of CDH1 mutations (22.2% of early-onset gastric cancers vs 11.4% of traditional gastric cancers; P = .0042) but a similar rate of TP53 mutations (63% of early-onset gastric cancers vs 56.6% of traditional gastric cancers; P = .2674) were seen in early-onset cancers in comparison with traditional gastric cancers. The diffuse/mixed types correlated with the TCGA genomically stable type, and the remaining Lauren types correlated with the TCGA chromosomal instability type. Diffuse and indeterminate histologic types (overall survival, 26.25 months for the intestinal type, 20.5 months for the mixed type, 12.62 months for the diffuse type, and 9 months for the indeterminate type; P = .027) and the presence of a CDH1 gene mutation (overall survival, 9 months for mutant CDH1 and 22 months for wild-type CDH1; P = .013) significantly correlated with worse survival. The TP53 gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high-penetrance genes (CDH1 and APC) and moderate-penetrance genes (ATM, NBN, and MUTYH) in 9.9% of cancers. Conclusions Early-onset gastric cancer has distinct genomic alterations, such as CDH1 mutations, but shares with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. Diffuse and indeterminate histologic types and the presence of a CDH1 mutation are associated with worse overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate-penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers.

Guidelines recommend surveillance after resection of colorectal cancer (CRC), but rates of adherence to surveillance are variable and have not been studied at National Cancer Institute (NCI)‐designated Comprehensive Cancer Centers. The aim of this study was to determine rates of adherence to standard postresection CRC surveillance recommendations including physician visits, carcinoembryonic antigen (CEA), computed tomography (CT), and colonoscopy after CRC resection at three NCI‐designated centers. Data on patients with resected CRC from 2010 to 2017 were reviewed. Adherence to physician visits was defined as having at least two visits within 14 months after surgical resection. CEA adherence was defined as having at least four CEA levels drawn within 14 months. CT and colonoscopy adherence were defined as completing each between 10 and 14 months from surgical resection. Chi‐square test and logistic regression analyses were performed for overall adherence and adherence to individual components. A total of 241 CRC patients were included. Overall adherence was 23%. While adherence to physician visits was over 98%, adherence to CEA levels, CT, and colonoscopy were each less than 50%. Center was an independent predictor of adherence to CEA, CT, and/or colonoscopy. Stage III disease predicted CT adherence, while distance traveled of 40 miles or less predicted colonoscopy adherence. Overall adherence to postresection CRC guideline‐recommended care is low at NCI‐designated centers. Adherence rates to surveillance vary by center, stage, and distance traveled for care. Understanding factors associated with adherence is critical to ensure CRC patients benefit from postresection surveillance.

Whipple disease (WD) is an infection caused by the bacterium Tropheryma whipplei (TW). Few cases have been reported in the USA. To report on the demographics, clinical manifestations, diagnostic findings, treatment, and outcomes of TW infection. Cases of TW infection diagnosed from 1995 to 2010 were identified in three US referral centers and from 1995 to 2015 in one. Definite classic WD was defined by positive periodic acid-Schiff (PAS) staining and probable WD by specific positive TW polymerase chain reaction (PCR) of intestinal specimens. Localized infections were defined by a positive TW PCR result from samples of other tissues/body fluids. Among the 33 cases of TW infections, 27 (82%) were male. Median age at diagnosis was 53 years (range 11–75). Diagnosis was supported by a positive TW PCR in 29 (88%) and/or a positive PAS in 16 (48%) patients. Classic WD was the most frequent presentation (n = 18, 55%), with 14 definite and 4 probable cases. Localized infections (n = 15, 45%) affected the central nervous system (n = 7), joints (n = 4), heart (n = 2), eye (n = 1), and skeletal muscle (n = 1). Blood PCR was negative in 9 of 17 (53%) cases at diagnosis. Ceftriaxone intravenously followed by trimethoprim and sulfamethoxazole orally was the most common regimen (n = 23, 70%). Antibiotic therapy resulted in clinical response in 24 (73%). TW infection can present as intestinal or localized disease. Negative small bowel PAS and PCR do not exclude the diagnosis of TW infection, and blood PCR is insensitive for active infection.

