Variant Characterization of a Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition of Risk to Lynch Syndrome
Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with...
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MDPI AG
2023-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/16/4074 |
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| author | Mouadh Barbirou Amanda A. Miller Amel Mezlini Balkiss Bouhaouala-Zahar Peter J. Tonellato |
| author_facet | Mouadh Barbirou Amanda A. Miller Amel Mezlini Balkiss Bouhaouala-Zahar Peter J. Tonellato |
| author_sort | Mouadh Barbirou |
| collection | DOAJ |
| description | Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, OncoKB, and My Cancer Genome databases. Of 94 germline familial variants identified with predicted functional impact, 37 SNPs/indels were detected in 28 genes, 2 of which (MLH1 and PRH1-TAS2R14) have known association with CRC and 4 others (PPP1R13B, LAMA5, FTO, and NLRP14) have known association with non-CRC cancers. In addition, 48 of 57 identified SVs overlap with 43 genes. Three of these genes (RELN, IRS2, and FOXP1) have a known association with non-CRC digestive cancers and one (RRAS2) has a known association with non-CRC cancer. Our study identified 83 novel, predicted functionally impactful germline variants grouped in three “variant risk clusters” shared in three familiarly associated LS groups (high, intermediate and low risk). This variant characterization study demonstrates that large pedigree investigations provide important evidence supporting the hypothesis that different “variant risk clusters” can convey different mechanisms of risk and oncogenesis of LS-CRC even within the same pedigree. |
| first_indexed | 2024-03-11T00:03:15Z |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T00:03:15Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-55bb233799ea452da7a951fbda0375242023-11-19T00:32:50ZengMDPI AGCancers2072-66942023-08-011516407410.3390/cancers15164074Variant Characterization of a Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition of Risk to Lynch SyndromeMouadh Barbirou0Amanda A. Miller1Amel Mezlini2Balkiss Bouhaouala-Zahar3Peter J. Tonellato4Circulating Tumor Cell Core Laboratory, Population Science Division, Medical Oncology Department, Medical College, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USACirculating Tumor Cell Core Laboratory, Population Science Division, Medical Oncology Department, Medical College, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USAMedical Oncology Division, Salah Azeiz Oncology Institute, University of Tunis El Manar, Tunis 1068, TunisiaMedical School, University of Tunis El Manar, Tunis 1068, TunisiaCenter for Biomedical Informatics, Department of Health Management and Informatics, School of Medicine, University of Missouri, Columbia, MI 65211, USARecently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, OncoKB, and My Cancer Genome databases. Of 94 germline familial variants identified with predicted functional impact, 37 SNPs/indels were detected in 28 genes, 2 of which (MLH1 and PRH1-TAS2R14) have known association with CRC and 4 others (PPP1R13B, LAMA5, FTO, and NLRP14) have known association with non-CRC cancers. In addition, 48 of 57 identified SVs overlap with 43 genes. Three of these genes (RELN, IRS2, and FOXP1) have a known association with non-CRC digestive cancers and one (RRAS2) has a known association with non-CRC cancer. Our study identified 83 novel, predicted functionally impactful germline variants grouped in three “variant risk clusters” shared in three familiarly associated LS groups (high, intermediate and low risk). This variant characterization study demonstrates that large pedigree investigations provide important evidence supporting the hypothesis that different “variant risk clusters” can convey different mechanisms of risk and oncogenesis of LS-CRC even within the same pedigree.https://www.mdpi.com/2072-6694/15/16/4074Lynch syndromecolorectal cancer“variant risk cluster” predispositionfamilial germline variantswhole-genome sequencing |
| spellingShingle | Mouadh Barbirou Amanda A. Miller Amel Mezlini Balkiss Bouhaouala-Zahar Peter J. Tonellato Variant Characterization of a Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition of Risk to Lynch Syndrome Cancers Lynch syndrome colorectal cancer “variant risk cluster” predisposition familial germline variants whole-genome sequencing |
| title | Variant Characterization of a Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition of Risk to Lynch Syndrome |
| title_full | Variant Characterization of a Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition of Risk to Lynch Syndrome |
| title_fullStr | Variant Characterization of a Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition of Risk to Lynch Syndrome |
| title_full_unstemmed | Variant Characterization of a Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition of Risk to Lynch Syndrome |
| title_short | Variant Characterization of a Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition of Risk to Lynch Syndrome |
| title_sort | variant characterization of a representative large pedigree suggests variant risk clusters convey varying predisposition of risk to lynch syndrome |
| topic | Lynch syndrome colorectal cancer “variant risk cluster” predisposition familial germline variants whole-genome sequencing |
| url | https://www.mdpi.com/2072-6694/15/16/4074 |
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