A Rare MSH2 Variant as a Candidate Marker for Lynch Syndrome II Screening in Tunisia: A Case of Diffuse Gastric Carcinoma.

Several syndromic forms of digestive cancers are known to predispose to early-onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LSII is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current work, our main aim was to identify the mutational spectrum underlying the genetic predisposition to diffuse gastric tumors occurring in a Tunisian family suspected of both HDGC and LS II syndromes. We selected the index case "JI-021", which was a woman diagnosed with a Diffuse Gastric Carcinoma and fulfilling the international guidelines for both HDGC and LSII syndromes. For DNA repair, a custom panel targeting 87 candidate genes recovering the four DNA repair pathways was used. Structural bioinformatics analysis was conducted to predict the effect of the revealed variants on the functional properties of the proteins. DNA repair genes panel screening identified two variants: a rare MSH2 c.728G>A classified as a variant with uncertain significance (VUS) and a novel FANCD2 variant c.1879G>T. The structural prediction model of the MSH2 variant and electrostatic potential calculation showed for the first time that MSH2 c.728G>A is likely pathogenic and is involved in the MSH2-MLH1 complex stability. It appears to affect the MSH2-MLH1 complex as well as DNA-complex stability. The c.1879G>T FANCD2 variant was predicted to destabilize the protein structure. Our results showed that the MSH2 p.R243Q variant is likely pathogenic and is involved in the MSH2-MLH1 complex stability, and molecular modeling analysis highlights a putative impact on the binding with MLH1 by disrupting the electrostatic potential, suggesting the revision of its status from VUS to likely pathogenic. This variant seems to be a shared variant in the Mediterranean region. These findings emphasize the importance of testing DNA repair genes for patients diagnosed with diffuse GC with suspicion of LSII and colorectal cancer allowing better clinical surveillance for more personalized medicine.

Preventing Ovarian Cancer in High-risk Women: One Surgery at a Time.

Eleven genes have been identified that increase the lifetime risk of developing ovarian cancer. The cumulative cancer risk of ovarian cancer varies with the mutation type and age. Ovarian cancer risk management options include surgical risk reduction with salpingo-oophorectomy and a newer step-wise approach with interval salpingectomy and delayed oophorectomy. Women should be counseled on the pros and cons of hysterectomy in the setting of reducing the risk of other cancers; eliminating the risk of endometrial cancer in Lynch Syndrome, potential risk of serous/serous-like endometrial cancer in BRCA1 carriers, and elimination of progestogen therapy that may increase breast cancer risk.

Benefits, harms and cost-effectiveness of cancer screening in Australia: an overview of modelling estimates.

INTRODUCTION: There are three government-funded population-based screening programs in Australia - the national breast cancer screening program (BreastScreen Australia), the National Cervical Screening Program (NCSP), and the National Bowel Cancer Screening Program (NBCSP). Options for early detection of other cancers (e.g. hepatocellular carcinoma and melanoma) are under investigation. This study provides an overview of the health benefits, harms and cost-effectiveness of population-level breast, cervical and colorectal cancer screening, targeted-risk screening for lung cancer and Lynch syndrome, and prostate specific antigen (PSA) testing in Australia. METHODS: The study reviewed and, where possible, updated the estimated health benefits, harms and cost-effectiveness of screening approaches from modelling studies for four cancer types, PSA testing and Lynch syndrome testing in Australia. Costs are presented in 2018 Australian dollars. RESULTS: The renewed NCSP (for women not HPV-vaccinated) and the NBCSP were estimated to be cost-effective versus no screening; the cost-effectiveness ratio (CER) was $16 632 per life-year saved (LYS) for the NCSP, and $3380/LYS for the NBCSP. BreastScreen Australia was predicted to have a CER of $40 279/LYS-$65 065/LYS. In 2017, the NCSP transitioned to 5-yearly primary HPV testing with partial genotyping for HPV types 16 and 18 for women aged 25-74 years. Alongside vaccination, this change is predicted to prevent a further 587 cervical cancer deaths in 2018-2035, and have a favourable benefit-to-harm balance versus prior practice (biennial cytology testing for women aged 18-69 years). On average, the NBCSP (biennial screening using an immunochemical faecal occult blood test for people aged 50-74 years) is estimated to prevent 2519 colorectal cancer deaths and result in 350 colonoscopy-related adverse events annually. The inaccuracy of PSA testing as a screening tool impedes the capacity to conduct meaningful cost-effectiveness analyses at a population level, based on current evidence. Three annual low-dose computed tomography screens for lung cancer using the US National Lung Screening Trial selection criteria would not be cost-effective in Australia. A comprehensive cost-effectiveness evaluation of systematic proband testing, cascade testing and subsequent surveillance for Lynch syndrome in Australia is currently underway. CONCLUSIONS: Current evidence supports a favourable cost-effectiveness and benefit-to-harm balance for the NCSP and NBCSP. An updated cost-effectiveness and benefits-to-harms analysis for BreastScreen Australia is required. Carefully founded quantitative estimates of health benefits, harms and cost-effectiveness provide an important aid to policy decision making, and form the basis for developing decision aids to guide individual screening decisions. Opportunities exist for lung cancer screening, systematic Lynch syndrome testing and informed decision making about PSA testing. However, more evidence is required on risk assessment, targeting of screening tests, optimal referral pathways, managing potential harms and delivering services in a cost-effective framework.

Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population?

BACKGROUND: Universal tumor testing for defective DNA mismatch repair (MMR) is recommended for all women diagnosed with endometrial cancer to identify those with underlying Lynch syndrome. However, the effectiveness of these screening methods in identifying individuals with Lynch syndrome across the population has not been well studied. The aim of this study was to evaluate outcomes of MMR immunohistochemistry (IHC), mutL homolog 1 (MLH1) methylation, and microsatellite instability (MSI) analysis among patients with endometrial cancer. METHODS: A complete systematic search of online databases (PubMed, EMBASE, MEDLINE, and the Cochrane Library) for 1990-2018 was performed. A DerSimonian-Laird random effects model meta-analysis was used to estimate the weighted prevalence of Lynch syndrome diagnoses. RESULTS: The comprehensive search produced 4400 publications. Twenty-nine peer-reviewed studies met the inclusion criteria. Patients with endometrial cancer (n = 6649) were identified, and 206 (3%) were confirmed to have Lynch syndrome through germline genetic testing after positive universal tumor molecular screening. Among 5917 patients who underwent tumor IHC, 28% had abnormal staining. Among 3140 patients who underwent MSI analysis, 31% had MSI. Among patients with endometrial cancer, the weighted prevalence of Lynch syndrome germline mutations was 15% (95% confidence interval [CI], 11%-18%) with deficient IHC staining and 19% (95% CI, 13%-26%) with a positive MSI analysis. Among 1159 patients who exhibited a loss of MLH1 staining, 143 (13.7%) were found to be MLH1 methylation-negative among those who underwent methylation testing, and 32 demonstrated a germline MLH1 mutation (2.8% of all absent MLH1 staining cases and 22.4% of all MLH1 methylation-negative cases). Forty-three percent of patients with endometrial cancer who were diagnosed with Lynch syndrome via tumor typing would have been missed by family history-based screening alone. CONCLUSIONS: Despite the widespread implementation of universal tumor testing in endometrial cancer, data regarding testing results remain limited. This study provides predictive values that will help practitioners to evaluate abnormal results in the context of Lynch syndrome and aid them in patient counseling.

Cutaneous sebaceous tumours and Lynch syndrome: long-term follow-up of 60 patients.

BACKGROUND: Sebaceous neoplasms (SN) may appear sporadically in the general population but may also be part of the Muir-Torre variant of Lynch syndrome (MT-LS). There are few studies in southern Europe on the incidence of MT-LS in the population of patients with SN. AIM: To retrospectively review patients with SN and to analyse their clinical features and the incidence of MT-LS. METHODS: Patients with SN diagnosed between 1995 and 2015 were enrolled in the study. The diagnosis of MT-LS was made according to established clinical criteria and, whenever possible, was confirmed by germline mutation analysis. RESULTS: In 60 patients (32 men, 28 women, mean age 69.22 years), 96 SN were diagnosed: 65 adenomas (67.7%), 16 sebaceomas (16.7%) and 15 carcinomas (15.6%). Of the 60 patients, 50 (83.3%) had a single SN and 10 (16.7%) had multiple lesions. Patients diagnosed with MT-LS (12 patients, 20%) were younger (63.25 years vs. 70.71 years), and had a higher incidence of extrafacial SN (4/12 patients, 33.3%), and were significantly (P < 0.001) more likely to have multiple SNs (8/12, 75%) and keratoacanthomas (KAs) (6/12, 50%). CONCLUSION: Our study confirms that all patients with SN should be investigated, as 20% of our patients were diagnosed with MT-LS. The most specific features of SN associated with MT-LS in our study were the presence of multiple lesions and association with KAs.

