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Fusobacterium nucleatum (Fn) is frequently found in colorectal cancers (CRCs). High loads of Fn DNA are detected in CRC tissues with microsatellite instability-high (MSI-H), or with the CpG island hypermethylation phenotype (CIMP). Fn infection is also associated with the inflammatory tumor microenvironment of CRC. A subtype of CRC exhibits inflammation-associated microsatellite alterations (IAMA), which are characterized by microsatellite instability-low (MSI-L) and/or an elevated level of microsatellite alterations at selected tetra-nucleotide repeats (EMAST). Here we describe two independent CRC cohorts in which heavy or moderate loads of Fn DNA are associated with MSI-H and L/E CRC respectively. We also show evidence that Fn produces factors that induce γ-H2AX, a hallmark of DNA double strand breaks (DSBs), in the infected cells.

Background & Aims Fifty percent of colorectal cancers show elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) and are associated with inflammation, metastasis, and poor patient outcome. EMAST results from interleukin 6–induced nuclear-to-cytosolic displacement of the DNA mismatch repair protein Mutated S Homolog 3, allowing frameshifts of dinucleotide and tetranucleotide but not mononucleotide microsatellites. Unlike mononucleotide frameshifts that universally shorten in length, we previously observed expansion and contraction frameshifts at tetranucleotide sequences. Here, we developed cell models to assess tetranucleotide frameshifts in real time. Methods We constructed plasmids containing native (AAAG)18 and altered-length ([AAAG]15 and [AAAG]12) human D9S242 locus that placed enhanced green fluorescent protein +1 bp/-1 bp out-of-frame for protein translation and stably transfected into DNA mismatch repair–deficient cells for clonal selection. We used flow cytometry to detect enhanced green fluorescent protein–positive cells to measure mutational behavior. Results Frameshift mutation rates were 31.6 to 71.1 × 10-4 mutations/cell/generation and correlated with microsatellite length (r2 = 0.986, P = .0375). Longer repeats showed modestly higher deletion over insertion rates, with both equivalent for shorter repeats. Accumulation of more deletion frameshifts contributed to a distinct mutational bias for each length (overall: 77.8% deletions vs 22.2% insertions), likely owing to continual deletional mutation of insertions. Approximately 78.9% of observed frameshifts were 1 AAAG repeat, 16.1% were 2 repeats, and 5.1% were 3 or more repeats, consistent with a slipped strand mispairing mutation model. Conclusions Tetranucleotide frameshifts show a deletion bias and undergo more than 1 deletion event via intermediates, with insertions converted into deletions. Tetranucleotide markers added to traditional microsatellite instability panels will be able to determine both EMAST and classic microsatellite instability, but needs to be assessed by multiple markers to account for mutational behavior and intermediates., Graphical abstract

OBJECTIVES: Strong evidence links obesity to esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), and pancreatic cancer (PC). However, national-level studies testing the link between obesity and recent temporal trends in the incidence of these cancers are lacking. METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) to identify the incidence of EC, GC, CRC, and PC. Cancer surgeries stratified by obesity (body mass index ≥30 kg/m2) were obtained from the National Inpatient Sample (NIS). We quantified trends in cancer incidence and resections in 2002–2013, across age groups, using the average annual percent change (AAPC). RESULTS: The incidence of CRC and GC increased in the 20–49 year age group (AAPC +1.5% and +0.7%, respectively, P < 0.001) and across all ages for PC. Conversely, the incidence of CRC and GC decreased in patients 50 years or older and all adults for EC. According to the NIS, the number of patients with obesity undergoing CRC resections increased in all ages (highest AAPC was +15.3% in the 18–49 year age group with rectal cancer, P = 0.047). This trend was opposite to a general decrease in nonobese patients undergoing CRC resections. Furthermore, EC, GC, and PC resections only increased in adults 50 years or older with obesity. DISCUSSION: Despite a temporal rise in young-onset CRC, GC, and PC, we only identify a corresponding increase in young adults with obesity undergoing CRC resections. These data support a hypothesis that the early onset of obesity may be shifting the risk of CRC to a younger age.

