Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors

BackgroundEpithelial tubo-ovarian cancer (EOC) has high mortality partly due to late diagnosis. Prevention is available but may be associated with adverse effects. A multifactorial risk model based on known genetic and epidemiological risk factors (RFs) for EOC can help identify women at higher risk who could benefit from targeted screening and prevention.MethodsWe developed a multifactorial EOC risk model for women of European ancestry incorporating the effects of pathogenic variants (PVs) in BRCA1, BRCA2, RAD51C, RAD51D and BRIP1, a Polygenic Risk Score (PRS) of arbitrary size, the effects of RFs and explicit family history (FH) using a synthetic model approach. The PRS, PV and RFs were assumed to act multiplicatively.ResultsBased on a currently available PRS for EOC that explains 5% of the EOC polygenic variance, the estimated lifetime risks under the multifactorial model in the general population vary from 0.5% to 4.6% for the first to 99th percentiles of the EOC risk distribution. The corresponding range for women with an affected first-degree relative is 1.9%–10.3%. Based on the combined risk distribution, 33% of RAD51D PV carriers are expected to have a lifetime EOC risk of less than 10%. RFs provided the widest distribution, followed by the PRS. In an independent partial model validation, absolute and relative 5-year risks were well calibrated in quintiles of predicted risk.ConclusionThis multifactorial risk model can facilitate stratification, in particular among women with FH of cancer and/or moderate-risk and high-risk PVs. The model is available via the CanRisk Tool (www.canrisk.org).

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A Comprehensive Epithelial Tubo-Ovarian Cancer Risk Prediction Model Incorporating Genetic and Epidemiological Risk Factors

10.1101/2020.12.04.20244046 ◽

2020 ◽

Author(s):

Andrew Lee ◽

Xin Yang ◽

Jonathan Tyrer ◽

Aleksandra Gentry-Maharaj ◽

Andy Ryan ◽

...

Keyword(s):

Risk Factors ◽

Ovarian Cancer ◽

Risk Model ◽

External Validation ◽

Control Sample ◽

Polygenic Risk Score ◽

Ovarian Cancer Risk ◽

Degree Relative ◽

Epidemiological Risk ◽

Incident Cases

AbstractBackgroundEpithelial tubo-ovarian cancer (EOC) has high mortality partly due to late diagnosis. Prevention is available but may be associated with adverse effects. Several genetic and epidemiological risk factors (RFs) for EOC have been identified. A multifactorial risk model can help identify females at higher risk who could benefit from targeted screening and prevention.MethodsWe developed an EOC risk model incorporating the effects of family history (FH), pathogenic variants (PVs) in BRCA1, BRCA2, RAD51C, RAD51D and BRIP1, a polygenic risk score (PRS) and the effects of RFs. The model was validated in a nested case-control sample of 1961 females from UKCTOCS (374 incident cases).ResultsEstimated lifetime risks in the general population vary from 0.5% to 4.6% for the 1st to 99th percentiles of the EOC risk-distribution. The corresponding range for females with an affected first-degree relative is 1.9% to 10.3%. RFs provided the widest distribution followed by the PRS. In the external validation, absolute and relative 5-year risks were well-calibrated in quintiles of predicted risk.ConclusionThis multifactorial risk model can facilitate stratification, in particular among females with FH of cancer and/or moderate- and high-risk PVs. The model is available via the CanRisk Tool (www.canrisk.org).

