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 seguimientoLynch 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.Fil: Cajal, Andrea. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; ArgentinaFil: Piñero, Tamara Alejandra. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; ArgentinaFil: Verzura, Alicia. Hospital Italiano; ArgentinaFil: Santino, Juan Pablo. Hospital Italiano; ArgentinaFil: Solano, Angela Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Kalfayan, Pablo G.. Hospital Italiano; ArgentinaFil: Ferro, Fabiana Alejandra. Hospital Italiano; ArgentinaFil: Vaccaro, Carlos A.. Hospital Italiano; Argentin

Geostatistics applied to the study of soil physiochemical characteristics in seasonal deciduous forest areas

Utilizaram-se m\ue9todos da geoestat\uedstica na identifica\ue7\ue3o do tamanho e da estrutura da variabilidade espacial de alguns atributos f\uedsico-qu\uedmicos do solo em \ue1reas de Floresta Estacional Decidual as quais foram denominadas floresta madura, floresta secund\ue1ria e capoeir\ue3o. As \ue1reas, localizadas no munic\uedpio de Santa Tereza, RS, foram amostradas durante o per\uedodo de 2002 a 2003, compreendendo as classes de solo: Chernossolo Argil\ufavico, Cambissolo Ta e Neossolo Lit\uf3lico. Realizou-se amostragem sistem\ue1tica com grid de espa\ue7amento regular entre os pontos variando de 30 m para o capoeir\ue3o e 40 m para floresta madura e secund\ue1ria, totalizando oitenta pontos amostrais em uma \ue1rea total de 7,34 ha. Foram coletadas amostras de solo \u201cin situ\u201d para an\ue1lise em laborat\uf3rio dos atributos densidade do solo, argila, pH, pot\ue1ssio, mat\ue9ria org\ue2nica e f\uf3sforo. A estrutura da variabilidade espacial foi identificada por meio dos semivariogramas, definindo-se os par\ue2metros necess\ue1rios para a krigagem. O atributo mais vari\ue1vel foi a mat\ue9ria org\ue2nica, n\ue3o obtendo ajuste a nenhum modelo te\uf3rico de semivariograma, enquanto que o pH foi o menor. Na an\ue1lise de estrutura da variabilidade espacial por meio da geoestat\uedstica, a argila e densidade, ambas em \ue1rea de floresta secund\ue1ria, e o pH nas \ue1reas experimentais apresentaram a maior depend\ueancia espacial. O modelo gaussiano para o atributo argila obteve o maior alcance da depend\ueancia espacial, sendo 400 e 388 m, nas \ue1reas de floresta secund\ue1ria e madura respectivamente. A valida\ue7\ue3o cruzada mostrou acuracidade no ajuste dos modelos variogr\ue1ficos, tendo a vari\ue1vel pH apresentado o melhor desempenho, 0,87; 0,94 e 0,92 nas \ue1reas de floresta madura, secund\ue1ria e capoeir\ue3o respectivamente.Methods of geostatistics were used in the identification of size and structure of space variability of some physiochemical attributes of soils under seasonal deciduous forest areas, which were called mature forest, secondary forest and "capoeir\ue3o". The areas, located in Santa Tereza, RS, were sampled during the period of 2002 and 2003, comprising the soil classes: Argiluvic Chernosol, Cambisol Ta and Litholic Neosol. Systematic sampling was performed with regular spacing grid of points varying of 30 m for "capoeir\ue3o" and 40 m for mature and secondary forest, in an amount of 80 sample points in a total area of 7.34 ha. For each point, measurements "in situ" were made of the soil bulk density, clay content, pH, potassium, organic matter and phosphorus. The structure of space variability was identified through the variograms, being defined the needed parameters for the Kriging. The most variable attribute was the organic matter, being not adjusted to any model of variogram, while the pH was the least. In the analysis of the space variability structure through the geostatistics, the clay and bulk density, both in area of secondary forest, and pH in the experimental areas, had showed the biggest space dependence. The Gauss model for the clay attribute obtained the largest reach (a), being 400 m and 388 m in the areas of secondary and mature forest, respectively. The crossed validation showed accuracy in the variographic models adjustment, being the pH variable the one which presented the optimum performance, 0.87; 0.94 and 0.92 in the areas of mature forest, secondary forest and "capoeir\ue3o", respectively

Geoestatística aplicada ao estudo das características físico-químicas do solo em áreas de Floresta Estacional Decidual