Microsatellite instability (MSI) refers to the biochemical detection of frameshifted microsatellite sequences from genomic DNA. Genesis of MSI is due to defective DNA mismatch repair (MMR) that fails to correct post DNA replicative slippage mistakes at microsatellites. Most of the estimated 100,000 genomic microsatellites are non-coding; however, ~150–300 microsatellites are coding such that, when frameshifted during the pathogenesis of an MSI tumor, can generate immunogenic neopeptide antigens that limit the growth of tumor and prolong patient survival. In addition to the immune reaction and longer survival, patients with MSI colorectal cancers tend to have poorly differentiated tumors with mucinous features that are located in the right colon. Patients with MSI tumors are more resistant to 5-fluorouracil-based adjuvant chemotherapy but may be responsive to PD-1 immune checkpoint blockade. Specific defects of MMR function not only drive MSI but also elevate microsatellite alterations at selected tetranucleotide repeats that may further modify patient outcome.

Objectives Inflammation-associated microsatellite alterations (also known as elevated microsatellite alterations at selected tetranucleotide repeats [EMAST]) result from IL-6-induced nuclear-to-cytosolic displacement of the DNA mismatch repair (MMR) protein MSH3, allowing frameshifts of dinucleotide or longer microsatellites within DNA. MSH3 also engages homologous recombination to repair double-strand breaks (DSBs), making MSH3 deficiency contributory to both EMAST and DSBs. EMAST is observed in cancers, but given its genesis by cytokines, it may be present in non-neoplastic inflammatory conditions. We examined ulcerative colitis (UC), a preneoplastic condition from prolonged inflammatory duration. Methods We assessed 70 UC colons without neoplasia, 5 UC specimens with dysplasia, 14 UC-derived colorectal cancers (CRCs), and 19 early-stage sporadic CRCs for microsatellite instability (MSI) via multiplexed polymerase chain reaction capable of simultaneous detection of MSI-H, MSI-L, and EMAST. We evaluated UC specimens for MSH3 expression via immunohistochemistry. Results UC, UC with dysplasia, and UC-derived CRCs demonstrated dinucleotide or longer microsatellite frameshifts, with UC showing coincident reduction of nuclear MSH3 expression. No UC specimen, with or without neoplasia, demonstrated mononucleotide frameshifts. EMAST frequency was higher in UC-derived CRCs than UC (71.4% vs 31.4%, P = 0.0045) and higher than early-stage sporadic CRCs (66.7% vs 26.3%, P = 0.0426). EMAST frequency was higher with UC duration >8 years compared with ≤8 years (40% vs 16%, P = 0.0459). Discussion Inflammation-associated microsatellite alterations/EMAST are prevalent in UC and signify genomic mutations in the absence of neoplasia. Duration of disease and advancement to neoplasia increases frequency of EMAST. MSH3 dysfunction is a potential contributory pathway toward neoplasia in UC that could be targeted by therapeutic intervention.

BACKGROUND: Colorectal and endometrial lesions increase with age. It is not known if these two precursor lesions in sporadic cases associate with each other AIM: To determine the association between colorectal polyps and endometrial polyps (EP) in African Americans (AA). METHODS: We reviewed records of patients referred to gynecology clinics and had colonoscopy at Howard University Hospital from January 2004 to December 2015. We defined cases as all patients who had EP and underwent colonoscopy. For controls, we used EP-free patients who underwent colonoscopy. Logistic regression analysis was used to assess the association between colon polyps and EP. RESULTS: The median age was 60 years in 118 Cases and 57 years in 664 Controls. The overall colorectal polyps prevalence in the two groups was not statistically different (54% in controls vs. 52% in cases, P=0.60). Sessile serrated adenoma/polyps (SSPs) were more frequent in cases (8% vs. 2% in controls, P=0.003). Sigmoid and rectal locations were more prevalent in controls than cases. In multivariate analysis and after adjusting for age, diabetes mellitus (DM) and BMI, SSPs associated with EP occurrence with an Odds Ratio of 4.6 (CI 1.2–16.7, P=0.022). CONCLUSION: Colorectal polyp prevalence was similar in EP patients compared to EP-free controls. However, we observed a significant association between higher-risk SSPs in patients with EP. The prevalence of smoking and DM was higher in these patients. Females with EP might benefit from a screening for colonic lesions in an age-independent manner.

