Incidence of the CHEK2 Germline Mutation and Its Impact on Clinicopathological Features, Treatment Responses, and Disease Course in Patients with Papillary Thyroid Carcinoma

Abstract

The CHEK2 gene is involved in the repair of damaged DNA. CHEK2 germline mutations impair this repair mechanism, causing genomic instability and increasing the risk of various cancers, including papillary thyroid carcinoma (PTC). Here, we asked whether CHEK2 germline mutations predict a worse clinical course for PTC. The study included 1547 unselected PTC patients (1358 women and 189 men) treated at a single center. The relationship between mutation status and clinicopathological characteristics, treatment responses, and disease outcome was assessed. CHEK2 mutations were found in 240 (15.5%) of patients. A CHEK2 I157T missense mutation was found in 12.3%, and CHEK2 truncating mutations (IVS2 + 1G > A, del5395, 1100delC) were found in 2.8%. The truncating mutations were more common in women (p = 0.038), and were associated with vascular invasion (OR, 6.91; p < 0.0001) and intermediate or high initial risk (OR, 1.92; p = 0.0481) in multivariate analysis. No significant differences in these parameters were observed in patients with the I157T missense mutation. In conclusion, the CHEK2 truncating mutations were associated with vascular invasion and with intermediate and high initial risk of recurrence/persistence. Neither the truncating nor the missense mutations were associated with worse primary treatment response and outcome of the disease.

CHEK2 mutations and papillary thyroid cancer: correlation or coincidence?

“…These studies, together with the three other Polish studies mentioned previously, found an increased I157T carrier frequency in papillary thyroid cancer patients compared to controls with odds ratios between 1,9 to 3,0 [7,8,14,16,17].…”

“…No statistically significant association was found between different individual truncating CHEK2 variants and thyroid cancer. When pooling the truncating mutations however, there was a statistically significant association (OR 4,54; 95%CI [1,40 – 14,68]; p = 0,0116), which was driven primarily by the IVS2 + 1G > A variant [ 14 ]. A case-control study of patients with non-anaplastic thyroid cancer in an Iranian population found no germline CHEK2 mutations in cases nor controls, though this probably reflects the low frequency of CHEK2 mutations in the Middle Eastern population [ 15 ].…”

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

“…A CHEK2 p.Ile157Thr missense mutation was found in 12.3%, and CHEK2 truncating mutations (IVS2+1G>A, del5395, 1100delC) were found in 2.8%. While truncating mutations were more common in women and were associated with vascular invasion and intermediate or high initial risk in multivariate analysis, no significant differences were observed in patients with the p.Ile157Thr missense mutation ( 37 ).…”

“…A subsequent study in the same population confirmed that a CHEK2 truncating mutation (1100delC, IVS2+1G>A, del5395) was associated with odds ratio of 5.7 (p= 0.006), and a CHEK2 missense p.Ile157Thr mutation was associated with odds ratio of 2.8 (p= 0.0001) for PTC ( 104 ). In a more recent Polish series that included 1547 unselected PTC patients (1358 women and 189 men), CHEK2 mutations were found in 240 (15.5%) patients ( 37 ). A CHEK2 p.Ile157Thr missense mutation was found in 12.3%, and CHEK2 truncating mutations (IVS2+1G>A, del5395, 1100delC) were found in 2.8%.…”