A pathogenic variant in CHEK2 shows a founder effect in Portuguese Roma patients with thyroid cancer

CHEK2 germline variants identified in familial nonmedullary thyroid cancer lead to impaired protein structure and function

“…Recent studies reported germline variants in DNA repair genes in NMTC and FNMTC patients ( 19 , 20 , 21 , 22 , 23 , 24 , 25 ). In this work, we identified two distinct CHEK2 missense variants (p.I157T and p.E321A), segregating with TC in two members from each family (F24 and F83), and with FND/NOS-TN in one family (F83).…”

“…Immunohistochemical detection of CHK2 protein was performed on archival FFPE tumor samples. A total of 12 familial cases, assessed for CHEK2 germline mutational status, were included: two from F24 (p.I157T carriers), two from F83 (p.E321A carriers), three CHEK2 p.Y156∗ carriers [described in a previous study ( 23 )], and the remaining were CHEK2 -negative patients. The adjacent normal tissue in each tumor sample was analyzed as control.…”

“…Genome-wide association studies, linkage analyses, targeted, and whole exome/genome sequencing led to the identification of several chromosomal loci [ MNG1 (14q32), TCO (19p13.2), NMTC1 (2q21), FTEN (8p23.1-p22), PRN (1q21), 6q22, 8q24, and 12q14] ( 8 ), as well as predisposing risk variants in genes such as DICER1, SRGAP1 , NKX2 -1, FOXE1 , SRRM2 , RTFC , HABP2 , MYO1F, MAP2K5 and, more recently, SPRY4 ( 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ). Additionally, germline variants in DNA repair related-genes, namely BRCA1/2 , ATM , CHEK2 , and MSH6 have been recently reported in cases with FNMTC and NMTC ( 19 , 20 , 21 , 22 , 23 , 24 , 25 ), suggesting a role for these genes in FNMTC pathogenesis. Despite these findings, the molecular basis of FNMTC remains largely unknown, since these genes are only mutated in a small fraction of the families.…”

“…CHEK2 is a tumor suppressor gene that encodes the serine/threonine protein kinase CHK2, which is a key mediator of the DNA damage checkpoint that responds to DNA double-strand breaks, playing a crucial role in the maintenance of genomic integrity ( 28 ). Mutations in CHEK2 not only exist in subsets of sporadic cancers, but they also predispose patients to several types of familial cancers ( 29 ), with increasing evidence emerging in the context of FNMTC ( 21 , 22 , 23 , 24 , 25 ). In this study, the identified CHK2 variants were structurally and functionally characterized, using biophysical methods and molecular dynamics (MD) simulations.…”

Susceptibility Genes and Chromosomal Regions Associated With Non-Syndromic Familial Non-Medullary Thyroid Carcinoma: Some Pathogenetic and Diagnostic Keys

“…The CHEK2 *1100delC variant is a well-established breast cancer risk variant in European populations ( 106 ) and was also associated with prostate cancer ( 107 ). A more recent study, reported a germline CHEK2 pathogenic variant (c.596dupA, p.Tyr199Ter) in the proband and in five additional members of a Portuguese Roma family with MNG and/or PTC; in this same family, two women were affected by breast cancer and classic PTC and one of the men by prostate cancer and PTC ( 38 ). A novel heterozygous germline mutation in CHEK2 (c.417C>A) was detected in all available affected members of a kindred with familial PTC ( 35 ).…”