Comprehensive genomic cancer risk assessment (GCRA) helps patients, family members, and providers make informed choices about cancer screening, surgical and chemotherapeutic risk reduction, and genetically targeted cancer therapies. The increasing availability of multigene panel tests for clinical applications allows testing of well-defined high-risk genes, as well as moderate-risk genes, for which the penetrance and spectrum of cancer risk are less well characterized. Moderate-risk genes are defined as genes that, when altered by a pathogenic variant, confer a two to five-fold relative risk of cancer. Two such genes included on many comprehensive cancer panels are the DNA repair genes ATM and CHEK2, best known for moderately increased risk of breast cancer development. However, the impact of screening and preventative interventions and spectrum of cancer risk beyond breast cancer associated with ATM and/or CHEK2 variants remain less well characterized. We convened a large, multidisciplinary, cross-sectional panel of GCRA clinicians to review challenging, peer-submitted cases of patients identified with ATM or CHEK2 variants. This paper summarizes the inter-professional case discussion and recommendations generated during the session, the level of concordance with respect to recommendations between the academic and community clinician participants for each case, and potential barriers to implementing recommended care in various practice settings.

The human microbiome has been linked to various host phenotypes and has been implicated in many complex human diseases. Recent genome-wide association studies (GWASs) have used microbiome variation as a complex trait and have uncovered human genetic variants that are associated with the microbiome. Here we summarize results from these studies and illustrate potential regulatory mechanisms by which host genetic variation can interact with microbiome composition. We argue that, similar to human GWASs, it is important to use functional genomics techniques to gain a mechanistic understanding of causal host-microbiome interactions and their role in human disease. We highlight experimental, functional, and computational genomics methodologies for the study of the genomic basis of host-microbiome interactions and describe how these approaches can be utilized to explain how human genetic variation can modulate the effects of the microbiome on the host.

The vitamin D related pathway has been evaluated in carcinogenesis but its genetic contribution remains poorly understood. We examined single-nucleotide polymorphisms (SNPs) in the vitamin D related pathway genes using data from a genome-wide association study (GWAS) of breast cancer in the African Diaspora that included 3,686 participants (1,657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated at SNP-level. After stringent Bonferroni corrections, we observed no significant association between variants in the vitamin D pathway and breast cancer risk at the pathway-, gene-, or SNP-level. In addition, no association was found for either the reported signals from GWASs of vitamin D related traits, or the SNPs within vitamin D receptor (VDR) binding regions. Furthermore, a decrease in genetically predicted 25(OH)D levels by Mendelian randomization was not associated with breast cancer (P = 0.23). However, an association for breast cancer with the pigment synthesis/metabolism pathway almost approached significance (pathway-level P = 0.08), driven primarily by a nonsense SNP rs41302073 in TYRP1, with an OR of 1.54 (95% CI = 1.24-1.91, Padj = 0.007). In conclusion, we found no evidence to support an association between vitamin D status and breast cancer risk in women of African ancestry, suggesting that vitamin D is unlikely to have significant effect on breast carcinogenesis. Interestingly, TYRP1 might be related to breast cancer through a non-vitamin D relevant mechanism but further studies are needed. This article is protected by copyright. All rights reserved.

The recently published American Gastroenterological Association (AGA) guideline on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) provides important and useful perspectives for individuals caring for and managing individuals with IBD and also for researchers focusing on this area (1). The guideline reviews key aspects of the roles that TDM increasingly has in the management of individuals with IBD and highlights key concepts. It also illustrates that many of these areas are supported by scanty evidence. Consequently, this also serves to prompt further study that might expand the evidence base accordingly.

Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD.

