Germline Variants of <i>CYBA</i> and <i>TRPM4</i> Predispose to Familial Colorectal Cancer
Familial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole-genome sequencing in 15 Polish families of many affected individuals, without mutations in known CRC predisposing genes. We focused on loss-of-function variants and functionally char...
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| Format: | Article |
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MDPI AG
2022-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/3/670 |
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| author | Lizhen Zhu Beiping Miao Dagmara Dymerska Magdalena Kuswik Elena Bueno-Martínez Lara Sanoguera-Miralles Eladio A. Velasco Nagarajan Paramasivam Matthias Schlesner Abhishek Kumar Ying Yuan Jan Lubinski Obul Reddy Bandapalli Kari Hemminki Asta Försti |
| author_facet | Lizhen Zhu Beiping Miao Dagmara Dymerska Magdalena Kuswik Elena Bueno-Martínez Lara Sanoguera-Miralles Eladio A. Velasco Nagarajan Paramasivam Matthias Schlesner Abhishek Kumar Ying Yuan Jan Lubinski Obul Reddy Bandapalli Kari Hemminki Asta Försti |
| author_sort | Lizhen Zhu |
| collection | DOAJ |
| description | Familial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole-genome sequencing in 15 Polish families of many affected individuals, without mutations in known CRC predisposing genes. We focused on loss-of-function variants and functionally characterized them. We identified a frameshift variant in the <i>CYBA</i> gene (c.246delC) in one family and a splice site variant in the <i>TRPM4</i> gene (c.25–1 G > T) in another family. While both variants were absent or extremely rare in gene variant databases, we identified four additional Polish familial CRC cases and two healthy elderly individuals with the <i>CYBA</i> variant (odds ratio 2.46, 95% confidence interval 0.48–12.69). Both variants led to a premature stop codon and to a truncated protein. Functional characterization of the variants showed that knockdown of <i>CYBA</i> or <i>TRPM4</i> depressed generation of reactive oxygen species (ROS) in LS174T and HT-29 cell lines. Knockdown of <i>TRPM4</i> resulted in decreased MUC2 protein production. <i>CYBA</i> encodes a component in the NADPH oxidase system which generates ROS and controls, e.g., bacterial colonization in the gut. Germline <i>CYBA</i> variants are associated with early onset inflammatory bowel disease, supported with experimental evidence on loss of intestinal mucus barrier function due to ROS deficiency. <i>TRPM4</i> encodes a calcium-activated ion channel, which, in a human colonic cancer cell line, controls calcium-mediated secretion of MUC2, a major component of intestinal mucus barrier. We suggest that the gene defects in <i>CYBA</i> and <i>TRPM4</i> mechanistically involve intestinal barrier integrity through ROS and mucus biology, which converges in chronic bowel inflammation. |
| first_indexed | 2024-03-10T00:07:21Z |
| format | Article |
| id | doaj.art-913c7ab5ed6f4a7baba2eda37e0837a6 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T00:07:21Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-913c7ab5ed6f4a7baba2eda37e0837a62023-11-23T16:06:49ZengMDPI AGCancers2072-66942022-01-0114367010.3390/cancers14030670Germline Variants of <i>CYBA</i> and <i>TRPM4</i> Predispose to Familial Colorectal CancerLizhen Zhu0Beiping Miao1Dagmara Dymerska2Magdalena Kuswik3Elena Bueno-Martínez4Lara Sanoguera-Miralles5Eladio A. Velasco6Nagarajan Paramasivam7Matthias Schlesner8Abhishek Kumar9Ying Yuan10Jan Lubinski11Obul Reddy Bandapalli12Kari Hemminki13Asta Försti14Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, GermanyDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, GermanyDepartment of Genetics and Pathology, Hereditary Cancer Center, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, PolandDepartment of Genetics and Pathology, Hereditary Cancer Center, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, PolandSplicing and Genetic Susceptibility to Cancer, Instituto de Biología y Genética