scholarly journals Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

2020 ◽  
pp. jmedgenet-2019-106739 ◽  
Author(s):  
Honglin Song ◽  
Ed M Dicks ◽  
Jonathan Tyrer ◽  
Maria Intermaggio ◽  
Georgia Chenevix-Trench ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Candidate Genes ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
European Ancestry ◽  
Ovarian Cancer Risk ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Deleterious Mutations ◽  
Increased Risk

PurposeThe known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.ResultsThe ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

scholarly journals Population based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high grade serous ovarian cancer

2019 ◽  
Author(s):  
Honglin Song ◽  
Ed Dicks ◽  
Jonathan P. Tyrer ◽  
Maria Intermaggio ◽  
Georgia Chenevix-Trench ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Candidate Genes ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
European Ancestry ◽  
Ovarian Cancer Risk ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Deleterious Mutations ◽  
Increased Risk

AbstractPurposeThe known EOC susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases verses controls were further examined in an independent set of 14,146 EOC cases and 28,661 controls from the ovarian cancer association consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.ResultsThe odds ratios (OR) associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 – 5.68; P = 0.00068), 1.99 for POLK (95% CI 1.15 – 3.43; P = 0.014), and 4.07 for SLX4 (95% CI 1.34-12.4; P = 0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 −1.00, P=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Tubal histopathological abnormalities in BRCA1/2 mutation carriers undergoing prophylactic salpingo-oophorectomy: a case–control study

2021 ◽  
pp. ijgc-2021-003153
Author(s):  
Federica Sina ◽  
Chiara Cassani ◽  
Chiara Comerio ◽  
Elena De Ponti ◽  
Francesca Zanellini ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
P53 Signature ◽  
Mutation Carriers ◽  
Increased Risk ◽  
Risk Of Malignancy ◽  
History Of ◽  
Intraepithelial Carcinoma ◽  
Malignant Lesions

ObjectiveTo describe tubal histopathological abnormalities in women with germline BRCA1/2 mutations and in controls.MethodsConsecutive women with BRCA1/2 mutations undergoing bilateral salpingo-oophorectomy between 2010 and 2020 in two centers (San Gerardo Hospital, Monza and San Matteo Hospital, Pavia) were considered in this analysis and compared with controls who had the same surgical procedure for benign conditions. Frequency of p53 signature, serous tubal intraepithelial carcinoma, and high-grade serous ovarian cancer were compared between the two groups.ResultsA total of 194 women with pathogenic BRCA1/2 mutations underwent prophylactic salpingo-oophorectomy. Of these, 138 women (71%) had a completely negative histological examination, while in 56 (29%) patients an ovarian or tubal alteration was reported. Among controls, 84% of patients had a p53wt signature, while 16% had a p53 signature. There was no difference in the frequency of a p53 signature between cases and controls; however, women with BRCA1/2 mutations were more likely to have pre-malignant or invasive alterations of tubal or ovarian epithelium (p=0.015). Among mutation carriers, older age both at genetic testing and at surgery was associated with an increased risk of having malignancies (OR=1.07, p=0.006 and OR=1.08, p=0.004, respectively). The risk of malignancy seems to be increased in patients with a familial history of high-grade serous ovarian cancer. Previous therapy with tamoxifen was significantly more frequent in patients with malignant lesions (40.0% vs 21.3%, p=0.006).ConclusionWe found that a p53 signature is a frequent finding both in BRCA1/2 mutation carriers and in controls, while pre-invasive and invasive lesions are more frequent in BRCA1/2 mutation carriers. Genetic and clinical characteristics are likely to affect the progression to malignancy.

Abstract B37: Germline mutations in new susceptibility genes for non-high-grade serous ovarian cancer

2020 ◽  
Author(s):  
Marina Pavanello ◽  
Ed Dicks ◽  
Honglin Song ◽  
Amir Ariff ◽  
Adelyn Bolithon ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Germline Mutations ◽  
Susceptibility Genes ◽  
High Grade ◽  
Serous Ovarian Cancer

Germline mutations in cancer susceptibility genes in high grade serous ovarian cancer in Serbia

2019 ◽  
Vol 64 (4) ◽  
pp. 281-290 ◽  
Author(s):  
Ana Krivokuca ◽  
Ivana Boljevic ◽  
Stevo Jovandic ◽  
Zvonko Magic ◽  
Aljosa Mandic ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Susceptibility ◽  
Germline Mutations ◽  
Susceptibility Genes ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cancer Susceptibility Genes

scholarly journals Multi-Tissue Transcriptome-Wide Association Study Identifies 26 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer

2018 ◽  
Author(s):  
Alexander Gusev ◽  
Kate Lawrenson ◽  
Felipe Segato ◽  
Marcos A.S. Fonseca ◽  
Siddhartha Kar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Association Study ◽  
Genetic Variants ◽  
Susceptibility Genes ◽  
Ovarian Cancer Risk ◽  
High Grade ◽  
Genome Wide ◽  
Unique Genes

ABSTRACTGenome-wide association studies (GWASs) have identified about 30 different susceptibility loci associated with high grade serous ovarian cancer (HGSOC) risk. We sought to identify potential susceptibility genes by integrating the risk variants at these regions with genetic variants impacting gene expression and splicing of nearby genes. We compiled gene expression and genotyping data from 2,169 samples for 6 different HGSOC-relevant tissue types. We integrated these data with GWAS data from 13,037 HGSOC cases and 40,941 controls, and performed a transcriptome-wide association study (TWAS) across >70,000 significantly heritable gene/exon features. We identified 24 transcriptome-wide significant associations for 14 unique genes, plus 90 significant exon-level associations in 20 unique genes. We implicated multiple novel genes at risk loci, e.g.LRRC46at 19q21.32 (TWASP=1×10−9) and aPRC1splicing event (TWASP=9×10−8) which was splice-variant specific and exhibited no eQTL signal. Functional analyses in HGSOC cell lines found evidence of essentiality forGOSR2, INTS1, KANSL1andPRC1; with the latter gene showing levels of essentiality comparable to that ofMYC. Overall, gene expression and splicing events explained 41% of SNP-heritability for HGSOC (s.e. 11%,P=2.5×10−4), implicated at least one target gene for 6/13 distinct genome-wide significant regions and revealed 2 known and 26 novel candidate susceptibility genes for HGSOC.STATEMENT OF SIGNIFICANCEFor many ovarian cancer risk regions, the target genes regulated by germline genetic variants are unknown. Using expression data from >2,100 individuals, this study identified novel associations of genes and splicing variants with ovarian cancer risk; with transcriptional variation now explaining over one-third of the SNP-heritability for this disease.

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