Methods of geostatistics were used in the identification of size and structure of space variability of some physiochemical attributes of soils under seasonal deciduous forest areas, which were called mature forest, secondary forest and “capoeirão”. The areas, located in Santa Tereza, RS, were sampled during the period of 2002 and 2003, comprising the soil classes: Argiluvic Chernosol, Cambisol Ta and Litholic Neosol. Systematic sampling was performed with regular spacing grid of points varying of 30 m for “capoeirão” and 40 m for mature and secondary forest, in an amount of 80 sample points in a total area of 7.34 ha. For each point, measurements "in situ" were made of the soil bulk density, clay content, pH, potassium, organic matter and phosphorus. The structure of space variability was identified through the variograms, being defined the needed parameters for the Kriging. The most variable attribute was the organic matter, being not adjusted to any model of variogram, while the pH was the least. In the analysis of the space variability structure through the geostatistics, the clay and bulk density, both in area of secondary forest, and pH in the experimental areas, had showed the biggest space dependence. The Gauss model for the clay attribute obtained the largest reach (a), being 400 m and 388 m in the areas of secondary and mature forest, respectively. The crossed validation showed accuracy in the variographic models adjustment, being the pH variable the one which presented the optimum performance, 0.87; 0.94 and 0.92 in the areas of mature forest, secondary forest and “capoeirão”, respectively.Utilizaram-se métodos da geoestatística na identificação do tamanho e da estrutura da variabilidade espacial de alguns atributos físico-químicos do solo em áreas de Floresta Estacional Decidual as quais foram denominadas floresta madura, floresta secundária e capoeirão. As áreas, localizadas no município de Santa Tereza, RS, foram amostradas durante o período de 2002 a 2003, compreendendo as classes de solo: Chernossolo Argilúvico, Cambissolo Ta e Neossolo Litólico. Realizou-se amostragem sistemática com grid de espaçamento regular entre os pontos variando de 30 m para o capoeirão e 40 m para floresta madura e secundária, totalizando oitenta pontos amostrais em uma área total de 7,34 ha. Foram coletadas amostras de solo "in situ" para análise em laboratório dos atributos densidade do solo, argila, pH, potássio, matéria orgânica e fósforo. A estrutura da variabilidade espacial foi identificada por meio dos semivariogramas, definindo-se os parâmetros necessários para a krigagem. O atributo mais variável foi a matéria orgânica, não obtendo ajuste a nenhum modelo teórico de semivariograma, enquanto que o pH foi o menor. Na análise de estrutura da variabilidade espacial por meio da geoestatística, a argila e densidade, ambas em área de floresta secundária, e o pH nas áreas experimentais apresentaram a maior dependência espacial. O modelo gaussiano para o atributo argila obteve o maior alcance da dependência espacial, sendo 400 e 388 m, nas áreas de floresta secundária e madura respectivamente. A validação cruzada mostrou acuracidade no ajuste dos modelos variográficos, tendo a variável pH apresentado o melhor desempenho, 0,87; 0,94 e 0,92 nas áreas de floresta madura, secundária e capoeirão respectivamente

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

Background: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. Methods: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. Results: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. Conclusion: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.Radium Hospital Foundation (Oslo, Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, Helse Sør-Øst (Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, the French Association Recherche contre le Cancer (ARC) in the analysis, and interpretation of data, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (Gefluc) in the analysis, and interpretation of data, the Association Nationale de la Recherche et de la Technologie (ANRT, CIFRE PhD fellowship to H.T.) in the analysis, and interpretation of data and by the OpenHealth Institute in the analysis, and interpretation of data. Barretos Cancer Hospital received financial support by FINEP-CT-INFRA (02/2010)info:eu-repo/semantics/publishedVersio

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender

Risk-Reducing Gynecological Surgery in Lynch Syndrome : Results of an International Survey from the Prospective Lynch Syndrome Database

Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT. Results: Risk-reducing hysterectomy and BSO are offered to path_MLH1 and path_MSH2 carriers in 20/21 (95%) contributing centers, to path_MSH6 carriers in 19/21 (91%) and to path_PMS2 carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (similar to 90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35-55 years). Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of path_MLH1, path_MSH2 and path_MSH6 variants but less so for path_PMS2 carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.Peer reviewe

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2:A Prospective Lynch Syndrome Database Study

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2

Uptake of hysterectomy and bilateral salpingooophorectomy in carriers of pathogenic mismatch repair variants:a Prospective Lynch Syndrome Database report

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants. Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years. Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery. Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants:findings from the Prospective Lynch Syndrome Database

Purpose Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. Methods We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. Results There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Conclusion Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers