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. 2020 Apr 13;12(4):956.
doi: 10.3390/cancers12040956.

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Klara Lhotova  1   2 , Lenka Stolarova  1 , Petra Zemankova  1   2 , Michal Vocka  3 , Marketa Janatova  1   2 , Marianna Borecka  1   2 , Marta Cerna  1 , Sandra Jelinkova  1 , Jan Kral  1 , Zuzana Volkova  1 , Marketa Urbanova  2 , Petra Kleiblova  2 , Eva Machackova  4 , Lenka Foretova  4 , Jana Hazova  4 , Petra Vasickova  4 , Filip Lhota  5 , Monika Koudova  5 , Leona Cerna  5 , Spiros Tavandzis  6 , Jana Indrakova  6 , Lucie Hruskova  7 , Marcela Kosarova  8 , Radek Vrtel  9 , Viktor Stranecky  10 , Stanislav Kmoch  10 , Michal Zikan  11 , Libor Macurek  12 , Zdenek Kleibl  1 , Jana Soukupova  1   2
Affiliations

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Klara Lhotova et al. Cancers (Basel). .

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.

Keywords: cancer risk; mutation; next-generation sequencing; ovarian cancer; predisposition genes.

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Conflict of interest statement

The authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Overall, 427 mutation carriers of 441 mutations in 18 known/anticipated breast cancer (BC)/ovarian cancer (OC) predisposition genes. In total, 399 carriers in genes significantly associated with OC in our study are highlighted in red letters. STK11 is highlighted as rarely mutated but established OC predisposition gene.
Figure 2
Figure 2
Proportion of mutation carriers in clinicopathological subgroups, including (A) Age at OC diagnosis; (B) Personal cancer history; (C) Family cancer history; (D) Stage at diagnosis; (E) Histology in 1320 OC patients.
Figure 3
Figure 3
Frequency of mutations in 10 BC/OC predisposition genes significantly associated with OC in our study in OC patients with high-grade (HG) serous and borderline tumors, respectively. The patients were subdivided into subgroups with positive (familial cases) and negative (sporadic cases) family cancer history, respectively.
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