Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms.
The identification of germline variants predisposing to hereditary nonpolyposis colorectal cancer (HNPCC) is crucial for clinical management of carriers, but several probands remain negative for such variants or bear variants of uncertain significance (VUS). Here we describe the results of integrati...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3835792?pdf=render |
| _version_ | 1818369226778345472 |
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| author | Laura De Lellis Gitana Maria Aceto Maria Cristina Curia Teresa Catalano Sandra Mammarella Serena Veschi Fabiana Fantini Pasquale Battista Vittoria Stigliano Luca Messerini Cristina Mareni Paola Sala Lucio Bertario Paolo Radice Alessandro Cama |
| author_facet | Laura De Lellis Gitana Maria Aceto Maria Cristina Curia Teresa Catalano Sandra Mammarella Serena Veschi Fabiana Fantini Pasquale Battista Vittoria Stigliano Luca Messerini Cristina Mareni Paola Sala Lucio Bertario Paolo Radice Alessandro Cama |
| author_sort | Laura De Lellis |
| collection | DOAJ |
| description | The identification of germline variants predisposing to hereditary nonpolyposis colorectal cancer (HNPCC) is crucial for clinical management of carriers, but several probands remain negative for such variants or bear variants of uncertain significance (VUS). Here we describe the results of integrative molecular analyses in 132 HNPCC patients providing evidences for improved genetic testing of HNPCC with traditional or next generation methods. Patients were screened for: germline allele-specific expression (ASE), nucleotide variants, rearrangements and promoter methylation of mismatch repair (MMR) genes; germline EPCAM rearrangements; tumor microsatellite instability (MSI) and immunohistochemical (IHC) MMR protein expression. Probands negative for pathogenic variants of MMR genes were screened for germline APC and MUTYH sequence variants. Most germline defects identified were sequence variants and rearrangements of MMR genes. Remarkably, altered germline ASE of MMR genes was detected in 8/22 (36.5%) probands analyzed, including 3 cases negative at other screenings. Moreover, ASE provided evidence for the pathogenic role and guided the characterization of a VUS shared by 2 additional probands. No germline MMR gene promoter methylation was observed and only one EPCAM rearrangement was detected. In several cases, tumor IHC and MSI diverged from germline screening results. Notably, APC or biallelic MUTYH germline defects were identified in 2/19 probands negative for pathogenic variants of MMR genes. Our results show that ASE complements gDNA-based analyses in the identification of MMR defects and in the characterization of VUS affecting gene expression, increasing the number of germline alterations detected. An appreciable fraction of probands negative for MMR gene variants harbors APC or MUTYH variants. These results indicate that germline ASE analysis and screening for APC and MUTYH defects should be included in HNPCC diagnostic algorithms. |
| first_indexed | 2024-12-13T23:20:29Z |
| format | Article |
| id | doaj.art-9c145006ac6b4836bf6d02782a6eeeea |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T23:20:29Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj.art-9c145006ac6b4836bf6d02782a6eeeea2022-12-21T23:27:48ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e8119410.1371/journal.pone.0081194Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms.Laura De LellisGitana Maria AcetoMaria Cristina CuriaTeresa CatalanoSandra MammarellaSerena VeschiFabiana FantiniPasquale BattistaVittoria StiglianoLuca MesseriniCristina MareniPaola SalaLucio BertarioPaolo RadiceAlessandro CamaThe identification of germline variants predisposing to hereditary nonpolyposis colorectal cancer (HNPCC) is crucial for clinical management of carriers, but several probands remain negative for such variants or bear variants of uncertain significance (VUS). Here we describe the results of integrative molecular analyses in 132 HNPCC patients providing evidences for improved genetic testing of HNPCC with traditional or next generation methods. Patients were screened for: germline allele-specific expression (ASE), nucleotide variants, rearrangements and promoter methylation of mismatch repair (MMR) genes; germline EPCAM rearrangements; tumor microsatellite instability (MSI) and immunohistochemical (IHC) MMR protein expression. Probands negative for pathogenic variants of MMR genes were screened for germline APC and MUTYH sequence variants. Most germline defects identified were sequence variants and rearrangements of MMR genes. Remarkably, altered germline ASE of MMR genes was detected in 8/22 (36.5%) probands analyzed, including 3 cases negative at other screenings. Moreover, ASE provided evidence for the pathogenic role and guided the characterization of a VUS shared by 2 additional probands. No germline MMR gene promoter methylation was observed and only one EPCAM rearrangement was detected. In several cases, tumor IHC and MSI diverged from germline screening results. Notably, APC or biallelic MUTYH germline defects were identified in 2/19 probands negative for pathogenic variants of MMR genes. Our results show that ASE complements gDNA-based analyses in the identification of MMR defects and in the characterization of VUS affecting gene expression, increasing the number of germline alterations detected. An appreciable fraction of probands negative for MMR gene variants harbors APC or MUTYH variants. These results indicate that germline ASE analysis and screening for APC and MUTYH defects should be included in HNPCC diagnostic algorithms.http://europepmc.org/articles/PMC3835792?pdf=render |
| spellingShingle | Laura De Lellis Gitana Maria Aceto Maria Cristina Curia Teresa Catalano Sandra Mammarella Serena Veschi Fabiana Fantini Pasquale Battista Vittoria Stigliano Luca Messerini Cristina Mareni Paola Sala Lucio Bertario Paolo Radice Alessandro Cama Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms. PLoS ONE |
| title | Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms. |
| title_full | Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms. |
| title_fullStr | Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms. |
| title_full_unstemmed | Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms. |
| title_short | Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms. |
| title_sort | integrative analysis of hereditary nonpolyposis colorectal cancer the contribution of allele specific expression and other assays to diagnostic algorithms |
| url | http://europepmc.org/articles/PMC3835792?pdf=render |
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