Colorectal cancer (CRC) disproportionately affects people from low socioeconomic backgrounds and some racial minorities. Disparities in CRC incidence and outcomes might result from differences in exposure to risk factors such as unhealthy diet and sedentary lifestyle; limited access to risk-reducing behaviors such as chemoprevention, screening, and follow-up of abnormal test results; or lack of access to high-quality treatment resources. These factors operate at the individual, provider, health system, community, and policy levels to perpetuate CRC disparities. However, CRC disparities can be eliminated. Addressing the complex factors that contribute to development and progression of CRC with multicomponent, adaptive interventions, at multiple levels of the care continuum, can reduce gaps in mortality. These might be addressed with a combination of health care and community-based interventions and policy changes that promote healthy behaviors and ensure access to high-quality and effective measures for CRC prevention, diagnosis, and treatment. Improving resources and coordinating efforts in communities where people of low socioeconomic status live and work would increase access to evidence-based interventions. Research is also needed to understand the role and potential mechanisms by which factors in diet, intestinal microbiome, and/or inflammation contribute to differences in colorectal carcinogenesis. Studies of large cohorts with diverse populations are needed to identify epidemiologic and molecular factors that contribute to CRC development in different populations.

Background & Aims Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers (CRCs) are poorly understood. Patients with stage II or III primary CRC with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability (E/L) are more likely to have disease recurrence after treatment. Hypoxia and/or inflammation not only promote metastasis, but also induce elevated microsatellite alterations at selected tetranucleotide repeats by causing deficiency of MSH3 in the cancer cell nucleus. We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival. Methods We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan. Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity (LOH) as possible consequences of MSH3 deficiency. Highly altered loci were examined for association with E/L in liver metastases. We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L. Results LOH at several loci at chromosome 9p24.2 (9p24.2-LOH) was associated with E/L in liver metastases (odds ratio = 10.5; 95% confidence interval: 2.69−40.80; P = .0007). We found no significant difference in the frequency of E/L, 9p24.2-LOH, mutations in KRAS or BRAF , or the combination of E/L and 9p24.2-LOH, between primary colorectal tumors and their matched metastases. Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival after CRC recurrence (hazard ratio = 0.25; 95% CI: 0.12−0.50; P = .0001), compared with patients without with E/L and 9p24.2-LOH. E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC (hazard ratio = 0.06; 95% CI: 0.01−0.57; P = .01). Conclusions E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors.

Background & Aims Colorectal cancer located at different anatomical subsites may have distinct etiologies and risk factors. Previous studies that have examined this hypothesis have yielded inconsistent results, possibly because most studies have been of insufficient size to identify heterogeneous associations with precision. Methods In the European Prospective Investigation into Cancer and Nutrition study, we used multivariable joint Cox proportional hazards models, which accounted for tumors at different anatomical sites (proximal colon, distal colon, and rectum) as competing risks, to examine the relationships between 14 established/suspected lifestyle, anthropometric, and reproductive/menstrual risk factors with colorectal cancer risk. Heterogeneity across sites was tested using Wald tests. Results After a median of 14.9 years of follow-up of 521,330 men and women, 6291 colorectal cancer cases occurred. Physical activity was related inversely to proximal colon and distal colon cancer, but not to rectal cancer (P heterogeneity = .03). Height was associated positively with proximal and distal colon cancer only, but not rectal cancer (P heterogeneity = .0001). For men, but not women, heterogeneous relationships were observed for body mass index (P heterogeneity = .008) and waist circumference (P heterogeneity = .03), with weaker positive associations found for rectal cancer, compared with proximal and distal colon cancer. Current smoking was associated with a greater risk of rectal and proximal colon cancer, but not distal colon cancer (P heterogeneity = .05). No heterogeneity by anatomical site was found for alcohol consumption, diabetes, nonsteroidal anti-inflammatory drug use, and reproductive/menstrual factors. Conclusions The relationships between physical activity, anthropometry, and smoking with colorectal cancer risk differed by subsite, supporting the hypothesis that tumors in different anatomical regions may have distinct etiologies.

