CHEK2p.I157T Mutation Is Associated with Increased Risk of Adult-Type Ovarian Granulosa Cell Tumors.

Peter Švajdler,Marián Švajdler,Monika Šedivcová,Michal Michal,Veronika Urbán,Peter Vasovčák,Roman Mezencev

doi:10.3390/cancers14051208

Abstract

Simple SummaryGranulosa cell tumors of the ovary represent a distinct subset of ovarian cancers typically characterized by hormonal disbalance, slow disease progression, and late recurrence years after surgical removal of the primary tumor. Risk factors associated with development of these rare tumors have not yet been established. In this study, we identified an association between increased risk of developing adult-type granulosa cell tumors (AGCTs) and a specific germline mutation in the CHEK2 gene. Our findings further support the relevance of this deleterious mutation in the increased risk of various cancer types, and opens a new avenue that can be exploited for future development of CHEK2-targeted preventive and therapeutic interventions directed at AGCTs.Pathogenic germline mutations c.1100delC and p.I157T in the CHEK2 gene have been associated with increased risk of breast, colon, kidney, prostate, and thyroid cancers; however, no associations have yet been identified between these two most common European founder mutations of the CHEK2 gene and ovarian cancers of any type. Our review of 78 female heterozygous carriers of these mutations (age > 18 years) found strikingly higher proportion of adult-type granulosa cell tumors of the ovary (AGCTs) among ovarian cancers that developed in these women (~36%) compared to women from the general population (1.3%). Based on this finding, we performed a cross-sectional study that included 93 cases previously diagnosed with granulosa cell tumors, refined and validated their AGCT diagnosis through an IHC study, determined their status for the two CHEK2 mutations, and compared the prevalence of these mutations in the AGCT cases and reference populations. The prevalence ratios for the p.I157T mutation in the AGCT group relative to the global (PR = 26.52; CI95: 12.55–56.03) and European non-Finnish populations (PR = 24.55; CI95: 11.60–51.97) support an association between the CHEK2p.I157T mutation and AGCTs. These rare gynecologic tumors have not been previously associated with known risk factors and genetic predispositions. Furthermore, our results support the importance of the determination of the FOXL2p.C134W somatic mutation for accurate diagnosis of AGCTs and suggest a combination of IHC markers that can serve as a surrogate diagnostic marker to infer the mutational status of this FOXL2 allele.

Highlights

Checkpoint kinase 2 is a serine/threonine protein kinase encoded by the CHEK2 gene involved in cellular responses to genotoxic stress
We report that FOXL2 is the most sensitive single IHC marker for the diagnosis of adult-type granulosa cell tumors of the ovary (AGCTs) that shows a fair concordance with the FOXL2p.C134W somatic mutation, which is pathognomonic for AGCTs
The CHEK2 missense p.I157T (c.470T>C) germline mutation, which was previously reported to increase the risk of breast, colon, kidney, prostate, and thyroid cancers [4], is associated with adult granulosa cell tumors (AGCTs)

Summary

Introduction

Checkpoint kinase 2 is a serine/threonine protein kinase encoded by the CHEK2 gene involved in cellular responses to genotoxic stress. Depending on the cell context and the DNA damage extent, responses mediated by the CHEK2 kinase can include cell cycle checkpoint activation, DNA repair, DNA damage tolerance, cell senescence, or apoptosis (reviewed in [1]). Pathogenic germline mutations in the CHEK2 gene have been consistently associated with mildly to moderately increased risk of developing cancers of the female breast, prostate, and kidney, and some evidence supports increased risk of developing colorectal cancers, papillary thyroid carcinoma, melanoma, endometrial, testicular, and male breast cancers, as well as some leukemias and lymphomas (reviewed in [2]). Depending on the populations studied, they have been shown to increase risk for breast and colorectal cancers twofold (c.1100delC)

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