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

Ceres Fernández-Rozadilla (1) , Miriam Alvarez-Barona (1) , Esther Schamschula (2, 3) , Sahra Bodo (4) , Anael Lopez-Novo (1) , Andres Dacal (5) , Consuelo Calviño-Costas (6) , Angel Lancho (5) , Jorge Amigo (1) , Xabier Bello (1) , Jose Manuel Cameselle-Teijeiro (7) , Ángel Carracedo (1, 8) , Chrystelle Colas (4, 9) , Martine Muleris (4) , Katharina Wimmer (2) , Clara Ruiz-Ponte (1, 8)

1 Grupo de Medicina Xenómica - Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain]
2 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
3 Department of Biosciences [Salzburg, Austria )
4 CRSA - Centre de Recherche Saint-Antoine
5 Servicio de Gastroenterología [Lugo, Spain]
6 Servicio de Pediatría [Lugo, Spain]
7 Servicio de Anatomía Patológica [Santiago de Compostela, Spain]
8 Grupo de Medicina Xenómica - Centro de Investigación Biomédica en Red de Enfermedades Raras - CIBERER [Santiago de Compostela, Spain]
9 Institut Curie [Paris]

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.

Mots clés: whole-exome sequencing; CMMRD; Lynch syndrome; genetic modifiers; phenotypic continuum

Domaines: Cancer; Hépatologie et Gastroentérologie; Pédiatrie; Génomique, Transcriptomique et Protéomique [q-bio.GN]

Ceres Fernández-Rozadilla, Miriam Alvarez-Barona, Esther Schamschula, Sahra Bodo, Anael Lopez-Novo, et al.. Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum. Cancers, 2019, 11 (8), pp.1081. ⟨10.3390/cancers11081081⟩. ⟨hal-02294122⟩