Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

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Abstract

Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates treatment and preventive strategies reducing OC mortality in mutation carriers. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We aimed to analyze 219 genes in 1333 Czech OC patients and 2278 population-matched controls using next-generation sequencing. We revealed germline mutations in 18 OC/BC predisposition genes in 32.0% of patients and in 2.5% of controls. Mutations in BRCA1/BRCA2, RAD51C/RAD51D, BARD1, and mismatch repair genes conferred high OC risk (OR > 5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR = 3.5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Our findings demonstrate the high proportion of patients with hereditary OC in Slavic population justifying genetic testing in all patients with OC, including BTO.

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Most cited references 38

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Inherited Mutations in Women With Ovarian Carcinoma.

Barbara Norquist, Maria I Harrell, Mark Brady … (2016)

Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized.

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Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Xin Yang, Goska Leslie, Alicja Doroszuk … (2019)

To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10 −76 ), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10 −3 ), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10 −3 ), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10 −2 ). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10 −3 ). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

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Genetic Testing and Results in a Population-Based Cohort of Breast Cancer Patients and Ovarian Cancer Patients

Allison Kurian, Kevin C Ward, Nadia Howlader … (2019)

Genetic testing for cancer risk has expanded rapidly. We examined clinical genetic testing and results among population-based patients with breast and ovarian cancer. The study included all women 20 years of age or older diagnosed with breast or ovarian cancer in California and Georgia between 2013 and 2014 and reported to the SEER registries covering the entire state populations. SEER data were linked to results from four laboratories that performed nearly all germline cancer genetic testing. Testing use and results were analyzed at the gene level. There were 77,085 patients with breast cancer and 6,001 with ovarian cancer. Nearly one quarter of those with breast cancer (24.1%) and one third of those with ovarian cancer (30.9%) had genetic test results. Among patients with ovarian cancer, testing was lower in blacks (21.6%; 95% CI, 18.1% to 25.4%; v whites, 33.8%; 95% CI, 32.3% to 35.3%) and uninsured patients (20.8%; 95% CI, 15.5% to 26.9%; v insured patients, 35.3%; 95% CI, 33.8% to 36.9%). Prevalent pathogenic variants in patients with breast cancer were BRCA1 (3.2%), BRCA2 (3.1%), CHEK 2 (1.6%), PALB2 (1.0%), ATM (0.7%), and NBN (0.4%); in patients with ovarian cancer, prevalent pathogenic variants were BRCA1 (8.7%), BRCA2 (5.8%), CHEK2 (1.4%), BRIP1 (0.9%), MSH2 (0.8%), and ATM (0.6%). Racial/ethnic differences in pathogenic variants included BRCA1 (ovarian cancer: whites, 7.2%; 95% CI, 5.9% to 8.8%; v Hispanics, 16.1%; 95% CI, 11.8% to 21.2%) and CHEK2 (breast cancer: whites, 2.3%; 95% CI, 1.8% to 2.8%; v blacks, 0.1%; 95% CI, 0% to 0.8%). When tested for all genes that current guidelines designate as associated with their cancer type, 7.8% of patients with breast cancer and 14.5% of patients with ovarian cancer had pathogenic variants. Clinically-tested patients with breast and ovarian cancer in two large, diverse states had 8% to 15% prevalence of actionable pathogenic variants. Substantial testing gaps and disparities among patients with ovarian cancer are targets for improvement.

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Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 13 April 2020

Publication date Collection: April 2020

Volume: 12

Issue: 4

Electronic Location Identifier: 956

Affiliations

[1 ]Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, 128 53 Prague, Czech Republic; Klara.Lhotova@ 123456lf1.cuni.cz (K.L.); lenka.stolarova@ 123456lf1.cuni.cz (L.S.); petra.boudova@ 123456lf1.cuni.cz (P.Z.); mjana@ 123456lf1.cuni.cz (M.J.); boreckam@ 123456gmail.com (M.B.); marta.cerna@ 123456lf1.cuni.cz (M.C.); sandra.jelinkova@ 123456lf1.cuni.cz (S.J.); jan.kral@ 123456lf1.cuni.cz (J.K.); zuzana.klusonova@ 123456lf1.cuni.cz (Z.V.); zdekleje@ 123456lf1.cuni.cz (Z.K.)

[2 ]Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 00 Prague, Czech Republic; Marketa.Urbanova@ 123456vfn.cz (M.U.); pekleje@ 123456lf1.cuni.cz (P.K.)

[3 ]Department of Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic; Michal.Vocka@ 123456vfn.cz

[4 ]Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; emachack@ 123456mou.cz (E.M.); foretova@ 123456mou.cz (L.F.); hazova@ 123456mou.cz (J.H.); vasickova@ 123456mou.cz (P.V.)

[5 ]Department of Medical Genetics, Centre for Medical Genetics and Reproductive Medicine, Gennet, 170 00 Prague, Czech Republic; Filip.Lhota@ 123456gennet.cz (F.L.); Monika.Koudova@ 123456gennet.cz (M.K.); Leona.Cerna@ 123456gennet.cz (L.C.)

[6 ]Department of Medical Genetics, AGEL Laboratories, AGEL Research and Training Institute, 741 01 Novy Jicin, Czech Republic; spiros.tavandzis@ 123456lab.agel.cz (S.T.); jana.indrakova@ 123456lab.agel.cz (J.I.)

[7 ]Department of Medical Genetics, GHC Genetics, 110 00 Prague, Czech Republic; hruskova@ 123456ghc.cz

[8 ]Department of Medical Genetics, Pronatal, 147 00 Prague, Czech Republic; kosarova@ 123456pronatal.cz

[9 ]Department of Medical Genetics, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University Olomouc, 779 00 Olomouc, Czech Republic; radek.vrtel@ 123456fnol.cz

[10 ]Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic; vstra@ 123456lf1.cuni.cz (V.S.); skmoch@ 123456lf1.cuni.cz (S.K.)

[11 ]Department of Gynecology and Obstetrics, Hospital Na Bulovce and First Faculty of Medicine, Charles University, 180 81 Prague, Czech Republic; michal.zikan@ 123456lf1.cuni.cz

[12 ]Laboratory of Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20 Prague, Czech Republic; libor.macurek@ 123456img.cas.cz

Author notes

[* ]Correspondence: jana.soukupova@ 123456lf1.cuni.cz ; Tel.: +420-224965739

Author information

Michal Vocka https://orcid.org/0000-0002-9386-657X

Marianna Borecka https://orcid.org/0000-0001-6413-222X

Petra Kleiblova https://orcid.org/0000-0002-4806-9854

Monika Koudova https://orcid.org/0000-0002-1323-4936

Spiros Tavandzis https://orcid.org/0000-0001-9845-2408

Libor Macurek https://orcid.org/0000-0002-0987-1238

Zdenek Kleibl https://orcid.org/0000-0003-2050-9667

Jana Soukupova https://orcid.org/0000-0003-2413-1542

Article

Publisher ID: cancers-12-00956

DOI: 10.3390/cancers12040956

PMC ID: 7226062

PubMed ID: 32295079

SO-VID: 41b4fe39-a7aa-4944-9271-f947bbb6bd06

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

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Most cited references 38

Inherited Mutations in Women With Ovarian Carcinoma.

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Genetic Testing and Results in a Population-Based Cohort of Breast Cancer Patients and Ovarian Cancer Patients

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