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Open AccessCommunication

Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum

Fundación Pública Galega de Medicina Xenómica SERGAS, Grupo de Medicina Xenómica_USC, IDIS, 15706 Santiago de Compostela, Spain
Division of Human Genetics, Medical University Innsbruck, 6020 Innsbruck, Austria
Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria
Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, 75571 Paris, France
Servicio de Gastroenterología, Hospital Universitario Lucus Augusti, IDIS, 27003 Lugo, Spain
Servicio de Pediatría, Hospital Universitario Lucus Augusti, 27003 Lugo, Spain
Servicio de Anatomía Patológica, Hospital Clínico Universitario, USC, 15706 Santiago de Compostela, Spain
Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Department of Genetics Institut Curie, Centre de Recherche Saint-Antoine, Sorbonne Université, 75571 Paris, France
Author to whom correspondence should be addressed.
Cancers 2019, 11(8), 1081;
Received: 11 July 2019 / Revised: 18 July 2019 / Accepted: 25 July 2019 / Published: 30 July 2019
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by heterozygous mutations in the mismatch repair (MMR) genes. Biallelic mutations in these genes lead however, to constitutive mismatch repair deficiency (CMMRD). In this study, we follow the diagnostic journey of a 12-year old patient with CRC, with a clinical phenotype overlapping CMMRD. We perform molecular and functional assays to discard a CMMRD diagnosis then identify by exome sequencing and validation in a cohort of 134 LS patients, a candidate variant in the MLH1 UTR region in homozygosis. We propose that this variant, together with other candidates, could be responsible for age-of-onset modulation. Our data support the idea that low-risk modifier alleles may influence early development of cancer in LS leading to a LS-to-CMMRD phenotypic continuum. Therefore, it is essential that larger efforts are directed to the identification and study of these genetic modifiers, in order to provide optimal cancer prevention strategies to these patients. View Full-Text
Keywords: Lynch syndrome; CMMRD; phenotypic continuum; genetic modifiers; whole-exome sequencing Lynch syndrome; CMMRD; phenotypic continuum; genetic modifiers; whole-exome sequencing
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Fernández-Rozadilla, C.; Alvarez-Barona, M.; Schamschula, E.; Bodo, S.; Lopez-Novo, A.; Dacal, A.; Calviño-Costas, C.; Lancho, A.; Amigo, J.; Bello, X.; Cameselle-Teijeiro, J.M.; Carracedo, A.; Colas, C.; Muleris, M.; Wimmer, K.; Ruiz-Ponte, C. Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum. Cancers 2019, 11, 1081.

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