Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes

Subramanian, Deepak; Zethoven, Magnus; McInerny, Simone; Morgan, James; Rowley, Simone M.; Lee, Jue Er Amanda; Li, Na; Gorringe, Kylie L.; James, P.; Campbell, Ian

doi:10.1038/s41467-020-15461-z

Cited by 29 publications

(36 citation statements)

References 82 publications

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“…As has been reported with all of these examples of CPGs in non-FC populations, we expected an array of potentially pathogenic variants in our candidate gene. Indeed, we observed eight potentially pathogenic FANCI variants in AUS HGSC cases, which included c.1813C>T. A recent genome-wide discovery study of AUS HGSC cases did not report FANCI among the list of potentially new CPGs for OC 74 . However, the missense FANCI variants found in our analysis of AUS samples, which were investigated in both studies, would have been excluded due to a focus on LoF variants 74 .…”

Section: Discussionmentioning

confidence: 60%

“…Indeed, we observed eight potentially pathogenic FANCI variants in AUS HGSC cases, which included c.1813C>T. A recent genome-wide discovery study of AUS HGSC cases did not report FANCI among the list of potentially new CPGs for OC 74 . However, the missense FANCI variants found in our analysis of AUS samples, which were investigated in both studies, would have been excluded due to a focus on LoF variants 74 . Our investigation of HGSC cases from the AUS population thus also suggest that FANCI variants may also play a role in OC in non-FC populations.…”

Section: Discussionmentioning

confidence: 60%

“…To determine if there are carriers of rare potentially pathogenic FANCI variants in non-FC populations, we investigated available WES data from 516 AUS HGSC cases 74 and 63 CDN BC families, all BRCA1 and BRCA2 mutation-negative ( Supplementary Table 1 ). We also investigated available sequencing data for FANCI from 4,878 AUS cancer-free controls.…”

Section: Resultsmentioning

confidence: 99%

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The genetic analysis of a founder Northern American population of European descent identifiesFANCIas a candidate familial ovarian cancer risk gene

Fierheller

Guitton-Sert

Alenezi

et al. 2020

Preprint

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Some familial ovarian cancer (OC) could be due to rare risk alleles in genes that each account for a relatively small proportion of cases not due to BRCA1 and BRCA2, major risk genes in the homologous recombination (HR) DNA repair pathway. We report a new candidate OC risk allele, FANCI c.1813C>T in a Fanconi anemia (FA) gene that plays a role upstream of the HR DNA repair pathway. This variant was identified by whole exome sequencing of a BRCA1 and BRCA2 mutation-negative French Canadian (FC) OC family from a population exhibiting founder effects. In FCs, the c.1813C>T allele was detected in 7% (3/43) of familial and 1.6% (7/439) of sporadic OC cases; and in 3.7% (3/82) of familial breast cancer (BC) cases with a family history of OC and in 1.9% (3/158) of BC only families. This allele was significantly associated with FC BRCA1 and BRCA2 mutation-negative OC families (OR=5.6; 95%CI=1.6-19; p=0.006). Although FANCI c.1813C>T was detected in 2.5% (74/2950) of cancer-free FC females, carriers had a personal history of known OC risk reducing factors, and female/male carriers were more likely to have reported a first-degree relative with OC ("ρ" =0.037; p=0.011). Eight rare potentially pathogenic FANCI variants were identified in 3.3% (17/516) of Australian OC cases, including 10 carriers of FANCI c.1813C>T. Potentially pathogenic FANCI variants were significantly more common in AUS OC cases with a family history of OC than in isolated OC cases (p=0.027). The odds ratios (OR) were >3 for carriers of any of the seven rarest FANCI alleles, and 1.5 for c.1813C>T. Data from the OC Association Consortium revealed that the ORs for the c.1813C>T allele were highest for the most common OC subtypes. Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the 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; unstable by formaldehyde or mitomycin C treatment; and exhibited sensitivity to cisplatin but not to olaparib (a poly [ADP-ribose] polymerase inhibitor). By tissue microarray analyses, FANCI protein was robustly expressed in fallopian tube epithelial cells but expressed at low-to-moderate levels in 88% (83/94) of high-grade serous carcinoma OC samples. This is the first study to describe potentially pathogenic variants in OC in a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that potentially pathogenic FANCI variants may modify OC risk in cancer families.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

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The genetic analysis of a founder Northern American population of European descent identifiesFANCIas a candidate familial ovarian cancer risk gene

