A snapshot of current genetic testing practice in Lynch syndrome: The results of a representative survey of 33 Latin American existing centres/registries
Adriana Della ValleBernard RossiEdenir Inêz PalmeroMarina AnteloCarlos VaccaroFrancisco López-KöstnerKarin ÁlvarezMarcia Cruz‐CorreaLuisina BrunoNora Manoukian ForonesJorge Andres Rugeles MindiolaJosé BulejeFlorencia SpirandelliMábel BohórquezAlicia Cock‐RadaYasser SullcahuamanIvana NascimentoKiyoko Abe‐SandesLeonardo S. Lino‐SilvaFlorencia PetracchiAlejandra MampelYeni Paola Moscoso RodríguezNorma RossiClaudio Benavides YañezCladelis RubioTirzah Braz Petta LajusElizabeth Lemos SilveiraGeiner Jiménez JiménezCarlos Mario Muñetón PeñaCarlos Reyes-SilvaMaría de la Luz Ayala-MadrigalJulio Sánchez del MonteRichard QuispeAlcides RecaldeFlorencia NeffaCarlos SarrocaHenrique de Campos Reis GalvãoMariano GolubickiTamara Alejandra PiñeroPablo KalfayanFabiana Alejandra FerroMaría L. GonzálezJulyann Pérez‐MayoralCélia Aparecida Marques PimentaSandra Patricia Bello UyabanAna PrötzelGuiliana ChávezMilagros DueñasMaría Luisa Guevara GilEnrique SpirandelliSergio ChialinaMagdalena EcheverryLuis José Palacios FuenmayorMariela Torres-CintrónThais F.Bonfim PalmaNadia Cambados HéritasClaudia MartinAlfonso SuárezMichael VallejoAna Rafaela de Souza TimóteoCarlos Afanador AyalaGabriela Jaramillo-KoupermannJesús Arturo Hernández-SandovalAngélica Hernández GuerreroConstantino Domínguez-BarreraJuan Carlos Bazo‐AlvarezPatrik WernhoffJohn‐Paul PlazzerYesilda BalavarcaEivind HovigPål MøllerMev Dominguez–Valentin
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MSH6
MSH2
Lynch Syndrome
PMS2
Muir-Torre syndrome (MTS) is currently considered as a clinical variant of Lynch syndrome (LS). The clinical significance of the screening of patients with MTS-associated cutaneous tumors for the identification of LS has not yet been established. In addition, the prevalence and molecular characteristics of mismatch repair (MMR) protein deficiency in such tumors has scarcely been investigated in the Japanese population.Immunohistochemistry (IHC) for MMR proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from 16 sebaceous neoplasms (SNs) resected from 13 patients and 32 keratoacanthomas (KAs) resected from 31 patients at our institution between January 2005 and March 2014. Tumors showing MMR protein loss were further subjected to genetic analysis for detecting the presence of germline and/or somatic alterations of the MMR genes to identify the precise molecular mechanisms underlying the protein loss.Among the 16 SNs resected from 13 patients, eight SNs resected from five patients (38.5%) showed loss of expression of MMR proteins (MLH1/PMS2 loss, one patient; MSH2/MSH6 loss, four patients). Genetic analyses showed a pathogenic germline MSH2 mutation in one patient, somatic hypermethylation of the MLH1 promoter region in one patient, and somatic alterations of MSH2 without detectable germline mutations of MSH2 in three patients. None of the KAs examined in the study showed any loss of MMR protein expression.The efficacy of routine screening of cutaneous neoplasms known to be associated with MTS by IHC for MMR proteins to identify LS may be fairly limited. MMR protein loss as determined by IHC in SNs is not always diagnostic of LS, and appears, in most cases, to be a result of somatic inactivation of the MMR genes.
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Aims Lynch syndrome (LS) is the commonest known cause of hereditary colorectal cancer. It is caused by pathogenic variants in the mismatch repair genes (MMR)- MLH1, MSH2, MSH6, PMS2, EPCAM. Variant classification can have a significant effect on management/surveillance choices, whether pathogenic, of uncertain significance or benign. The risk classification of these variants is not permanent and can be upgraded or downgraded over time as more information on that variant becomes available.
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Aims Lynch syndrome (LS) is the commonest known cause of hereditary colorectal cancer, caused by pathogenic variants in the mismatch repair genes (MMR)- MLH1, MSH2, MSH6, PMS2, EPCAM. To date little research has been published on the specific variants that exist in Ireland. Variant classification can have a significant effect on management choices, whether pathogenic, of uncertain significance or benign. Pathogenic MMR variants vary in their predisposition to causing colorectal and gynaecological cancers.