Guía de práctica clínica. Diagnóstico y prevención del cáncer colorrectal. Actualización 2018 / Clinical practice guideline. Diagnosis and prevention of colorectal cancer. 2018 Update

Este documento actualiza las recomendaciones realizadas por la Sociedad Española de Medicina Familiar y Comunitaria y la Asociación Española de Gastroenterología para el diagnóstico y la prevención del cáncer colorrectal (CCR). Para establecer la calidad de la evidencia y los niveles de recomendación de las intervenciones se ha utilizado la metodología basada en el sistema GRADE (Grading of Recommendations Assessment, Development and Evaluation). Este documento establece intervalos de demora óptimos en función de los síntomas y el test de SOH inmunológico (SOHi) y recomienda reducir las barreras para la confirmación diagnóstica en los pacientes con síntomas. En cuanto al cribado en población de riesgo medio, se proponen estrategias para conseguir la implantación universal del cribado poblacional basado en SOHi bienal e incrementar la participación de la población diana, incluyendo la implicación de atención primaria. Esta guía de práctica clínica recomienda el cribado universal del síndrome de Lynch mediante la inmunohistoquímica de las proteínas reparadoras o la inestabilidad de microsatélites en los CCR incidentes y el uso de paneles de genes en los pacientes con poliposis adenomatosas. También actualiza las estrategias para reducir la incidencia y la mortalidad tanto de CCR como de otros tumores asociados a los síndromes hereditarios. En cuanto al CCR familiar no hereditario y la vigilancia tras resección de CCR, adenomas y lesiones serradas, se establecen recomendaciones en función del riesgo atribuible y la reducción del riesgo de la intervención propuesta. Finalmente, en el documento se incluyen recomendaciones respecto a los intervalos de vigilancia en la enfermedad inflamatoria intestinal y la actitud ante la displasia

This document updates the recommendations made by the Spanish Society of Family and Community Medicine and the Spanish Association of Gastroenterology for the diagnosis and prevention of colorectal cancer (CRC). In order to evaluate the quality of the evidence and determine the recommendation levels of the interventions, we used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. This document establishes optimal delay intervals based on symptoms and the faecal immunochemical test (FIT) and recommends reducing the barriers for diagnostic confirmation in symptomatic subjects. With regard to CRC screening in the average-risk population, we propose strategies to achieve the universal implementation of organised CRC screening programmes based on biennial FIT and to increase the participation of the target population, including the involvement of Primary Healthcare. This Clinical Practice Guideline recommends universal screening for Lynch syndrome with mismatch repair proteins immunohistochemistry or microsatellite instability in incident CRCs and the use of gene panels in patients with adenomatous polyposis. It also updates the strategies to reduce the incidence and mortality of both CRC and other tumours associated with hereditary syndromes. Regarding non-hereditary familial CRC and surveillance after resection of adenomas, serrated lesions or CRC, we established the recommendations based on the attributable risk and the risk reduction of the proposed intervention. Finally, the document includes recommendations regarding surveillance intervals in inflammatory bowel disease and the attitude towards dysplasia

Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review.

BACKGROUND: Lynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer. CASE PRESENTATION: Here we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome. CONCLUSIONS: Both MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.

The use of panel testing in familial breast and ovarian cancer.

Advances in sequencing technology have led to the introduction of panel testing in hereditary breast and ovarian cancer. While direct-to-consumer testing services have become widely available, the clinical validity of many of the genes on panel tests remains contentious and risk management guidelines are often lacking. This article gives an overview of advantages with panel testing as well as important challenges, including clinical translation of test results.

Multi-disciplinary summit on genetics services for women with gynecologic cancers: A Society of Gynecologic Oncology White Paper.