Over the past three decades since molecular analyses of somatic gene alterations in primary human cancer specimens first became tractable, many of the recurrent somatic genetic and epigenetic defects present in colorectal cancers (CRCs) have been identified. The accumulation of multiple loss-of-function defects in selected tumor suppressor genes and gain-of-function defects in selected oncogenes, together with epigenetic alterations, such as DNA methylation changes, is believed to be critical in initiating colorectal tumorigenesis and the progression of dysplastic precursors to invasive and ultimately metastatic lesions (1–4). Among the most common tumor suppressor gene mutations in CRCs are those in the APC (adenomatous polyposis coli) and TP53 genes (2–4). The most common oncogene mutations in CRC include point mutations activating the functions of the KRAS, PI3KCA (phosphoinositide-3-kinase, catalytic, alpha polypeptide), BRAF, and NRAS proteins (2–4). The oncogene missense mutations found in the KRAS and NRAS genes in about 40–45% of CRCs most commonly affect codons 12 and 13, but a subset of CRCs have KRAS or NRAS colon 61 missense mutations (2, 3). Substitution of glutamic acid for the wild type valine at codon 600 (V600E) accounts for the vast majority of BRAF activating mutations in CRC (2, 3). Mutations activating KRAS or NRAS are mutually exclusive with BRAF activating mutations (2–4).

Previous studies have suggested an increase in the incidence of colorectal cancer (CRC) in young adults (younger than 50 years). Among older people, African Americans have disproportionally higher CRC incidence and mortality. It is unclear if this CRC disparity also applies to CRC diagnosed among young people

Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair (MMR). About 15% of sporadic colorectal cancers (CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting in mono- and di-nucleotide frameshifts to classify it as microsatellite instability-high (MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic non-MSI-H CRCs demonstrate frameshifts at di- and tetra-nucleotide microsatellites to classify it as MSI-low/elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement. The trigger for MSH3 displacement appears to be inflammation and/or oxidative stress, and unlike MSI-H CRC patients, patients with MSI-L/EMAST CRCs show poor prognosis. These inflammatory-associated microsatellite alterations are a consequence of the local tumor microenvironment, and in theory, if the microenvironment is manipulated to lower inflammation, the microsatellite alterations and MSH3 dysfunction should be corrected. Here we describe the mechanisms and significance of inflammatory-associated microsatellite alterations, and propose three areas to deeply explore the consequences and prevention of inflammation's effect upon the DNA MMR system.

Cancer from the gastrointestinal tract and its associated excretory organs will occur in more than 300,000 Americans in 2017, with colorectal cancer responsible for >40% of that burden; there will be more than 150,000 deaths from this group of cancers in the same time period. Disparities among subgroups related to the incidence and mortality of these cancers exist. The epidemiology and risk factors associated with each cancer bear out differences for racial groups in the United States. Esophageal adenocarcinoma is more frequent in non-Hispanic whites, whereas esophageal squamous cell carcinoma with risk factors of tobacco and alcohol is more frequent among blacks. Liver cancer has been most frequent among Asian/Pacific Islanders, chiefly due to hepatitis B vertical transmission, but other racial groups show increasing rates due to hepatitis C and emergence of cirrhosis from non-alcoholic fatty liver disease. Gastric cancer incidence remains highest among Asian/Pacific Islanders likely due to gene−environment interaction. In addition to esophageal squamous cell carcinoma, cancers of the small bowel, pancreas, and colorectum show the highest rates among blacks, where the explanations for the disparity are not as obvious and are likely multifactorial, including socioeconomic and health care access, treatment, and prevention (vaccination and screening) differences, dietary and composition of the gut microbiome, as well as biologic and genetic influences. Cognizance of these disparities in gastrointestinal cancer risk, as well as approaches that apply precision medicine methods to populations with the increased risk, may reduce the observed disparities for digestive cancers.

Colon cancer develops and progresses as a consequence of abnormal cellular molecular changes, many of which result in mutant DNA. Modern molecular techniques allow examination of individual patient genetic data that ascribe risk, predict outcome, and/or modify an approach to therapy. DNA testing and molecular screening are in use today and are becoming a critical and necessary part of routine patient care. Assessing at-risk patients for hereditary colon cancer is predicted to move from individual gene testing that is commonly performed today to whole exome or whole genome sequencing, providing additional vast information of the patient's genome that might not be related to the colon cancer syndrome. Detecting mutant DNA from shed tumor cells in fecal material for colon cancer screening will increase in diagnostic accuracy over time, with improvements in the panel of mutant DNA being examined and through clinical testing. DNA mutations and other molecular changes detected directly from within the colon cancer help to inform and guide the physician for the best approach for optimal patient care and outcome. The use of epidermal growth factor receptor-targeted therapy in advanced colon cancer patients requires knowledge of the mutation status for KRAS and BRAF genes, and knowing the mutational status of PIK3CA may predict how patients respond to aspirin to prevent colon cancer recurrence. Biologically driven decision-making, or precision medicine, is becoming increasingly adopted for optimal care and outcome for colon cancer patients. Gastroenterologists will need to be increasingly aware.