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Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, accounts for approximately 1–5% of all colorectal cancers. Germline mutations in a group of deoxyribonucleic acid (DNA) mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS1, and PMS2) are responsible for Lynch syndrome cases. This study focuses on the determination of MMR (MLH1, MSH2, MSH6, and PMS2) protein expression profile by immunohistochemical analysis and its association with clinicopathological characteristics in clinically diagnosed Malaysian Lynch syndrome patients. Fifty patients who fulfilled any of the revised Bethesda Guidelines criteria were recruited from four collaborating centers in Malaysia. Clinicopathological information of clinically diagnosed Lynch syndrome cases that underwent bowel resection was reviewed. Immunohistochemical analysis for MLH1, MSH2, MSH6, and PMS2 proteins were performed on paraffin-embedded carcinomatous tissues. Colorectal cancer protein expression analysis for MLH1, MSH2, MSH6, and PMS2 antigens showed absence of expression of any MMR proteins in 18 out of 50 clinically diagnosed Lynch syndrome patients (36.0%). There was a significant association between abnormal MMR protein expression with tumor size (p = 0.012), histological differentiation of cancers (p = 0.012), and growth pattern of tumor (p = 0.01). Abnormal expression of MMR protein in colorectal cancers in clinically diagnosed Lynch syndrome patients was associated with specific clinicopathological characteristics such as tumor size, histological differentiation of cancers, and growth pattern of tumor. Immunohistochemical analysis proved to be an advantageous pre-screening tool for Lynch syndrome in Malaysian patients and highly predictive of a germline mutation in DNA MMR genes.
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To determine the ratio of deficient mismatch repair (dMMR) proteins and Lynch syndrome among patients undergoing colorectal cancer resection.From June 2014 to May 2016, immunohistochemistry for mismatch repair proteins including mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and PMS1 homolog 2 (PMS2) were carried out on 207 surgically resected specimens. Samples with lost expression of MMR proteins underwent genetic testing.Loss of expression of MMR proteins were found among 21 patients and accounted for 10.14% of the colorectal cancers. dMMR was more common in patients ≤50 years old, or with proximal tumor at splenic flexure and mucinous adenocarcinoma. Ten patients underwent genetic testing, with three pathogenic mutations (MSH6 c.3013C>T, MLH1 c.199G>A and a novel MSH6 c.584delT) and four ambiguous mutations identified. At least 1.4% of the colorectal cancers were diagnosed as Lynch syndrome.Routine screening for Lynch syndrome among patients with colorectal cancer with MMR protein immunohistochemistry as preliminary screening method and MMR gene sequencing as diagnostic method is effective and feasible. It can reduce missed diagnosis of Lynch syndrome and bring lifelong benefit to patients and their families.
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The association between Lynch syndrome and sebaceous neoplasms is well characterized. The absence of expression of mismatch repair proteins (MMRPs) by immunohistochemistry (IHC) is often used in other Lynch-associated tumors to guide testing. IHC for MLH1, PMS2, MSH2, and MSH6 was performed on 36 benign and malignant sebaceous neoplasms with the absence of one or more MMRP in 38.9% of cases. Among lesions with abnormal IHC, 71.4% were missing both MSH2 and MSH6, 21.4% lacked MLH1 and PMS2, and 7.1% lacked only MSH6. Of the 10 patients with absent MMRP, 5 had gene-test confirmed Lynch syndrome, 3 had no suggestive personal or family medical history and 2 had no recorded data. Tumor-infiltrating lymphocytes in neoplasms with absent MMRP were statistically significantly greater than in those with intact MMRP (16.5 vs. 9.7, P = 0.027). MMRP deficiency is common in sebaceous neoplasms, suggesting the importance of screening for Lynch syndrome in these patients.
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Mutations in some mismatch repair (MMR) genes are associated with Lynch syndrome (LS; also called hereditary nonpolyposis colorectal cancer [HNPCC]), an autosomal dominant cancer susceptibility syndrome. Colorectal cancer (CRC) is the most frequent cancer observed in LS. However, tumors occur at a variety of extracolonic sites and individuals may have multiple primary cancers. LS is the most common hereditary form of CRC, accounting for approximately 1% of all CRC. Since the first account of mutations in MSH2 causing this cancer susceptibility syndrome in 1993, mutations in three additional MMR genes, MLH1, MSH6, and PMS2, have been shown to cause LS. More than 1,500 different variants have been identified in these four genes and approximately 80% of the alterations have been identified in MLH1 and MSH2. There have been a few previous attempts to systematically record MMR variants associated with LS patients; however, they were not complete nor were they continuously updated. Thus, it was our goal to generate and maintain a comprehensive catalogue of MMR variants from genes known to be mutated in LS (http://www.med.mun.ca/MMRvariants; last accessed 8 February 2007). Providing such a resource should aid investigators in understanding the significance of the variants. Hum Mutat 28(7), 669–673, 2007. © 2007 Wiley-Liss, Inc.
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Lynch syndrome (LS) is the most common form of hereditary colorectal cancer (CRC), and previously it was called hereditary non-polyposis colorectal cancer (HNPCC). LS is an inherited tumor predisposing condition caused by mutations in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2) or in the EPCAM gene, which inactivates MSH2 via promoter hypermethylation. The proteins produced by MLH1, MSH2, MSH6 and PMS2 form heterodimeric complexes, which play an essential role in DNA repair. Genotype–phenotype correlations are established because cancer risk depends on the mutated MMR gene. The genotype deficient in MMR genes (MMR deficient) is associated with a lifetime cancer risk of 58–75% with frequent observations of the development of synchronous/metachronous tumors. Lynch-associated CRCs behave differently than sporadic CRCs, which has significant implications for clinical management. Histopathological examination of Lynch-associated CRCs often reveals abundant lymphocytes infiltrating the tumor.
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