María L. Gonzalez

Lynch syndrome in South America: past, present and future.

After decades of unawareness about Lynch syndrome, the medical community in South America is increasingly interested and informed. The visits and support of mentors like H. T. Lynch had been crucial to this awakening. Several countries have at least one registry with skilled personnel in genetic counseling and research. However, this only represents a very restricted resource for the region. According to the GETH, there are 27 hereditary cancer care centers in South America (21 in Brazil, 3 in Argentina, 1 in Uruguay, 1 in Chile and 1 in Peru). These registries differ in fundamental aspects of function, capabilities and funding, but are able to conduct high quality clinical, research and educational activities due to the dedication and personal effort of their members, and organizational support. More support from the governments as well as the participation of the community would boost the initiatives of people leading these groups. Meantime, the collaboration among the South American registries and the involvement of registries and leaders from developed countries will allow to maximize the efficiency in caring for affected patients and their families. The aim of this article is to describe how the knowledge of LS began to be spread in South America, how the first registries were organized and to summarize the current state of progress. In addition, we will provide an update of the clinical and molecular findings in the region.

MLH1 Ile219Val Polymorphism in Argentinean Families with Suspected Lynch Syndrome

Heredity is a major risk factor for colorectal cancer (CRC). Identification of individuals and families at increased risk allows for targeted surveillance, which has been shown to reduce morbidity and mortality from CRC (1, 2). Lynch syndrome is a multi-tumor syndrome with particularly high risks for colorectal, endometrial, and ovarian cancer (3–6). The syndrome is caused by germline DNA-mismatch repair (MMR) gene mutations with major contributions from MLH1 (MIM#120436) (42%), MSH2 (MIM#609309) (33%), MSH6 (MIM#600678) (18%), and PMS2 (MIM#600259) (8%). Only about one-third of the Lynch syndrome families fulfill the Amsterdam criteria (AC) (7–9). The cumulative incidence of any cancer at 70 years of age is 72% for MLH1 and MSH2 mutation carriers but lower in MSH6 (52%) and PMS2 (18%) mutation carriers. MSH6 and PMS2 carriers developed no cancers before 40 years of age (10). Mutation screening in a relatively large proportion of South American families with suspected Lynch syndrome has recently identified 99 disease-predisposing mutations in MLH1 and MSH2, which mutation spectrum is predominated by MLH1 (60%) and MSH2 (40%). Among the reported mutations, genetic hot-spot regions, new and potential founder mutations have been described in the South American population (11, 12). Several genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in at least 15 independent loci associated with CRC risk (odds ratio ranging from 1.10 to 1.26 per risk allele) (13–15). Although there is no evidence that these SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall and therefore any evidence of proven clinical utility in Lynch syndrome (16). The MLH1 Ile219Val (rs1799977) is a common germline alteration, located in exon 8 at the nucleotide 655. This polymorphism has been described in a high frequency of the South American Lynch syndrome population, but no modifier effect of CRC risk and MMR disease-predisposing mutation carriers was observed (17). However, it has been reported to confer a twofold-increased risk of CRC development in sporadic Mexican patients (18). Other conditions that have been associated with this polymorphism include childhood acute lymphoblastic leukemia, breast cancer, radiation-induced rectal or bladder toxicity, and ulcerative colitis (19–23). It is unknown whether the MLH1 Ile219Val polymorphism has an effect on cancer risk and in the MMR capacity in Argentinean families with suspected Lynch syndrome. Thus, we aim to determine its frequency, its correlation with disease-predisposing MMR gene mutations, and to delineate the clinical characteristics from these families.

From colorectal cancer pattern to the characterization of individuals at risk: picture for genetic research in Latin America: From colorectal cancer pattern to the characterization of individuals at risk: picture for genetic research in Latin America

Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%–80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency.

Evaluation of MLH1 variants of unclear significance

Inactivating mutations in the MLH1 gene cause the cancer predisposition Lynch syndrome, but for small coding genetic variants it is mostly unclear if they are inactivating or not. Nine such MLH1 variants have been identified in South American colorectal cancer (CRC) patients (p.Tyr97Asp, p.His112Gln, p.Pro141Ala, p.Arg265Pro, p.Asn338Ser, p.Ile501del, p.Arg575Lys, p.Lys618del, p.Leu676Pro), and evidence of pathogenicity or neutrality was not available for the majority of these variants. We therefore performed biochemical laboratory testing of the variant proteins and compared the results to protein in silico predictions on structure and conservation. Additionally, we collected all available clinical information of the families to come to a conclusion concerning their pathogenic potential and facilitate clinical diagnosis in the affected families. We provide evidence that four of the alterations are causative for Lynch syndrome, four are likely neutral and one shows compromised activity which can currently not be classified with respect to its pathogenic potential. The work demonstrates that biochemical testing, corroborated by congruent evolutionary and structural information, can serve to reliably classify uncertain variants when other data are insufficient.

787 Risk of Death and Thromboembolism in Patients That Do Not Resume Anticoagulation After an Episode of Peptic Ulcer Bleeding

Background: The existing literature regarding smoking and alcohol consumption and risk of gastrointestinal bleeding (GIB) is sparse and conflicting. In an attempt to study modifiable risk factors of GIB, we assessed the risk of GIB associated with smoking and alcohol consumption in a large prospective cohort of men. Methods: We studied 51,529 men in the Health Professional follow-up Study (HPFS) who were aged 40-75 years at baseline in 1986. We identified men with GIB requiring hospitalization and/or blood transfusion based on their responses to biennial questionnaires from 2006-2012 and reviewed medical records to validate self-report. Information about smoking and alcohol consumption was updated every two and four years, respectively. We used Cox proportional hazards regression to calculate the relative risks (RR) and 95% confidence intervals (CI) adjusting for age, study year, body mass index, physical activity, regular aspirin and nonsteroidal anti-inflammatory drug use, and alcohol/smoking. Results: We documented 311 episodes of GIB during a 26-year follow up period. After adjustments for other potential risk factors, individuals who consumed >15 g/day of alcohol had a multivariate RR of 1.65 (95% CI, 1.10-2.47; p for linear trend 0.004) when compared with men who did not consume alcohol. Intake of > 15 g/day of alcohol appeared to be primarily related to upper GIB (multivariable RR 1.74; 95% CI, 0.98-3.08; p for linear trend 0.007). Risk of GIB increased linearly with amount of liquor consumed (p for linear trend 15 g/day of alcohol was significantly associated with peptic ulcer disease (multivariable RR 1.85; 95% CI, 0.97-3.54; p for linear trend 0.02), but not esophagitis/gastritis/duodentitis, or diverticular bleeding. There were few cases of bleeding due to portal hypertension (n=4). Current and past smokers did not appear to have increased risk of GIB when compared to those who never smoked (multivariable RR 0.89; 95% CI, 0.45-1.76 and 1.12, 95% CI 0.88-1.41, respectively). We also did not find a significant association between pack years of smoking and risk of GIB (multivariable RR 1.01; 95% CI, 0.63-1.62 when comparing men with at least 45 pack-years of exposure to never smokers). Conclusions: In this large prospective study, alcohol consumption, but not smoking, was associated with an increased risk of GIB. Associations were most notable for upper GI bleeding associated with intake of liquor.

Su1247 Postcolonoscopy Colorectal Cancer (PCCRC) in a Population of a Closed System of Health Care Provision

BACKGROUND: Previous studies have demonstrated that patients post cholecystectomy have had no definitive association with colorectal adenomatous polyps. It is thought that chronic inflammation from bile acids may lead to increase development of colorectal polyps. Post cholecystectomy chronic diarrhea is likely from bile acid exposure. Additionally chronic constipation is thought to be an risk factor for colorectal cancer. The purpose of this study is to investigate for an increased risk for colorectal adenomas in post cholecystectomy patients and to look for the association of polyps with chronic diarrhea in these patients. METHODS: We performed a retrospective chart review of the patients who underwent cholecystectomy between 01/200112/2012 who also had a colonoscopy following surgery. Patients without a personal history of IBD, colorectal polyps and/or family history of colorectal cancer were included in the study. Patients were further divided into two groups, those with and without chronic diarrhea. Polyps were further classified based on histology and location. RESULTS: A total of 395 patients were included in the study (63% female, with a mean age of 50 y). The average number of years between the cholecystectomy and a colonoscopy was 2.6 years. An increased risk for colorectal polyps 151(38%) (95% confidence interval (CI)-0.33-0.43) was found among these patients when compared to an average risk in general population aged 50 y (20%). A total of 28% patients in the study were found to have proximal colon polyps (0.28, 95% CI 0.21 to 0.36) and no significant difference was found when compared to the average risk population (13-37%). In contrast an increased risk of polyps in distal colon 48% (0.48, 95% CI: 0.40 to 0.56) was found when compared to the average risk population (25-40%). Twenty five percent of patients had polyps in both proximal and distal colon 37/151 (0.25; 95% CI 0.18 to 0.32), statistics were not compared to the general population. Hyper plastic polyps were found in 37% (0.37, 95%CI: 0.29 to 0.45) patients, which were not found to be at increased risk when compared to average risk (20-40%). Adenomas, 55% (0.55, 95% CI: 0.46 to 0.63), were found to be at increased risk when compared to average risk (25-30%). Additionally an increased risk was found for serrated polyps, 9% (0.09, 95% CI 0.05 to 0.15), when compared to average risk (1-7%). In patients with chronic diarrhea the proportion of polyps was 0.26 compared to 0.43 in those without chronic diarrhea. (Odds ratio=0.47, 95% CI 0.29-0.75, P=0.002), revealing a negative association of polyps with chronic diarrhea in this set of patients. CONCLUSIONS: Cholecystectomy was found to increase the risk for distal colorectal adenomas/polyps. Chronic diarrhea was found to be negatively associated with colorectal polyps in this set of patients.