Colorectal cancer (CRC) burden is not equal among populations in the United States. African Americans have the highest CRC incidence and mortality of all US populations, and rates are not decreasing to the levels of non-Hispanic Whites.1 In addition to increased cancer risk, adenoma risk is also higher in African Americans, and both adenomas and cancers occur more frequently in the proximal colon and at younger ages in African Americans.2 Reasons for population differences are multifactorial and include differences in tumor biology and behavior, genetic risk, access to health care, and screening rates.3,4 As demonstrated by the Delaware CRC screening program, strategies to maximize screening hold significant promise for correcting CRC disparities.5 Current US Multisociety Task Force guidelines recommend CRC screening for all populations at average risk beginning at age 50 years, and individuals at increased risk (such as those with family history, inherited genetic syndromes or inflammatory bowel disease) are recommended to begin screening earlier.6 Owing to increased and earlier neoplasia risk, some professional organizations recommend screening in African Americans starting at age 45.3 Others raise concerns about the impact of complicating existing standardized guidelines and the unclear benefit of earlier age screening in African Americans despite an increased proportion of CRC under the age of 50 years. They recommend that efforts should focus instead on improving screening efforts in African Americans starting at age 50. Given this controversy, it is timely to examine how our profession can take the lead in reducing CRC disparities among African Americans. Several strategies should be considered when prioritizing our efforts (Table 1). Table 1 Strategies to Decrease Disparities in Colorectal Cancer (CRC) Among African Americans (AAs) African Americans are less knowledgeable about CRC and screening guidelines compared with Caucasians,7 and are less likely to transmit a family history of cancer.4 Both lack of knowledge about screening benefits and fatalistic views about cancer are associated with reduced likelihood of screening among African Americans.8 Interventions designed to educate patients about CRC and screening guidelines can improve screening rates and attitudes,9,10 and those that contain culturally sensitive materials have been shown to boost screening among African Americans.9 These and other studies suggest that lack of knowledge about CRC screening benefits is a surmountable barrier, but challenges remain. For example, ≤40% of African Americans aged 65 years and older in some US areas are estimated to read below a 5th-grade level,9 limiting the use of some CRC screening materials. In addition, standardized patient education approaches may not work in all populations and age groups, potentially necessitating individualized interventions and inclusion of personnel to engage in community-based education and outreach. The impact of provider endorsement on screening rates cannot be under-estimated. Lack of provider recommendation is an important barrier to screening in African Americans.11 However, studies that evaluate the impact of provider education on CRC screening in African Americans are lacking. Continuing medical education seminars can increase CRC knowledge, but whether this translates to improved screening rates is not clear.12 Just as there are no standardized approaches for patient education, there are no standardized strategies to improve provider education. Moreover, providers cite insufficient time as a barrier to recommending CRC screening to patients,13 potentially causing additional delay in timely CRC screening for this higher risk population. Strategies focused on physician education about the increased CRC burden among African Americans may improve CRC screening, but more research is needed to demonstrate this. Patient navigation is a proven strategy for increasing CRC screening rates in African Americans and also improves no show rates and bowel preparation.3,14 A randomized trial in older African Americans of phone navigation and printed material versus printed material alone found a 53% increase in endoscopic screening in the navigation group with health literate subjects showing a stronger effect from navigation.14 Financial modeling based on a program in New York City found patient navigation to be cost effective,15 whereas a randomized trial noted greater costs for tailored navigation.16 Implementation of patient navigation from research studies into the “real world” can be complex and requires flexibility and cooperation among stakeholders.17 Thus, although patient navigation can increase screening among African Americans, logistics and cost are major barriers to widespread adoption. Efforts should focus on overcoming these barriers through education, research, and advocacy for patient navigation in CRC screening. A more controversial strategy is to lower the initial screening age recommendation for African Americans. Arguments supporting this strategy include increased rates of significant neoplasia, higher stage of CRC at younger ages, and proximal location of tumors among African Americans.3 Lieberman et al2 showed that the rate of high risk polyps (>9 mm) was increased 17%–38% in African American men ages 50-69 years and 25%– 50% in African American women ages 50-64 years compared with Caucasian men and women in these age groups. Although the risk of large polyps was not statistically different for African American men and women