OBJECTIVE: To assess current practice, advise minimum standards, and identify educational gaps relevant to genetic screening, counseling, and testing of women affected by gynecologic cancers. METHODS: The Society of Gynecologic Oncology (SGO) organized a multidisciplinary summit that included representatives from the American College of Obstetricians and Gynecologists (ACOG), the American Society Clinical Oncology (ASCO), the National Society of Genetic Counselors (NSGC), and patient advocacy groups, BrightPink and Facing our Risk of Cancer Empowered (FORCE). Three subject areas were discussed: care delivery models for genetic testing, barriers to genetic testing, and educational opportunities for providers of genetic testing. RESULTS: The group endorsed current SGO, National Comprehensive Cancer Network (NCCN), and NSGC genetic testing guidelines for women affected with ovarian, tubal, peritoneal cancers, or DNA mismatch repair deficient endometrial cancer. Three main areas of unmet need were identified: timely and universal genetic testing for women with ovarian, fallopian tube, and peritoneal cancers; education regarding minimum standards for genetic counseling and testing; and barriers to implementation of testing of both affected individuals as well as cascade testing of family members. Consensus building among all stakeholders resulted in an action plan to address gaps in education of gynecologic oncology providers and delivery of cancer genetics care.

Current and future role of genetic screening in gynecologic malignancies.

The world of hereditary cancers has seen exponential growth in recent years. While hereditary breast and ovarian cancer and Lynch syndrome account for the majority of mutations encountered by gynecologists, newly identified deleterious genetic mutations continue to be unearthed with their associated risks of malignancies. However, these advances in genetic cancer predispositions then force practitioners and their patients to confront the uncertainties of these less commonly identified mutations and the fact that there is limited evidence to guide them in expected cancer risk and appropriate risk-reduction strategies. Given the speed of information, it is imperative to involve cancer genetics experts when counseling these patients. In addition, coordination of screening and care in conjunction with specialty high-risk clinics, if available, allows for patients to have centralized management for multiple cancer risks under the guidance of physicians with experience counseling these patients. The objective of this review is to present the current literature regarding genetic mutations associated with gynecologic malignancies as well to propose screening and risk-reduction options for these high-risk patients.

A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes.

BACKGROUND: As panel testing becomes more common in clinical practice, it is important to understand the prevalence and trends associated with the pathogenic variants (PVs) identified. This is especially true for genetically heterogeneous cancers, such as breast cancer (BC), in which PVs in different genes may be associated with various risks and cancer subtypes. The authors evaluated the outcomes of genetic testing among women who had a personal history of BC. METHODS: A total of 35,409 women with a single diagnosis of BC who underwent clinical genetic testing with a 25-gene panel were included in the current analysis. Women with multiple BCs and men with BC were excluded. The frequency and distribution of PVs were assessed for the overall cohort, among women with triple-negative BC (TNBC) (n = 4797), and by age at diagnosis. RESULTS: PVs were identified in 9.3% of women tested; 51.5% of PVs were identified in genes other than breast cancer 1 (BRCA1) and BRCA2, including checkpoint kinase 2 (CHEK2) (11.7%), ataxia telangiectasia mutated (ATM; ATM serine/threonine kinase) (9.7%), and partner and localizer of BRCA2 (PALB2) (9.3%). The prevalence of PVs in BRCA1, PALB2, BRCA1-associated RING domain 1 (BARD1), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and RAD51 paralog C (RAD51C) was statistically higher among women with TNBC. The PV rate was higher among women aged <40 years, lower among women aged >59 years, and relatively constant (8.5%-9.0%) among women who were diagnosed between ages 40 and 59 years. CONCLUSIONS: These results demonstrate that panel testing increased the number of women identified as carrying a PV in this cohort compared with BRCA testing alone. Furthermore, the proportion of women identified who carried a PV in this cohort did not decrease between ages 40 and 59 years. Cancer 2017;123:1721-1730. © 2017 American Cancer Society.

Metachronous Uterine Endometrioid Adenocarcinoma and Peritoneal Mesothelioma in Lynch Syndrome: A Case Report.

Lynch syndrome is a hereditary disease with germline mutation in a DNA mismatch repair gene, most often presenting with colorectal and/or endometrial carcinomas; however, the spectrum of Lynch syndrome-associated tumors is expanding. In this article, we report a case of a primary peritoneal epithelioid mesothelioma that developed in a Lynch syndrome patient 10 months after diagnosis of uterine endometrioid adenocarcinoma. To our knowledge, this is the first reported case of a Lynch syndrome patient with metachronous uterine endometrioid adenocarcinoma and primary peritoneal mesothelioma.