Colorectal cancer (CRC) is a significant health burden especially among African Americans (AA). Epidemiological studies have correlated low serum vitamin D with CRC risk, and, while hypovitaminosis D is more common and more severe in AA, the mechanisms by which vitamin D modulates CRC risk and how these differ by race are not well understood. Active vitamin D (1α,25(OH) 2 D 3 ) has chemoprotective effects primarily through transcriptional regulation of target genes in the colon. We hypothesized that transcriptional response to 1α,25(OH) 2 D 3 differs between AA and European Americans (EA) irrespective of serum vitamin D and that regulatory variants could impact transcriptional response. We treated ex vivo colon cultures from 34 healthy subjects (16 AA and 18 EA) with 0.1 μM 1α,25(OH) 2 D 3 or vehicle control for 6 h and performed genome-wide transcriptional profiling. We found 8 genes with significant differences in transcriptional response to 1α,25(OH) 2 D 3 between AA and EA with definitive replication of inter-ethnic differences for uridine phosphorylase 1 ( UPP1 ) and zinc finger-SWIM containing 4 ( ZSWIM4 ). We performed expression quantitative trait loci (eQTL) mapping and identified response cis- eQTLs for ZSWIM4 as well as for histone deacetylase 3 ( HDAC3 ), the latter of which showed a trend toward significant inter-ethnic differences in transcriptional response. Allele frequency differences of eQTLs for ZSWIM4 and HDAC3 accounted for observed transcriptional differences between populations. Taken together, our results demonstrate that transcriptional response to 1α,25(OH) 2 D 3 differs between AA and EA independent of serum 25(OH)D levels. We provide evidence in support of a genetic regulatory mechanism underlying transcriptional differences between populations for ZSWIM4 and HDAC3 . Further work is needed to elucidate how response eQTLs modify vitamin D response and whether genotype and/or transcriptional response correlate with chemopreventive effects. Relevant biomarkers, such as tissue-specific 1α,25(OH) 2 D 3 transcriptional response, could identify individuals likely to benefit from vitamin D for CRC prevention as well as elucidate basic mechanisms underlying CRC disparities.

A number of inherited syndromes affect the gastrointestinal tract, including Lynch syndrome and other hereditary colorectal cancers, hereditary polyposis, hereditary gastric cancer, hereditary pancreatic cancer, and hereditary pancreatitis. Recognition and diagnosis of these syndromes are paramount because affected individuals and family members can be offered life-saving screening, risk-reducing surgeries, and other therapies. Genetic counseling and testing are critical components of risk assessment and diagnosis of inherited syndromes. With the advent of next-generation sequencing, multigene panels have significantly changed the practice of genetic counseling and testing. Gastroenterology providers interface with patients who are at risk for inherited gastrointestinal syndromes; thus, providers should learn to recognize these syndromes and know when to refer their patients. Additionally, gastroenterology providers should have an understanding of genetic counseling and be able to interpret multigene panel test results. This article provides an overview of and practical tips for the assessment and diagnosis of hereditary gastrointestinal cancer syndromes and pancreatitis.

Purpose of review: Identification of Lynch syndrome is important from an individual patient and public health standpoint. As paradigms for Lynch syndrome diagnosis have shifted in recent years, this review will discuss rationale and limitations for current strategies as well as provide an overview of future directions in the field. Recent findings: In recent years, the use of clinical criteria and risk scores for identification of Lynch syndrome have been augmented by universal testing of all newly diagnosed colorectal cancers with molecular methods to screen for mismatch repair deficiency with high sensitivity and specificity. Studies of implementation and outcomes of universal testing in clinical practice have demonstrated significant heterogeneity that results in suboptimal uptake and contributes to disparities in diagnosis. Emerging technologies, such as next-generation sequencing, hold significant promise as a screening strategy for Lynch syndrome. Summary: Universal testing for Lynch syndrome is being performed with increasing frequency, although real-world outcomes have demonstrated room for improvement. Future directions in Lynch syndrome diagnosis will involve optimization of universal testing workflow and application of new genetics technologies.