The discipline of gastroenterology, hepatology and pancreatology has changed dramatically since its inception as a specialty of internal medicine. The specialty originally focused and pursued an understanding of the pathology and physiology of the gastrointestinal tract, liver and pancreas scientifically, something which is still in active evolution.. We began to comprehend gut motility, stomach acid secretion, the epidemiology of digestive cancers, autoimmune diseases of the gut, pancreas and liver, and how infectious diseases are transmitted and affect the GI tract. Treatment slowly became possible with the acquired knowledge, and created approaches for therapeutics. Histamine type 2 blockers and proton pump inhibitors, nucleotide and nucleoside analogs, immune modulators, and a myriad of antibiotics have been studied and used effectively to alleviate patient suffering from GI diseases. Radiological imaging helped determine the absence, presence, or extent of disease non-invasively. Endoscopy of the alimentary tract and its related growing list of special devices have provided a huge leap forward in caring for patients with GI disease, allowing direct visualization of and sampling from the GI tract, and providing an avenue for direct therapeutic intervention. We have now entered the genomic era, providing another leap forward in the care of patients with GI diseases. This era commenced with the identification genetic mutations as the basis of Mendelian-inherited diseases involving the GI tract, such as familial adenomatous polyposis [1,2], cystic fibrosis [3–5], and genetic hemochromatosis [6]. The genetic information could be predictive if one carried the mutation; it could be also be predictive to family members when they did not carry the mutation, foregoing unnecessary surveillance efforts and applying those healthcare resources aptly to mutant carriers. Genetic information has progressed dramatically and now extends past heritable diseases; it applies to many GI conditions in terms of risk (e.g. genome wide association studies or GWAS, or the presence or absence of a mutation directly within tumor tissue), prediction of biological behavior, outcome and survival, and in the approach and use of therapeutics (e.g. cetuximab in wild type KRAS colorectal cancer, or 6-thioguanine and 6-methylmercaptopurine metabolite levels for optimal use of azathioprine or 6-mercaptopurine). The field is rapidly evolving. A convergence of advancing knowledge of GI tract disease, technical advances and reduced costs for next generation sequencing and other analytic technologies such as proteomics and metabolomics, easier access to sampling human tissue with advances in image-directed biopsies and minimally invasive tissue removal, and a growing number of interventions discovered to improve the health of patients with GI diseases make this era an exciting time for helping our patients and fundamentally changing our GI practices. Biomarkers are a key part of precision (personalized or individualized) medicine. Molecular biomarkers are derived from the genetic, genomic and other high-throughput platforms in analysis of blood, tissue, fecal, urine or other biological material that can inform the practitioner on the next best course of action for the individual patient [7]. Biomarkers ideally lead to prescriptive targeted treatment changes that can improve the outcome of patients with GI disease; this is the essence and part of the definition of precision medicine [8]. Biomarkers can also be diagnostic or prognostic, being more informative for a clinical course rather than a targeted individualized treatment prescription. The assumption and reality is that GI patients with a specific disease are biologically heterogeneous, and molecular biomarkers can differentiate patients into subtype groupings of more homogeneous individuals sharing an actionable characteristic amenable to molecularly targeted therapies beneficial to that subgroup or individual. Both biomarkers and targeted individualized therapies are the cornerstone of President Obama’s Precision Medicine Initiative put forth in early 2015 [9]. This initiative aims to further revolutionize the practice of medicine by generating additional scientific evidence to move the concept of precision medicine into everyday clinical practice. Parallel and complimentary ventures such as the 100,000 Genomes Project in the UK aim to identify novel genetic diagnoses and create opportunities for the use of genomics in healthcare [10]. This special issue of Gastroenterology lays a foundation and provides a current understanding to the approach to precision medicine for several GI disorders, a timely topic given the growing international investments in personalized care. We as editors of this special issue, along with the entire Gastroenterology Board of Editors, selected the topic of genetics, genetic testing, and biomarkers in digestive diseases because of the rapid advances in these topics among the GI diseases over just the past few years. Recent studies outlined in many of the articles within this special issue highlight how fast information has moved, and how quick biomarkers and potential therapeutic targets for treatment purposes are lining up for phased human clinical studies, pharmaceutical testing portfolios, and routine patient use. The transformation from bench to practice has been greatly accelerated with newer and cheaper genomic analytic capabilities and information technologies, and rapid dissemination of information. New molecular biomarker tests are being put out to the clinical commercial market on a regular basis. Many aspects of this rapid change have and will continue to become part of daily clinical GI practice. For this special issue of Gastroenterology, we recruited leading authorities to update our readers in the genetics, genetic testing, and biomarkers of digestive diseases. The 12 reviews and 2 commentaries in this issue cover many aspects of the GI tract, hepatobiliary system and pancreas. The two commentaries are more general than disease-focused, and deal with the generation and recording of genetic information. The commentary by Ananthakrishnan and Lieberman examines the current and future ideal use of electronic health records for genetic and biomarker information that pertains to the practitioner and researcher, laboratory, and patient [11]. Ngeow and Eng’s commentary addresses a path forward in the post-genomic area, including the examination of gene-gene or gene-environment interactions, and clinical implementation of genomics [12]. Among the 12 disease-focused reviews, four articles examine biomarkers and genetics and their clinical application in colorectal cancer (CRC). Stoffel and Boland provide genetic testing insights in inherited forms of CRC [13], and Carethers and Jung highlight the genetics and potential biomarkers for use in patients with sporadic CRC [14]. Okugawa, Grady and Goel showcase how epigenetic alterations in CRC provide biomarkers for patient care [15], and Robertson and Imperiale review the clinical application of biomarkers within stool tests for CRC screening [16]. Three articles focus on the rapidly advancing use of genetics and biomarkers for inflammatory bowel disease (IBD). McGovern, Kugathasan and Cho provide an update on GWAS data from large IBD studies [17], Dubinsky and Braun showcase the use of microbial biomarkers for IBD diagnosis [18], and Sands highlights inflammatory biomarkers for IBD [19]. Two articles focus on the liver: Pietrangelo reviews classic hemochromatosis genetics and testing [20], and Zucman-Rossi, Villaneuva, Nault and Llovet provide a comprehensive review of the genetics and biomarkers for hepatocellular carcinoma [21]. The remaining three reviews highlight the esophagus, stomach, and pancreas. Reid, Paulson and Li present the most up-to-date genetic analyses of Barrett’s esophagus and esophageal adenocarcinoma [22]. Tan and Yeoh supply the latest insights of the genetics of gastric adenocarcinoma [23], while Whitcomb, Shelton and Brand present the latest on the biomarkers and genetics of inherited and sporadic forms of pancreatic cancer [24]. We are very grateful to the contributing authors as well as the insightful manuscript reviewers and editorial staff for their time and energy in creating these outstanding articles with useful figures and tables for the readers of Gastroenterology. We hope that readers of this special issue of Gastroenterology will find it full of new insights into this rapidly moving field in clinical GI practice. We hope you enjoy the up-to-date information, and see the alignment with current and future aspects of the Precision Medicine Initiative and the other related global efforts. We trust that this issue provides a new and timely reference as precision medicine, biomarkers, and genetics move more fully into GI clinics to direct patient care.

