A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene
Abstract Background Familial ovarian cancer (OC) cases not harbouring pathogenic variants in either of the BRCA1 and BRCA2 OC-predisposing genes, which function in homologous recombination (HR) of DNA, could involve pathogenic variants in other DNA repair pathway genes. Methods Whole exome sequencin...
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2021
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oai:doaj.org-article:52b67832911d434ca9c1266c56a3622d2021-12-05T12:17:47ZA functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene10.1186/s13073-021-00998-51756-994Xhttps://doaj.org/article/52b67832911d434ca9c1266c56a3622d2021-12-01T00:00:00Zhttps://doi.org/10.1186/s13073-021-00998-5https://doaj.org/toc/1756-994XAbstract Background Familial ovarian cancer (OC) cases not harbouring pathogenic variants in either of the BRCA1 and BRCA2 OC-predisposing genes, which function in homologous recombination (HR) of DNA, could involve pathogenic variants in other DNA repair pathway genes. Methods Whole exome sequencing was used to identify rare variants in HR genes in a BRCA1 and BRCA2 pathogenic variant negative OC family of French Canadian (FC) ancestry, a population exhibiting genetic drift. OC cases and cancer-free individuals from FC and non-FC populations were investigated for carrier frequency of FANCI c.1813C>T; p.L605F, the top-ranking candidate. Gene and protein expression were investigated in cancer cell lines and tissue microarrays, respectively. Results In FC subjects, c.1813C>T was more common in familial (7.1%, 3/42) than sporadic (1.6%, 7/439) OC cases (P = 0.048). Carriers were detected in 2.5% (74/2950) of cancer-free females though female/male carriers were more likely to have a first-degree relative with OC (121/5249, 2.3%; Spearman correlation = 0.037; P = 0.011), suggesting a role in risk. Many of the cancer-free females had host factors known to reduce risk to OC which could influence cancer risk in this population. There was an increased carrier frequency of FANCI c.1813C>T in BRCA1 and BRCA2 pathogenic variant negative OC families, when including the discovery family, compared to cancer-free females (3/23, 13%; OR = 5.8; 95%CI = 1.7–19; P = 0.005). In non-FC subjects, 10 candidate FANCI variants were identified in 4.1% (21/516) of Australian OC cases negative for pathogenic variants in BRCA1 and BRCA2, including 10 carriers of FANCI c.1813C>T. Candidate variants were significantly more common in familial OC than in sporadic OC (P = 0.04). Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the Fanconi anaemia (FA) pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level, destabilized by DNA damaging agent treatment in both HeLa and OC cell lines, and exhibited sensitivity to cisplatin but not to a poly (ADP-ribose) polymerase inhibitor. By tissue microarray analyses, FANCI protein was consistently expressed in fallopian tube epithelial cells and only expressed at low-to-moderate levels in 88% (83/94) of OC samples. Conclusions This is the first study to describe candidate OC variants in FANCI, a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that pathogenic FANCI variants may modify OC risk in cancer families.Caitlin T. FierhellerLaure Guitton-SertWejdan M. AleneziTimothée RevilKathleen K. OrosYuandi GaoKarine BedardSuzanna L. ArcandCorinne SerruyaSupriya BehlLiliane MeunierHubert FleuryEleanor FewingsDeepak N. SubramanianJavad NadafJeffrey P. BruceRachel BellDiane ProvencherWilliam D. FoulkesZaki El HaffafAnne-Marie Mes-MassonJacek MajewskiTrevor J. PughMarc TischkowitzPaul A. JamesIan G. CampbellCelia M. T. GreenwoodJiannis RagoussisJean-Yves MassonPatricia N. ToninBMCarticleFANCIOvarian cancerCancer-predisposing geneWhole exome sequencingTissue microarrayProtein expressionMedicineRGeneticsQH426-470ENGenome Medicine, Vol 13, Iss 1, Pp 1-26 (2021) |
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DOAJ |
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DOAJ |
| language |
EN |
| topic |
FANCI Ovarian cancer Cancer-predisposing gene Whole exome sequencing Tissue microarray Protein expression Medicine R Genetics QH426-470 |
| spellingShingle |
FANCI Ovarian cancer Cancer-predisposing gene Whole exome sequencing Tissue microarray Protein expression Medicine R Genetics QH426-470 Caitlin T. Fierheller Laure Guitton-Sert Wejdan M. Alenezi Timothée Revil Kathleen K. Oros Yuandi Gao Karine Bedard Suzanna L. Arcand Corinne Serruya Supriya Behl Liliane Meunier Hubert Fleury Eleanor Fewings Deepak N. Subramanian Javad Nadaf Jeffrey P. Bruce Rachel Bell Diane Provencher William D. Foulkes Zaki El Haffaf Anne-Marie Mes-Masson Jacek Majewski Trevor J. Pugh Marc Tischkowitz Paul A. James Ian G. Campbell Celia M. T. Greenwood Jiannis Ragoussis Jean-Yves Masson Patricia N. Tonin A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene |
