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Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer
Familial pancreatic cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 c...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305658/ https://www.ncbi.nlm.nih.gov/pubmed/34357098 http://dx.doi.org/10.3390/jpm11070631 |
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author | Slater, Emily P. Wilke, Lisa M. Böhm, Lutz Benedikt Strauch, Konstantin Lutz, Manuel Gercke, Norman Matthäi, Elvira Hemminki, Kari Försti, Asta Schlesner, Matthias Paramasivam, Nagarajan Bartsch, Detlef K. |
author_facet | Slater, Emily P. Wilke, Lisa M. Böhm, Lutz Benedikt Strauch, Konstantin Lutz, Manuel Gercke, Norman Matthäi, Elvira Hemminki, Kari Försti, Asta Schlesner, Matthias Paramasivam, Nagarajan Bartsch, Detlef K. |
author_sort | Slater, Emily P. |
collection | PubMed |
description | Familial pancreatic cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 could be detected in 10–15% of analyzed families. Thus, the genetic basis of disease susceptibility in the majority of FPC families remains unknown. In an attempt to identify new candidate genes, we performed whole-genome sequencing on affected patients from 15 FPC families, without detecting BRCA1/2, CDKN2A or PALB2 mutations, using an Illumina based platform. Annotations from CADD, PolyPhen-2, SIFT, Mutation Taster and PROVEAN were used to assess the potential impact of a variant on the function of a gene. Variants that did not segregate with pancreatic disease in respective families were excluded. Potential predisposing candidate genes ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 were identified in 7 of 15 families. All identified gene mutations segregated with pancreatic disease, but sometimes with incomplete penetrance. An analysis of up to 46 additional FPC families revealed that the identified gene mutations appeared to be unique in most cases, despite a potentially deleterious ACAD9 Ala326Thr germline variant, which occurred in 4 (8.7%) of 46 FPC families. Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants. |
format | Online Article Text |
id | pubmed-8305658 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-83056582021-07-25 Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer Slater, Emily P. Wilke, Lisa M. Böhm, Lutz Benedikt Strauch, Konstantin Lutz, Manuel Gercke, Norman Matthäi, Elvira Hemminki, Kari Försti, Asta Schlesner, Matthias Paramasivam, Nagarajan Bartsch, Detlef K. J Pers Med Article Familial pancreatic cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 could be detected in 10–15% of analyzed families. Thus, the genetic basis of disease susceptibility in the majority of FPC families remains unknown. In an attempt to identify new candidate genes, we performed whole-genome sequencing on affected patients from 15 FPC families, without detecting BRCA1/2, CDKN2A or PALB2 mutations, using an Illumina based platform. Annotations from CADD, PolyPhen-2, SIFT, Mutation Taster and PROVEAN were used to assess the potential impact of a variant on the function of a gene. Variants that did not segregate with pancreatic disease in respective families were excluded. Potential predisposing candidate genes ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 were identified in 7 of 15 families. All identified gene mutations segregated with pancreatic disease, but sometimes with incomplete penetrance. An analysis of up to 46 additional FPC families revealed that the identified gene mutations appeared to be unique in most cases, despite a potentially deleterious ACAD9 Ala326Thr germline variant, which occurred in 4 (8.7%) of 46 FPC families. Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants. MDPI 2021-07-02 /pmc/articles/PMC8305658/ /pubmed/34357098 http://dx.doi.org/10.3390/jpm11070631 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Slater, Emily P. Wilke, Lisa M. Böhm, Lutz Benedikt Strauch, Konstantin Lutz, Manuel Gercke, Norman Matthäi, Elvira Hemminki, Kari Försti, Asta Schlesner, Matthias Paramasivam, Nagarajan Bartsch, Detlef K. Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer |
title | Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer |
title_full | Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer |
title_fullStr | Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer |
title_full_unstemmed | Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer |
title_short | Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer |
title_sort | combinations of low-frequency genetic variants might predispose to familial pancreatic cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305658/ https://www.ncbi.nlm.nih.gov/pubmed/34357098 http://dx.doi.org/10.3390/jpm11070631 |
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