A Germline <i>CHEK2</i> Mutation in a Family with Papillary Thyroid Cancer

Zhao, Yanyang; Tian, Yu; Chen, Lan; Xie, Donghui; Wang, Feiliang; Fu, Liping; Cheng, Chaoze; Li, Yao; Zhu, Xiaoquan; Miao, Gang

doi:10.1089/thy.2019.0774

Cited by 20 publications

(25 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The c.1100del variant causes a frameshift and premature termination codon, p.(Thr367Metfs*15), responsible for the loss of the response to DNA damage and for the impairment of the CHEK2 kinase activity [ 47 , 52 ]. This variant has been reported in Li-Fraumeni Syndrome and also in several cancer types as breast, ovarian, prostatic, colon, thyroid malignancies [ 50 , 58 , 59 , 60 ].…”

Section: Resultsmentioning

confidence: 97%

“…Moreover, the c.793-1G>A variant was identified in a woman with a family history of osteosarcoma and young-onset BC that suggested a Li-Fraumeni like syndrome. Intriguingly, the proband had papillary thyroid cancer, recently described in CHEK2 patients [ 59 ]. Unfortunately, segregation studies could not be performed in the deceased parents, and we could not determine if the variant, detected also in her asymptomatic brother, was inherited from the maternal branch, in which breast, gastrointestinal, and brain cancers occurred, or from the paternal side, where three paternal uncles had PrC.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

Germani

Petrucci

Marchis

et al. 2020

JCM

View full text Add to dashboard Cite

The 5–10% of breast/ovarian cancers (BC and OC) are inherited, and germline pathogenic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10–20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 113 non-BRCA patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC, and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the CHEK2 gene, and a new pathogenic variant was detected in the RECQL gene. These results supported the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches.

show abstract

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

Germani

Petrucci

Marchis

et al. 2020

JCM

View full text Add to dashboard Cite

show abstract

“…Even so, no somatic alteration in any cancer-related gene was found in this sample, and we, therefore, speculate whether the CHEK2 mutation found here would abrogate the ability of the CHEK2 protein to stabilize P53. Indeed, data from kindred with familial PTC exhibiting an unrelated truncating CHEK2 mutation suggest that this event leads to diminished intratumoral P53 levels ( Zhao et al 2020 ). Even so, both case 1 as well as case 3 was without credible somatic driver alterations in PTC-related genes altogether.…”

Section: Discussionmentioning

confidence: 99%

Pan-genomic characterization of high-risk pediatric papillary thyroid carcinoma

Stenman

Backman

Johansson

et al. 2021

Endocrine-Related Cancer

View full text Add to dashboard Cite

Pediatric papillary thyroid carcinoma (pPTCs) are often indolent tumors with excellent long-term outcome, although subsets of cases are clinically troublesome and recur. Although generally thought to exhibit similar molecular aberrancies as their counterpart tumors in adults, the pan-genomic landscape of clinically aggressive pPTCs has not been previously described. In this study, five pairs of primary and synchronously metastatic pPTC from patients with high-risk phenotypes were characterized using parallel whole-genome and transcriptome sequencing. Primary tumors and their metastatic components displayed an exceedingly low number of coding somatic mutations and gross chromosomal alterations overall, with surprisingly few shared mutational events. Two cases exhibited one established gene fusion event each (SQSTM1-NTRK3 and NCOA4-RET) in both primary and metastatic tissues, and one case each was positive for a BRAF V600E mutation and a germline truncating CHEK2 mutation respectively. One single case was without apparent driver events and was considered a genetic orphan. Non-coding mutations in cancer-associated regions were generally not present. By expressional analyses, fusion-driven primary and metastatic pPTC clustered separately from the mutation-driven cases and the sole genetic orphan. We conclude that pPTCs are genetically indolent tumors with exceedingly stable genomes. Several mutations found exclusively in the metastatic samples may represent novel genetic events that drive the metastatic behavior, and the differences in mutational compositions suggest early clonal divergence between primary tumors and metastases. Moreover, an overrepresentation of mutational and expressional dysregulation of immune regulatory pathways was noted among fusion-positive pPTC metastases, suggesting that these tumors might facilitate spread through immune evasive mechanisms.

show abstract

“…PTC is a well-differentiated papillary carcinoma with a relatively low mortality rate among types of TC (14). However, the persistence and recurrence rates in patients with PTC are high, ≥30% in certain demographics (8,9).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the dysregulated expression or mutation of mRNAs may be a promising predictor of poor prognosis in PTC. Previous studies have documented that numerous key mRNAs, such as checkpoint kinase 2 (CHEK2) and distal-less homeobox 6 (DLX6), are closely associated with the aggressive pathogenesis of PTC ( 12 – 14 ). It is likely that multiple mRNAs may allow for the development of a signature model and provide more statistically predictive results of PTCs patients.…”

Section: Introductionmentioning

confidence: 99%

Potential five‑mRNA signature model for the prediction of prognosis in patients with papillary thyroid carcinoma

et al. 2020

View full text Add to dashboard Cite

Although the mortality rate of papillary thyroid carcinoma (PTC) is relatively low, the recurrence rates of PTC remain high. The high recurrence rates are related to the difficulties in treatment. Gene expression profiles has provided novel insights into potential therapeutic targets and molecular biomarkers of PTC. The aim of the present study was to identify mRNA signatures which may categorize PTCs into high-and low-risk subgroups and aid with the predictions for prognoses. The mRNA expression profiles of PTC and normal thyroid tissue samples were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNAs were identified using the 'EdgeR' software package. Gene signatures associated with the overall survival of PTC were selected, and enrichment analysis was performed to explore the biological pathways and functions of the prognostic mRNAs using the Database for Visualization, Annotation and Integration Discovery. A signature model was established to investigate a specific and robust risk stratification for PTC. A total of 1,085 differentially expressed mRNAs were identified between the PTC and normal thyroid tissue samples. Among them, 361 mRNAs were associated with overall survival (P<0.05). A 5-mRNA prognostic signature for PTC (ADRA1B, RIPPLY3, PCOLCE, TEKT1 and SALL3) was identified to classify the patients into high-and low-risk subgroups. These prognostic mRNAs were enriched in Gene Ontology terms such as 'calcium ion binding', 'enzyme inhibitor activity', 'carbohydrate binding', 'transcriptional activator activity', 'RNA polymerase II core promoter proximal region sequence-specific binding' and 'glutathione transferase activity', and Kyoto Encyclopedia of Genes and Genomes signaling pathways such as 'pertussis', 'ascorbate and aldarate metabolism', 'systemic lupus erythematosus', 'drug metabolism-cytochrome P450 and 'complement and coagulation cascades'. The 5-mRNA signature model may be useful during consultations with patients with PTC to improve the prediction of their prognosis. In addition, the prognostic signature identified in the present study may reveal novel therapeutic targets for patients with PTC.

show abstract

A Germline CHEK2 Mutation in a Family with Papillary Thyroid Cancer

Cited by 20 publications

References 20 publications

Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

Pan-genomic characterization of high-risk pediatric papillary thyroid carcinoma

Potential five‑mRNA signature model for the prediction of prognosis in patients with papillary thyroid carcinoma

Contact Info

Product

Resources

About