Recurrent Germline Mutations of CHEK2 as a New Susceptibility Gene in Patients with Pheochromocytomas and Paragangliomas.

Yinjie Gao,Anli Tong,Min Nie,Chao Ling,Huiping Wang,Yunying Cui,Xiaosen Ma,Dario De Biase

doi:10.1155/2021/1392386

Yinjie Gao, Anli Tong + Show 6 more

Open Access

https://doi.org/10.1155/2021/1392386

Copy DOI

Abstract

Purpose Recently, pheochromocytomas and paragangliomas (PPGLs) have been strongly suspected as hereditary tumors, as approximately 40% of patients carry germline mutations. In the cancers where defects occur to corrupt DNA repair and facilitate tumorigenesis, a CHEK2 strong association has been observed. Therefore, the purpose of this study was to investigate the effect of CHEK2 mutations for its possible pathogenicity in PPGLs. Methods Four patients with CHEK2 mutations were recruited, as previously detected by the whole exome sequencing. Sanger sequencing was used to verify the germline mutations as well as the loss of heterozygosities (LOHs) in their somatic DNAs. Immunohistochemistry was used to analyze the expression of CHEK2 and its downstream target p53 Ser20 (phosphorylated p53). Results The average age of studied patients was 44.25 ± 11.18 years, at the time diagnosis. One patient had multiple tumors which recurred quickly, while two patients had distant metastasis. None of the patient had any relevant family history. Four germline CHEK2 mutations were identified (c.246_260del; c.715G > A; c.1008+3A > T; and c.1111C > T). All the patients were predicted to have either pathogenic or suspected pathogenic mutations. There was no LOH of CHEK2 gene in somatic DNAs found. Additionally, neither CHEK2 proteins nor its downstream target p53 Ser20 were expressed in the tumor tissues. The inactivation of CHEK2 leads to the decrease in the p53 phosphorylation, which might promote tumorigenesis. Conclusions For the first time, CHEK2 was identified as a susceptibility gene for PPGLs. However, the penetrance of CHEK2 gene with genotype-phenotype correlation needs to be investigated.

Highlights

In the cancers where defects occur to corrupt DNA repair and facilitate tumorigenesis, a checkpoint kinase 2 (CHEK2) strong association has been observed. erefore, the purpose of this study was to investigate the effect of CHEK2 mutations for its possible pathogenicity in pheochromocytomas and paragangliomas (PPGLs)
As candidate tumor suppressor, CHEK2 contributes to molecular pathogenesis in various human malignancy. ereby, heterozygous CHEK2 gene germline mutations have been observed in patients with the Li-Fraumeni cancer-predisposition syndrome (LFS), with other cancers such as breast cancer, colon cancer, thyroid cancer, bladder cancer, ovarian cancer, gastric cancer, renal cancer, and prostate cancer [13]
We previously shown that the CHEK2 gene mutations accounted for 3.3% (4/121) of PPGLs patients, in which pathogenic mutations of the related genes were not detected, whereas in 1.3% (4/314) of PPGLs patients recruited cohort from Peking Union Medical College Hospital, a frequency equivalent to a few identified PPGLs susceptibility genes including SDHA, TMEM127, MAX, and FH was found [14,15,16,17]

Summary

Introduction

Pheochromocytomas and paragangliomas (PPGLs) have been strongly suspected as hereditary tumors, as approximately 40% of patients carry germline mutations. Almost 40% of PPGLs patients carry germline mutations in a growing list of genes including SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, MAX, TEMEM127, FH, NF1, and KIF1B [3, 4]. Genes such as EGLN1, EGLN2, MDH2, SLC25A11, MERTK, DLST, and KMT2D are shown to be related to PPGLs [5,6,7,8,9,10]. Definitive validation of CHEK2 gene was required to ascertain it as a new candidate susceptibility gene in PPGLs and for the potential value for genetic risk assessment, prognosis, and surveillance

Objectives

Methods

Results

Conclusion