Cost-effectiveness of routine screening for Lynch syndrome in endometrial cancer patients up to 70years of age.

PURPOSE: To assess cost-effectiveness of routine screening for Lynch Syndrome (LS) in endometrial cancer (EC) patients ≤70years of age. METHODS: Consecutive EC patients ≤70years of age were screened for LS by analysis of microsatellite instability, immunohistochemistry and MLH1 hypermethylation. Costs and health benefit in life years gained (LYG) included surveillance for LS carriers among EC patients and relatives. We calculated incremental cost-effectiveness ratios (ICERs) comparing LS screening among EC patients ≤70years with ≤50years and the revised Bethesda guidelines. RESULTS: Screening for LS in 179 EC patients identified 7 LS carriers; 1 was ≤50 and 6 were 51-70years. Per age category 18 and 9 relatives were identified as LS carrier. Screening resulted in 74,7 LYG (45,4 and 29,3 LYG per age category). The ICER for LS screening in EC patients ≤70 compared with ≤50years was €5,252/LYG. The revised Bethesda guidelines missed 4/7 (57%) LS carriers among EC patients. The ICER for LS screening in EC patients ≤70years of age compared with the revised Bethesda guidelines was €6,668/LYG. Both ICERs remained <€16,000/LYG in sensitivity analyses. CONCLUSION: Routine LS screening in EC patients ≤70years is a cost-effective strategy, allowing colorectal cancer prevention in EC patients and their relatives.

Lynch Syndrome: Female Genital Tract Cancer Diagnosis and Screening.

Lynch syndrome is responsible for approximately 5% of endometrial cancers and 1% of ovarian cancers. The molecular basis for Lynch syndrome is a heritable functional deficiency in the DNA mismatch repair system, typically due to a germline mutation. This review discusses the rationales and relative merits of current Lynch syndrome screening tests for endometrial and ovarian cancers and provides pathologists with an informed algorithmic approach to Lynch syndrome testing in gynecologic cancers. Pitfalls in test interpretation and strategies to resolve discordant test results are presented. The potential role for next-generation sequencing panels in future screening efforts is discussed.

Laboratory Assays in Evaluation of Lynch Syndrome in Patients with Endometrial Carcinoma.

This article reviews the main tissue testing modalities for Lynch Syndrome in the pathology laboratory, such as immunohistochemistry and PCR based analyses, and discusses their routine application, interpretation pitfalls, and troubleshooting of common technical performance issues. Discrepancies between laboratory and genetic testing may arise, and are examined in the context of the complexity of molecular abnormalities associated with Lynch Syndrome. The merits of targeted versus universal screening in a changing healthcare climate are addressed. In the absence of comprehensive screening programs, specific tumor topography and histological features that may prompt pathologist-initiated molecular tumor testing are outlined.

Prophylactic Gynecologic Specimens from Hereditary Cancer Carriers.

Hereditary breast ovarian cancer and Lynch/hereditary nonpolyposis colorectal cancer syndrome account for most hereditary gynecologic cancers. In the absence of effective cancer screening and other preventative strategies, risk-reducing surgery in women who are known to be at genetic risk of BRCA-associated or of Lynch syndrome carcinomas is effective in significantly decreasing the lifetime risk of developing malignancy. Reflex genomic testing of high-grade ovarian cancers and reflex immunohistochemistry in endometrial cancers will lead to greater recognition of germline-associated cancers. Approaches to processing surgical specimens, the recognition and classification of cancer precursor lesions, and differentiation from their mimics are discussed.

[Founder mutation in Lynch syndrome]. / Mutación fundadora en síndrome de Lynch tipo II.

