Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers
Lynch-like syndrome (LLS) is an increasingly common clinical challenge with an underlying molecular basis mostly unknown. To shed light onto it, we focused on a very young LLS early-onset colorectal cancer (CRC) cohort (diagnosis ≤ 40 y.o.), performing germline and tumor whole-exome sequencing (WES)...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/6/1259 |
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| author | Mariano Golubicki Marcos Díaz-Gay Laia Bonjoch Sebastià Franch-Expósito Jenifer Muñoz Miriam Cuatrecasas Teresa Ocaña Soledad Iseas Guillermo Mendez Marcela Carballido Juan Robbio Daniel Cisterna Enrique Roca Antoni Castells Francesc Balaguer Sergi Castellví-Bel Marina Antelo |
| author_facet | Mariano Golubicki Marcos Díaz-Gay Laia Bonjoch Sebastià Franch-Expósito Jenifer Muñoz Miriam Cuatrecasas Teresa Ocaña Soledad Iseas Guillermo Mendez Marcela Carballido Juan Robbio Daniel Cisterna Enrique Roca Antoni Castells Francesc Balaguer Sergi Castellví-Bel Marina Antelo |
| author_sort | Mariano Golubicki |
| collection | DOAJ |
| description | Lynch-like syndrome (LLS) is an increasingly common clinical challenge with an underlying molecular basis mostly unknown. To shed light onto it, we focused on a very young LLS early-onset colorectal cancer (CRC) cohort (diagnosis ≤ 40 y.o.), performing germline and tumor whole-exome sequencing (WES) of 15 patients, and additionally analyzing their corresponding tumor mutational burden (TMB) and mutational signatures. We identified four cases (27%) with double somatic putative variants in mismatch repair (MMR) core genes, as well as three additional cases (20%) with double <i>MSH3</i> somatic alterations in tumors with unexplained MSH2/MSH6 loss of expression, and two cases (13%) with <i>POLD1</i> potential biallelic alterations. Average TMB was significantly higher for LLS cases with double somatic alterations. Lastly, nine predicted deleterious variants in genes involved in the DNA repair functions and/or previously associated with CRC were found in nine probands, four of which also showed MMR biallelic somatic inactivation. In conclusion, we contribute new insights into LLS CRC, postulating <i>MSH3</i> and <i>POLD1</i> double somatic alterations as an underlying cause of a microsatellite instability (MSI) phenotype, proposing intrinsic biological differences between LLS with and without somatic alterations, and suggesting new predisposing candidate genes in this scenario. |
| first_indexed | 2024-03-10T13:17:06Z |
| format | Article |
| id | doaj.art-1aeba41723474dea914aec75addb2551 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T13:17:06Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-1aeba41723474dea914aec75addb25512023-11-21T10:15:23ZengMDPI AGCancers2072-66942021-03-01136125910.3390/cancers13061259Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal CancersMariano Golubicki0Marcos Díaz-Gay1Laia Bonjoch2Sebastià Franch-Expósito3Jenifer Muñoz4Miriam Cuatrecasas5Teresa Ocaña6Soledad Iseas7Guillermo Mendez8Marcela Carballido9Juan Robbio10Daniel Cisterna11Enrique Roca12Antoni Castells13Francesc Balaguer14Sergi Castellví-Bel15Marina Antelo16Oncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires C1264, ArgentinaCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Gastroenterology Department, Institut d’ Investigacions BiomèdiquesAugust Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Gastroenterology Department, Institut d’ Investigacions BiomèdiquesAugust Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Gastroenterology Department, Institut d’ Investigacions BiomèdiquesAugust Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Gastroenterology Department, Institut d’ Investigacions BiomèdiquesAugust Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, SpainPathology Department, Hospital Clínic, 08036 Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Gastroenterology Department, Institut d’ Investigacions BiomèdiquesAugust Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, SpainOncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires C1264, ArgentinaOncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires C1264, ArgentinaOncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires C1264, ArgentinaOncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires C1264, ArgentinaMolecular Biology Lab, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires C1264, ArgentinaOncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires C1264, ArgentinaCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Gastroenterology Department, Institut d’ Investigacions BiomèdiquesAugust Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Gastroenterology Department, Institut d’ Investigacions BiomèdiquesAugust Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Gastroenterology Department, Institut d’ Investigacions BiomèdiquesAugust Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, SpainOncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires C1264, ArgentinaLynch-like syndrome (LLS) is an increasingly common clinical challenge with an underlying molecular basis mostly unknown. To shed light onto it, we focused on a very young LLS early-onset colorectal cancer (CRC) cohort (diagnosis ≤ 40 y.o.), performing germline and tumor whole-exome sequencing (WES) of 15 patients, and additionally analyzing their corresponding tumor mutational burden (TMB) and mutational signatures. We identified four cases (27%) with double somatic putative variants in mismatch repair (MMR) core genes, as well as three additional cases (20%) with double <i>MSH3</i> somatic alterations in tumors with unexplained MSH2/MSH6 loss of expression, and two cases (13%) with <i>POLD1</i> potential biallelic alterations. Average TMB was significantly higher for LLS cases with double somatic alterations. Lastly, nine predicted deleterious variants in genes involved in the DNA repair functions and/or previously associated with CRC were found in nine probands, four of which also showed MMR biallelic somatic inactivation. In conclusion, we contribute new insights into LLS CRC, postulating <i>MSH3</i> and <i>POLD1</i> double somatic alterations as an underlying cause of a microsatellite instability (MSI) phenotype, proposing intrinsic biological differences between LLS with and without somatic alterations, and suggesting new predisposing candidate genes in this scenario.https://www.mdpi.com/2072-6694/13/6/1259colorectal cancerbiallelic somatic alterationearly-onset cancerLynch-like syndromemismatch repairwhole-exome sequencing |
| spellingShingle | Mariano Golubicki Marcos Díaz-Gay Laia Bonjoch Sebastià Franch-Expósito Jenifer Muñoz Miriam Cuatrecasas Teresa Ocaña Soledad Iseas Guillermo Mendez Marcela Carballido Juan Robbio Daniel Cisterna Enrique Roca Antoni Castells Francesc Balaguer Sergi Castellví-Bel Marina Antelo Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers Cancers colorectal cancer biallelic somatic alteration early-onset cancer Lynch-like syndrome mismatch repair whole-exome sequencing |
| title | Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers |
| title_full | Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers |
| title_fullStr | Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers |
| title_full_unstemmed | Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers |
| title_short | Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers |
| title_sort | comprehensive genomic characterization of fifteen early onset lynch like syndrome colorectal cancers |
| topic | colorectal cancer biallelic somatic alteration early-onset cancer Lynch-like syndrome mismatch repair whole-exome sequencing |
| url | https://www.mdpi.com/2072-6694/13/6/1259 |
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