Adela Castillejo1, Gardenia Vargas2, María Isabel Castillejo1, Matilde Navarro2, Víctor Manuel Barberá1, Sara González2, Eva Hernández-Illán3, Joan Brunet4, Teresa Ramón y Cajal5, Judith Balmaña6, Silvestre Oltra7, Sílvia Iglesias2, Angela Velasco4, Ares Solanes8, Olga Campos2, Ana Beatriz Sánchez Heras9, Javier Gallego10, Estela Carrasco11, Dolors González Juan5, Angel Segura12, Isabel Chirivella13, María José Juan14, Isabel Tena15, Conxi Lázaro2, Ignacio Blanco16, Marta Pineda2, Gabriel Capellá2, José Luis Soto17. 1. Molecular Genetics Laboratory, Elche University Hospital, Elche, Alicante, Spain. 2. Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. 3. Laboratory of Investigation, Alicante University Hospital, Alicante, Spain. 4. Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IdIBGI, Girona, Spain. 5. Medical Oncology Service, Santa Creu i Sant Pau Hospital, Barcelona, Spain. 6. University Hospital of Vall d'Hebron, Barcelona, Spain. 7. Genetics Department, La Fe University Hospital, Valencia, Spain. 8. Hereditary Cancer Program, Catalan Institute of Oncology, Badalona, Barcelona, Spain. 9. Genetic Counselling in Cancer, Hereditary Cancer Program, Elche University Hospital, Elche, Alicante, Spain; Department of Medical Oncology, Elche University Hospital, Elche, Alicante, Spain. 10. Department of Medical Oncology, Elche University Hospital, Elche, Alicante, Spain. 11. Vall d́Hebron Institute of Oncology, Barcelona, Spain. 12. Genetic Counselling in Cancer, Hereditary Cancer Program, La Fe University Hospital, Valencia, Spain. 13. Genetic Counselling in Cancer, Hereditary Cancer Program, Clinical University Hospital of Valencia, Valencia, Spain. 14. Genetic Counselling in Cancer, Hereditary Cancer Program, Valencian Institute of Oncology, Valencia, Spain. 15. Genetic Counselling in Cancer, Hereditary Cancer Program, Provincial Hospital of Castellón, Castellón, Spain. 16. Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain; Hereditary Cancer Program, Catalan Institute of Oncology, Badalona, Barcelona, Spain. 17. Molecular Genetics Laboratory, Elche University Hospital, Elche, Alicante, Spain. Electronic address: soto_jos@gva.es.
Abstract
BACKGROUND AND AIMS: Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. METHODS: Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. RESULTS: We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P=0.02) and wildtype patients (P<0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P<0.0001). CONCLUSIONS: A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.
BACKGROUND AND AIMS: Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposispatients show some phenotypic similarities to Lynch syndromepatients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. METHODS: Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. RESULTS: We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P=0.02) and wildtype patients (P<0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P<0.0001). CONCLUSIONS: A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.
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