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

10.1101/2020.05.04.20090407 ◽

2020 ◽

Cited By ~ 1

Author(s):

Caitlin T Fierheller ◽

Laure Guitton-Sert ◽

Wejdan M Alenezi ◽

Timothée Revil ◽

Kathleen K Oros ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Family History ◽

Serous Carcinoma ◽

Ovarian Cancer Risk ◽

Repair Pathway ◽

Degree Relative ◽

Pathogenic Variants ◽

Familial Ovarian Cancer ◽

History Of

AbstractSome 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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Ovarian cancer risk model needs a more meaningful clinical parameter

BMJ ◽

10.1136/bmj.g6689 ◽

2014 ◽

Vol 349 (nov18 9) ◽

pp. g6689-g6689

Author(s):

F. J. Candido-dos-Reis

Keyword(s):

Ovarian Cancer ◽

Cancer Risk ◽

Risk Model ◽

Clinical Parameter ◽

Ovarian Cancer Risk

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Estrogen Receptor-β Expression of Ovarian Tumors and Its Association with Ovarian Cancer Risk Factors

Cancer Epidemiology Biomarkers & Prevention ◽

10.1158/1055-9965.epi-20-0618 ◽

2020 ◽

Vol 29 (11) ◽

pp. 2211-2219

Author(s):

Amy L. Shafrir ◽

Ana Babic ◽

Margaret Gates Kuliszewski ◽

Megan S. Rice ◽

Mary K. Townsend ◽

...

Keyword(s):

Risk Factors ◽

Ovarian Cancer ◽

Estrogen Receptor ◽

Cancer Risk ◽

Ovarian Tumors ◽

Estrogen Receptor Β ◽

Ovarian Cancer Risk ◽

Cancer Risk Factors

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Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: A Mendelian randomization analysis

PLoS Medicine ◽

10.1371/journal.pmed.1002893 ◽

2019 ◽

Vol 16 (8) ◽

pp. e1002893 ◽

Cited By ~ 18

Author(s):

James Yarmolinsky ◽

Caroline L. Relton ◽

Artitaya Lophatananon ◽

Kenneth Muir ◽

Usha Menon ◽

...

Keyword(s):

Risk Factors ◽

Ovarian Cancer ◽

Cancer Risk ◽

Epithelial Ovarian Cancer ◽

Mendelian Randomization ◽

Ovarian Cancer Risk ◽

Mendelian Randomization Analysis ◽

Randomization Analysis

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Ovarian cancer risk factors by tumor dominance, a surrogate for cell of origin

International Journal of Cancer ◽

10.1002/ijc.28064 ◽

2013 ◽

Vol 133 (3) ◽

pp. 730-739 ◽

Cited By ~ 17

Author(s):

Joanne Kotsopoulos ◽

Kathryn L. Terry ◽

Elizabeth M. Poole ◽

Bernard Rosner ◽

Megan A. Murphy ◽

...

Keyword(s):

Risk Factors ◽

Ovarian Cancer ◽

Cancer Risk ◽

Ovarian Cancer Risk ◽

Cell Of Origin ◽

Cancer Risk Factors

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Abstract 854: Ovarian cancer risk factors by histologic subtypes: evidence for etiologic heterogeneity

10.1158/1538-7445.am2015-854 ◽

2015 ◽

Author(s):

Nicolas A. Wentzensen ◽

Elizabeth Poole ◽

Alan A. Arslan ◽

Alpa V. Patel ◽

V Wendy Setiawan ◽

...

Keyword(s):

Risk Factors ◽

Ovarian Cancer ◽

Cancer Risk ◽

Ovarian Cancer Risk ◽

Cancer Risk Factors ◽

Etiologic Heterogeneity ◽

Histologic Subtypes

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Abstract A107: Ovarian cancer risk factors by tumor dominance, a surrogate for cell of origin

10.1158/1940-6207.prev-11-a107 ◽

2011 ◽

Author(s):

Kathryn L. Terry ◽

Megan Murphy ◽

Susan E. Hankinson ◽

Christopher P. Crum ◽

Daniel W. Cramer ◽

...

Keyword(s):

Risk Factors ◽

Ovarian Cancer ◽

Cancer Risk ◽

Ovarian Cancer Risk ◽

Cell Of Origin ◽

Cancer Risk Factors

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

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106739 ◽

2020 ◽

pp. jmedgenet-2019-106739 ◽

Cited By ~ 1

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.

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