Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum
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 journe...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/8/1081 |
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| author | Ceres Fernández-Rozadilla Miriam Alvarez-Barona Esther Schamschula Sahra Bodo Anael Lopez-Novo Andres Dacal Consuelo Calviño-Costas Angel Lancho Jorge Amigo Xabier Bello Jose Manuel Cameselle-Teijeiro Angel Carracedo Chrystelle Colas Martine Muleris Katharina Wimmer Clara Ruiz-Ponte |
| author_facet | Ceres Fernández-Rozadilla Miriam Alvarez-Barona Esther Schamschula Sahra Bodo Anael Lopez-Novo Andres Dacal Consuelo Calviño-Costas Angel Lancho Jorge Amigo Xabier Bello Jose Manuel Cameselle-Teijeiro Angel Carracedo Chrystelle Colas Martine Muleris Katharina Wimmer Clara Ruiz-Ponte |
| author_sort | Ceres Fernández-Rozadilla |
| collection | DOAJ |
| description | 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 <i>MLH1</i> 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. |
| first_indexed | 2024-03-12T09:29:36Z |
| format | Article |
| id | doaj.art-cbfe801554d04511b2da14763479d857 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T09:29:36Z |
| publishDate | 2019-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-cbfe801554d04511b2da14763479d8572023-09-02T13:56:27ZengMDPI AGCancers2072-66942019-07-01118108110.3390/cancers11081081cancers11081081Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic ContinuumCeres Fernández-Rozadilla0Miriam Alvarez-Barona1Esther Schamschula2Sahra Bodo3Anael Lopez-Novo4Andres Dacal5Consuelo Calviño-Costas6Angel Lancho7Jorge Amigo8Xabier Bello9Jose Manuel Cameselle-Teijeiro10Angel Carracedo11Chrystelle Colas12Martine Muleris13Katharina Wimmer14Clara Ruiz-Ponte15Fundación Pública Galega de Medicina Xenómica SERGAS, Grupo de Medicina Xenómica_USC, IDIS, 15706 Santiago de Compostela, SpainFundación Pública Galega de Medicina Xenómica SERGAS, Grupo de Medicina Xenómica_USC, IDIS, 15706 Santiago de Compostela, SpainDivision of Human Genetics, Medical University Innsbruck, 6020 Innsbruck, AustriaSorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, 75571 Paris, FranceFundación Pública Galega de Medicina Xenómica SERGAS, Grupo de Medicina Xenómica_USC, IDIS, 15706 Santiago de Compostela, SpainServicio de Gastroenterología, Hospital Universitario Lucus Augusti, IDIS, 27003 Lugo, SpainServicio de Pediatría, Hospital Universitario Lucus Augusti, 27003 Lugo, SpainServicio de Gastroenterología, Hospital Universitario Lucus Augusti, IDIS, 27003 Lugo, SpainFundación Pública Galega de Medicina Xenómica SERGAS, Grupo de Medicina Xenómica_USC, IDIS, 15706 Santiago de Compostela, SpainFundación Pública Galega de Medicina Xenómica SERGAS, Grupo de Medicina Xenómica_USC, IDIS, 15706 Santiago de Compostela, SpainServicio de Anatomía Patológica, Hospital Clínico Universitario, USC, 15706 Santiago de Compostela, SpainFundación Pública Galega de Medicina Xenómica SERGAS, Grupo de Medicina Xenómica_USC, IDIS, 15706 Santiago de Compostela, SpainDepartment of Genetics Institut Curie, Centre de Recherche Saint-Antoine, Sorbonne Université, 75571 Paris, FranceSorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, 75571 Paris, FranceDivision of Human Genetics, Medical University Innsbruck, 6020 Innsbruck, AustriaFundación Pública Galega de Medicina Xenómica SERGAS, Grupo de Medicina Xenómica_USC, IDIS, 15706 Santiago de Compostela, SpainLynch 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 <i>MLH1</i> 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.https://www.mdpi.com/2072-6694/11/8/1081Lynch syndromeCMMRDphenotypic continuumgenetic modifierswhole-exome sequencing |
| spellingShingle | Ceres Fernández-Rozadilla Miriam Alvarez-Barona Esther Schamschula Sahra Bodo Anael Lopez-Novo Andres Dacal Consuelo Calviño-Costas Angel Lancho Jorge Amigo Xabier Bello Jose Manuel Cameselle-Teijeiro Angel Carracedo Chrystelle Colas Martine Muleris Katharina Wimmer Clara Ruiz-Ponte Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum Cancers Lynch syndrome CMMRD phenotypic continuum genetic modifiers whole-exome sequencing |
| title | Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum |
| title_full | Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum |
| title_fullStr | Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum |
| title_full_unstemmed | Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum |
| title_short | Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum |
| title_sort | early colorectal cancers provide new evidence for a lynch syndrome to cmmrd phenotypic continuum |
| topic | Lynch syndrome CMMRD phenotypic continuum genetic modifiers whole-exome sequencing |
| url | https://www.mdpi.com/2072-6694/11/8/1081 |
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