Molecular (CSIC-UVa), 47003 Valladolid, SpainSplicing and Genetic Susceptibility to Cancer, Instituto de Biología y Genética Molecular (CSIC-UVa), 47003 Valladolid, SpainSplicing and Genetic Susceptibility to Cancer, Instituto de Biología y Genética Molecular (CSIC-UVa), 47003 Valladolid, SpainComputational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT), D-69120 Heidelberg, GermanyBioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), D-69120 Heidelberg, GermanyDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, GermanyDepartment of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, ChinaDepartment of Genetics and Pathology, Hereditary Cancer Center, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, PolandDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, GermanyDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, GermanyDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, GermanyFamilial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole-genome sequencing in 15 Polish families of many affected individuals, without mutations in known CRC predisposing genes. We focused on loss-of-function variants and functionally characterized them. We identified a frameshift variant in the <i>CYBA</i> gene (c.246delC) in one family and a splice site variant in the <i>TRPM4</i> gene (c.25–1 G > T) in another family. While both variants were absent or extremely rare in gene variant databases, we identified four additional Polish familial CRC cases and two healthy elderly individuals with the <i>CYBA</i> variant (odds ratio 2.46, 95% confidence interval 0.48–12.69). Both variants led to a premature stop codon and to a truncated protein. Functional characterization of the variants showed that knockdown of <i>CYBA</i> or <i>TRPM4</i> depressed generation of reactive oxygen species (ROS) in LS174T and HT-29 cell lines. Knockdown of <i>TRPM4</i> resulted in decreased MUC2 protein production. <i>CYBA</i> encodes a component in the NADPH oxidase system which generates ROS and controls, e.g., bacterial colonization in the gut. Germline <i>CYBA</i> variants are associated with early onset inflammatory bowel disease, supported with experimental evidence on loss of intestinal mucus barrier function due to ROS deficiency. <i>TRPM4</i> encodes a calcium-activated ion channel, which, in a human colonic cancer cell line, controls calcium-mediated secretion of MUC2, a major component of intestinal mucus barrier. We suggest that the gene defects in <i>CYBA</i> and <i>TRPM4</i> mechanistically involve intestinal barrier integrity through ROS and mucus biology, which converges in chronic bowel inflammation.https://www.mdpi.com/2072-6694/14/3/670whole-genome sequencingcancer predispositionmucinreactive oxygen species |
| spellingShingle | Lizhen Zhu Beiping Miao Dagmara Dymerska Magdalena Kuswik Elena Bueno-Martínez Lara Sanoguera-Miralles Eladio A. Velasco Nagarajan Paramasivam Matthias Schlesner Abhishek Kumar Ying Yuan Jan Lubinski Obul Reddy Bandapalli Kari Hemminki Asta Försti Germline Variants of <i>CYBA</i> and <i>TRPM4</i> Predispose to Familial Colorectal Cancer Cancers whole-genome sequencing cancer predisposition mucin reactive oxygen species |
| title | Germline Variants of <i>CYBA</i> and <i>TRPM4</i> Predispose to Familial Colorectal Cancer |
| title_full | Germline Variants of <i>CYBA</i> and <i>TRPM4</i> Predispose to Familial Colorectal Cancer |
| title_fullStr | Germline Variants of <i>CYBA</i> and <i>TRPM4</i> Predispose to Familial Colorectal Cancer |
| title_full_unstemmed | Germline Variants of <i>CYBA</i> and <i>TRPM4</i> Predispose to Familial Colorectal Cancer |
| title_short | Germline Variants of <i>CYBA</i> and <i>TRPM4</i> Predispose to Familial Colorectal Cancer |
| title_sort | germline variants of i cyba i and i trpm4 i predispose to familial colorectal cancer |
| topic | whole-genome sequencing cancer predisposition mucin reactive oxygen species |
| url | https://www.mdpi.com/2072-6694/14/3/670 |
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