Lynch syndrome is the most frequent syndrome in hereditary colorectal cancer, a family-specific deleterious mutations in genes encoding DNA reparation proteins: MLH1 (mutL homolog 1), MSH2, MSH6 (mutS homolog 2 y 6, respectively), PMS2 (PMS1 homolog 2, mismatch repair system component) y MUTYH (mutY DNA glycosylase). The c.2252_2253delAA, p.Lys751Serfs*3 mutation in MLH1 gene segregates with a haplotype reported in the northern region of Italy and whose origin was attributed to a founder effect. This mutation co-segregates with typical characteristics of Lynch syndrome, including early age at onset and multiple primary tumors in the same individual, a high frequency of pancreatic cancer, high microsatellite instability and lack of PMS2 expression. This report describes a mutation in an Argentinian patient with endometrioid adenocarcinoma of uterus. Her first-degree relatives had a history of colon cancer diagnosed before 50 years, fulfilling the Amsterdam Criteria I and Lynch syndrome II. The high pathogenicity associated to this mutation makes necessary the study of all members from families with hereditary cancer, allowing pre-symptomatic genetic diagnosis, early assessment and the instauration of preventive treatments.

Mutación fundadora en síndrome de Lynch tipo II / Founder mutation in Lynch syndrome

El síndrome de Lynch es la más frecuente de las neoplasias colorrectales hereditarias. Se origina por mutaciones germinales deletéreas familia-específicas en los genes que codifican proteínas de reparación del ADN: MLH1 (homólogo humano de mutL), MSH2 y MSH6 (homólogo humano de mutS 2 y 6, respectivamente), PMS2 (homólogo humano de PMS1 2) y MUTYH (homólogo humano de la ADN-glycosilasa mutY). La mutación c.2252_2253delAA, p.Lys751Serfs*3 en el exón 19 del gen MLH1 segrega con un haplotipo descripto en la región norte de Italia y cuyo origen fue atribuido a un efecto fundador. Esta mutación co-segrega con características típicas del síndrome de Lynch, incluyendo afectación temprana y múltiples tumores primarios en el mismo individuo, una alta frecuencia de cáncer pancreático, elevada inestabilidad microsatelital y falta de expresión de PMS2. En el presente trabajo se comunica dicha mutación en una paciente argentina con adenocarcinoma endometroide de útero en cuya historia familiar existen antecedentes de cáncer de colon diagnosticado antes de los 50 años en familiares de primer grado, reuniendo los criterios de Ámsterdam I y síndrome de Lynch II. Los polimorfismos presentes en la paciente coinciden con el haplotipo descripto en una región del norte de Italia. El alto grado de patogenicidad asociada a esta mutación hace imprescindible el estudio de todos los integrantes de las familias con cáncer hereditario permitiendo el diagnóstico genético pre-sintomático, la instauración de tratamientos o conductas preventivas y su seguimiento.

Lynch syndrome is the most frequent syndrome in hereditary colorectal cancer, a family-specific deleterious mutations in genes encoding DNA reparation proteins: MLH1 (mutL homolog 1), MSH2, MSH6 (mutS homolog 2 y 6, respectively), PMS2 (PMS1 homolog 2, mismatch repair system component) y MUTYH (mutY DNA glycosylase).The c.2252_2253delAA, p.Lys751Serfs*3 mutation in MLH1 gene segregates with a haplotype reported in the northern region of Italy and whose origin was attributed to a founder effect. This mutation co-segregates with typical characteristics of Lynch syndrome, including early age at onset and multiple primary tumors in the same individual, a high frequency of pancreatic cancer, high microsatellite instability and lack of PMS2 expression. This report describes a mutation in an Argentinian patient with endometrioid adenocarcinoma of uterus. Her first-degree relatives had a history of colon cancer diagnosed before 50 years, fulfilling the Amsterdam Criteria I and Lynch syndrome II. The high pathogenicity associated to this mutation makes necessary the study of all members from families with hereditary cancer, allowing pre-symptomatic genetic diagnosis, early assessment and the instauration of preventive treatments.

[Diagnosis and treatment of Lynch syndrome]. / Lynchin oireyhtymän diagnostiikka ja hoito.

Lynch syndrome (LS) refers to an autosomal dominant genetic predisposition to develop colon cancer or cancers or the uterine corpus, stomach, urinary tract, ovaries, small intestine, mammary gland or bile ducts at a young age. The predisposition to cancer is caused by a germline mutation in one of the genes of the mismatch repair (MMR) system. International recommendations suggest immunohistochemical analysis of tumor tissue from at least those having developed colorectal cancer or endometrial cancer at an age of less than 70 years. This would allow the selection of patients to be referred for gene testing as well as identification of mutation carriers, for whom a regular colonoscopy follow-up is arranged at an interval of 2 to 3 years.