| description |
Abstract Background Familial ovarian cancer (OC) cases not harbouring pathogenic variants in either of the BRCA1 and BRCA2 OC-predisposing genes, which function in homologous recombination (HR) of DNA, could involve pathogenic variants in other DNA repair pathway genes. Methods Whole exome sequencing was used to identify rare variants in HR genes in a BRCA1 and BRCA2 pathogenic variant negative OC family of French Canadian (FC) ancestry, a population exhibiting genetic drift. OC cases and cancer-free individuals from FC and non-FC populations were investigated for carrier frequency of FANCI c.1813C>T; p.L605F, the top-ranking candidate. Gene and protein expression were investigated in cancer cell lines and tissue microarrays, respectively. Results In FC subjects, c.1813C>T was more common in familial (7.1%, 3/42) than sporadic (1.6%, 7/439) OC cases (P = 0.048). Carriers were detected in 2.5% (74/2950) of cancer-free females though female/male carriers were more likely to have a first-degree relative with OC (121/5249, 2.3%; Spearman correlation = 0.037; P = 0.011), suggesting a role in risk. Many of the cancer-free females had host factors known to reduce risk to OC which could influence cancer risk in this population. There was an increased carrier frequency of FANCI c.1813C>T in BRCA1 and BRCA2 pathogenic variant negative OC families, when including the discovery family, compared to cancer-free females (3/23, 13%; OR = 5.8; 95%CI = 1.7–19; P = 0.005). In non-FC subjects, 10 candidate FANCI variants were identified in 4.1% (21/516) of Australian OC cases negative for pathogenic variants in BRCA1 and BRCA2, including 10 carriers of FANCI c.1813C>T. Candidate variants were significantly more common in familial OC than in sporadic OC (P = 0.04). Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the Fanconi anaemia (FA) pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level, destabilized by DNA damaging agent treatment in both HeLa and OC cell lines, and exhibited sensitivity to cisplatin but not to a poly (ADP-ribose) polymerase inhibitor. By tissue microarray analyses, FANCI protein was consistently expressed in fallopian tube epithelial cells and only expressed at low-to-moderate levels in 88% (83/94) of OC samples. Conclusions This is the first study to describe candidate OC variants in FANCI, a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that pathogenic FANCI variants may modify OC risk in cancer families. |
| format |
article |
| author |
Caitlin T. Fierheller Laure Guitton-Sert Wejdan M. Alenezi Timothée Revil Kathleen K. Oros Yuandi Gao Karine Bedard Suzanna L. Arcand Corinne Serruya Supriya Behl Liliane Meunier Hubert Fleury Eleanor Fewings Deepak N. Subramanian Javad Nadaf Jeffrey P. Bruce Rachel Bell Diane Provencher William D. Foulkes Zaki El Haffaf Anne-Marie Mes-Masson Jacek Majewski Trevor J. Pugh Marc Tischkowitz Paul A. James Ian G. Campbell Celia M. T. Greenwood Jiannis Ragoussis Jean-Yves Masson Patricia N. Tonin |
| author_facet |
Caitlin T. Fierheller Laure Guitton-Sert Wejdan M. Alenezi Timothée Revil Kathleen K. Oros Yuandi Gao Karine Bedard Suzanna L. Arcand Corinne Serruya Supriya Behl Liliane Meunier Hubert Fleury Eleanor Fewings Deepak N. Subramanian Javad Nadaf Jeffrey P. Bruce Rachel Bell Diane Provencher William D. Foulkes Zaki El Haffaf Anne-Marie Mes-Masson Jacek Majewski Trevor J. Pugh Marc Tischkowitz Paul A. James Ian G. Campbell Celia M. T. Greenwood Jiannis Ragoussis Jean-Yves Masson Patricia N. Tonin |
| author_sort |
Caitlin T. Fierheller |
| title |
A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene |
| title_short |
A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene |
| title_full |
A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene |
| title_fullStr |
A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene |
| title_full_unstemmed |
A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene |
| title_sort |
functionally impaired missense variant identified in french canadian families implicates fanci as a candidate ovarian cancer-predisposing gene |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/52b67832911d434ca9c1266c56a3622d |
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