I was born the fourth son and the tenth of 12 children. My parents pushed education as the way for their children to get ahead in life. They both had a college education. My father graduated in 1948 with a mechanical engineering degree after a medical deferment during World War II, and my mother was a secretary for her father’s real estate company before marriage and was our constant in the home while my dad worked for the City of Detroit. My parents raised us with good morals and strived to provide individual needs for each child’s personality and traits. I grew up in Detroit, was educated in elementary school by Catholic nuns and lay teachers, and went to the city’s public magnet high school, Cass Tech. Growing up in a large family was the only norm I knew. We ate dinner as a family, attended church weekly, fought with each other, encouraged each other, and competed with each other. At least one of us seemed to make it to the emergency room at least once a year. To this day, all of my siblings get along. Despite a tight budget, the oldest 11 children attained more than 17 college degrees from two universities located in Detroit, with all costs for education borne through scholarships, grants, and loans. My youngest brother and my parent’s 12th child has trisomy 21, and his Down’s syndrome had an influence on the career choices of some of my family members. My own choice to pursue medicine as a career stemmed from an exploration of the Encyclopedia Britannica, with its anatomy overlays that mesmerized me. Fate has a way of happening. My eventual pursuit of medicine ultimately led to meeting my wife during fellowship and raising four beautiful children. To this day, I try to instill a push for education in my own children, along with many interested kids with whom I come in contact.