Fierheller

Guitton-Sert

Alenezi

et al. 2020

Preprint

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“…In the recent past, the combination of microarray technology and bioinformatics has facilitated the understanding of molecular mechanisms and reliable diagnostic and therapeutic targets for diseases. Through these techniques, many new genes involved in complex human diseases such as cancer and autoimmune complications have also been discovered [ 6 , 7 ]. Several studies have identified disease-related genes and functional pathways by analyzing the expression profile between SLE and healthy controls [ 8 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

IFN-γ Mediates the Development of Systemic Lupus Erythematosus

Liu

Wang

et al. 2020

BioMed Research International

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Objective. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect all organs in the body. It is characterized by overexpression of antibodies against autoantigen. Although previous bioinformatics analyses have identified several genetic factors underlying SLE, they did not discriminate between naive and individuals exposed to anti-SLE drugs. Here, we evaluated specific genes and pathways in active and recently diagnosed SLE population. Methods. GSE46907 matrix downloaded from Gene Expression Omnibus (GEO) was analyzed using R, Metascape, STRING, and Cytoscape to identify differentially expressed genes (DEGs), enrichment pathways, protein-protein interaction (PPI), and hub genes between naive SLE individuals and healthy controls. Results. A total of 134 DEGs were identified, in which 29 were downregulated, whereas 105 were upregulated in active and newly diagnosed SLE cases. GO term analysis revealed that transcriptional induction of the DEGs was particularly enhanced in response to secretion of interferon-γ and interferon-α and regulation of cytokine production innate immune responses among others. KEGG pathway analysis showed that the expression of DEGs was particularly enhanced in interferon signaling, IFN antiviral responses by activated genes, class I major histocompatibility complex (MHC-I) mediated antigen processing and presentation, and amyloid fiber formation. STAT1, IRF7, MX1, OASL, ISG15, IFIT3, IFIH1, IFIT1, OAS2, and GBP1 were the top 10 DEGs. Conclusions. Our findings suggest that interferon-related gene expression and pathways are common features for SLE pathogenesis, and IFN-γ and IFN-γ-inducible GBP1 gene in naive SLE were emphasized. Together, the identified genes and cellular pathways have expanded our understanding on the mechanism underlying development of SLE. They have also opened a new frontier on potential biomarkers for diagnosis, biotherapy, and prognosis for SLE.

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“…Loss-of-function variants in the MMR genes MLH1, MSH2, MSH6 and PMS2 have been reported as risk factors for clear cell and endometrioid ovarian carcinomas [15,21]. Loss-of-function variants in the HDR genes BRCA1, BRCA2, PALB2, BRIP1, RAD51C and RAD51D have been described, among others, to strongly increase the risk for serous ovarian cancer [19,[21][22][23][24][25]. In addition, evidence has been accumulated that deleterious variants in HDR genes are also predictors of therapeutic outcome [16,18].…”

Section: Introductionmentioning

confidence: 99%

Germline variation of Ribonuclease H2 genes in ovarian cancer patients

et al. 2020

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Epithelial ovarian carcinoma (EOC) is a genetically heterogeneous disease that is partly driven by molecular defects in mismatch repair (MMR) or homology-directed DNA repair (HDR). Ribonuclease H2 serves to remove mis-incorporated ribonucleotides from DNA which alleviates HDR mechanisms and guides the MMR machinery. Although Ribonuclease H2 has been implicated in cancer, the role of germline variants for ovarian cancer is unknown. In the present case-control study, we sequenced the coding and flanking untranslated regions of the RNASEH2A, RNASEH2B and RNASEH2C genes, encoding all three subunits of Ribonuclease H2, in a total of 602 German patients with EOC and of 940 healthy females from the same population. We identified one patient with a truncating variant in RNASEH2B, p.C44X, resulting in a premature stop codon. This patient had high-grade serous EOC with an 8 years survival after platinum/taxane-based therapy. Subsequent analysis of TCGA data similarly showed a significantly longer progression-free survival in ovarian cancer patients with low RNASEH2B or RNASEH2C expression levels. In conclusion, loss-of-function variants in Ribonuclease H2 genes are not common predisposing factors in ovarian cancer but the possibility that they modulate therapeutic platinum response deserves further investigation.

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Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes

Cited by 29 publications

References 82 publications

The genetic analysis of a founder Northern American population of European descent identifiesFANCIas a candidate familial ovarian cancer risk gene

The genetic analysis of a founder Northern American population of European descent identifiesFANCIas a candidate familial ovarian cancer risk gene

IFN-γ Mediates the Development of Systemic Lupus Erythematosus

Germline variation of Ribonuclease H2 genes in ovarian cancer patients

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