MLH1 intronic variants mapping to + 5 position of splice donor sites lead to deleterious effects on RNA splicing.

Autor: Piñero TA; Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB) [HIBA-IUHI-CONICET], C1199ABH, Buenos Aires, Argentina.; Programa de Cáncer Hereditario (Pro.Can.He.), Hospital Italiano de Buenos Aires, C1199ABH, Buenos Aires, Argentina., Soukarieh O; Inserm U1245, IRIB, UNIROUEN, Normandie Univ, Normandy Centre for Genomic and Personalized Medicine, 76183, Rouen Cedex 1, France., Rolain M; Inserm U1245, IRIB, UNIROUEN, Normandie Univ, Normandy Centre for Genomic and Personalized Medicine, 76183, Rouen Cedex 1, France., Alvarez K; Laboratorio de Oncología y Genética Molecular, Unidad de Coloproctología, Clínica Las Condes, 7591046, Santiago de Chile, Chile., López-Köstner F; Laboratorio de Oncología y Genética Molecular, Unidad de Coloproctología, Clínica Las Condes, 7591046, Santiago de Chile, Chile., Torrezan GT; Genomic and Molecular Biology Group, International Research Center, A. C. Camargo Cancer Center, São Paulo, 01508-010, Brazil., Carraro DM; Genomic and Molecular Biology Group, International Research Center, A. C. Camargo Cancer Center, São Paulo, 01508-010, Brazil., De Oliveira Nascimento IL; Laboratório de Imunologia e Biología Molecular, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, BA, 40110-902, Brazil., Bomfim TF; Laboratório de Imunologia e Biología Molecular, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, BA, 40110-902, Brazil., Machado-Lopes TMB; Laboratório de Imunologia e Biología Molecular, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, BA, 40110-902, Brazil., Freitas JC; Laboratório de Imunologia e Biología Molecular, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, BA, 40110-902, Brazil.; Departamento de Ciências da Vida, Universidade do Estado da Bahia, Salvador, BA, 41150-000, Brazil., Toralles MB; Laboratório de Imunologia e Biología Molecular, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, BA, 40110-902, Brazil., Sandes KA; Laboratório de Imunologia e Biología Molecular, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, BA, 40110-902, Brazil., Rossi BM; Hospital Sirio Libanes, São Paulo, 01308-050, Brazil., Junior SA; Colorectal Tumor Nucleus of the Pelvic Surgery Department, A.C. Camargo Cancer Center, São Paulo, SP, 01509-010, Brazil., Meira J; Hospital Universitário Prof. Edgard Santos, Universidade Federal da Bahia, Salvador, 40301-155, Brazil., Dominguez-Valentin M; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0369, Oslo, Norway.; Instituto de Investigación, Universidad Católica de Trujillo, Chimbote, Peru., Møller P; Department of Tumor Biology, The Norwegian Radium Hospital, Part of Oslo University Hospital, 0369, Oslo, Norway., Vaccaro CA; Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB) [HIBA-IUHI-CONICET], C1199ABH, Buenos Aires, Argentina.; Programa de Cáncer Hereditario (Pro.Can.He.), Hospital Italiano de Buenos Aires, C1199ABH, Buenos Aires, Argentina., Martins A; Inserm U1245, IRIB, UNIROUEN, Normandie Univ, Normandy Centre for Genomic and Personalized Medicine, 76183, Rouen Cedex 1, France., Pavicic WH; Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB) [HIBA-IUHI-CONICET], C1199ABH, Buenos Aires, Argentina. walter.pavicic@hospitalitaliano.org.ar.; Programa de Cáncer Hereditario (Pro.Can.He.), Hospital Italiano de Buenos Aires, C1199ABH, Buenos Aires, Argentina. walter.pavicic@hospitalitaliano.org.ar.
Jazyk: angličtina
Zdroj: Familial cancer [Fam Cancer] 2020 Oct; Vol. 19 (4), pp. 323-336.
DOI: 10.1007/s10689-020-00182-5
Abstrakt: Germline pathogenic variants in the DNA mismatch repair genes (MMR): MLH1, MSH2, MSH6, and PMS2, are causative of Lynch syndrome (LS). However, many of the variants mapping outside the invariant splice site positions (IVS ± 1, IVS ± 2) are classified as variants of unknown significance (VUS). Three such variants (MLH1 c.588+5G>C, c.588+5G>T and c.677+5G>A) were identified in 8 unrelated LS families from Argentina, Brazil and Chile. Herein, we collected clinical information on these families and performed segregation analysis and RNA splicing studies to assess the implication of these VUS in LS etiology. Pedigrees showed a clear pattern of variant co-segregation with colorectal cancer and/or other LS-associated malignancies. Tumors presented deficient expression of MLH1-PMS2 proteins in 7/7 of the LS families, and MSI-high status in 3/3 cases. Moreover, RNA analyses revealed that c.588+5G>C and c.588+5G>T induce skipping of exon 7 whereas c.677+5G>A causes skipping of exon 8. In sum, we report that the combined clinical findings in the families and the molecular studies provided the evidences needed to demonstrate that the three MLH1 variants are causative of LS and to classify c.588+5G>C and c.677+5G>A as class 5 (pathogenic), and c.588+5G>T as class 4 (likely-pathogenic). Our findings underline the importance of performing clinical and family analyses, as well as RNA splicing assays in order to determine the clinical significance of intronic variants, and contribute to the genetic counseling and clinical management of patients and their relatives.
Databáze: MEDLINE
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