Low Prevalence of CHEK2 Gene Mutations in Multiethnic Cohorts of Breast Cancer Patients in Malaysia

Abstract

CHEK2 is a protein kinase that is involved in cell-cycle checkpoint control after DNA damage. Germline mutations in CHEK2 gene have been associated with increase in breast cancer risk. The aim of this study is to identify the CHEK2 gene germline mutations among high-risk breast cancer patients and its contribution to the multiethnic population in Malaysia. We screened the entire coding region of CHEK2 gene on 59 high-risk breast cancer patients who tested negative for BRCA1/2 germline mutations from UKM Medical Centre (UKMMC), Hospital Kuala Lumpur (HKL) and Hospital Putrajaya (HPJ). Sequence variants identified were screened further in case-control cohorts consisting of 878 unselected invasive breast cancer patients (180 Malays, 526 Chinese and 172 Indian) and 270 healthy individuals (90 Malays, 90 Chinese and 90 Indian). By screening the entire coding region of the CHEK2 gene, two missense mutations, c.480A>G (p.I160M) and c.538C>T (p.R180C) were identified in two unrelated patients (3.4%). Further screening of these missense mutations on the case-control cohorts unveiled the variant p.I160M in 2/172 (1.1%) Indian cases and 1/90 (1.1%) Indian control, variant p.R180C in 2/526 (0.38%) Chinese cases and 0/90 Chinese control, and in 2/180 (1.1%) of Malay cases and 1/90 (1.1%) of Malay control. The results of this study suggest that CHEK2 mutations are rare among high-risk breast cancer patients and may play a minor contributing role in breast carcinogenesis among Malaysian population.

Breast Cancer Associated Mutations Reported Among Malaysian Malay, Chinese and Indian Patients

“…The increased risk of breast cancer due to CHEK2 was detected mainly in European populations with an estimated breast cancer risk ratio associated with CHEK2*1100 delC in families without BRCA1 and BRCA2 mutation of 1.70 (95%CI=1.32-2.20) in females and 10.28 (95%Cl=3.54-29.87) in males [43] . However, CHEK2*1100 delC mutation was not found in Malaysian breast cancer cohort by Thirthagiri et al, 2009 [44] and Mohamad et al, 2015 [13] in their studies. Mohamad and colleagues [13] sequenced the entire coding region of CHEK2 gene and reported four sequence variants, which include two missense mutations and two silent mutations.…”

“…However, CHEK2*1100 delC mutation was not found in Malaysian breast cancer cohort by Thirthagiri et al, 2009 [44] and Mohamad et al, 2015 [13] in their studies. Mohamad and colleagues [13] sequenced the entire coding region of CHEK2 gene and reported four sequence variants, which include two missense mutations and two silent mutations. The two missense mutations, I160M and R180C, were found in two unrelated MM patients among 59 high-risk breast cancer patients who were tested negative for BRCA1 and BRCA2 germline mutations.…”

“…However, Mohamad and colleagues [13] concluded that the variation found in Malaysian is rare and it may not predispose to increased risk of breast cancer.…”

“…There are several research groups in Malaysia that have conducted breast cancer SNPs studies. Among them are Balraj [9] , Toh [10] , Thirthagiri [11] and Kang [12] who focused on BRCA1 and BRCA2; Mohamed [13] on CHEK2, Phuah [14] on PALB2 and Lee [15] on TP53. The lists of breast cancer genes research in Malaysia population are as shown in Table 2.…”

Novel Nonsense Variants c.58C>T (p.Q20X) and c.256G>T (p.E85X) in the CHEK2 Gene Identified dentified in Breast Cancer Patients from Balochistan

“…The two nonsense variations observed were novels falling at SQ/TQ domain of the CHEK2 kinase (Figure 2) resulting the synthesis of an immature protein. CHEK2 gene response to DNA damage and play a vital role in DNA repair mechanism, germline mutations in CHEK2 gene have been reported to increase the occurrence of breast cancer in patients negative with BRCA1 mutation (Desrichard et al, 2011;Mohamad et al, 2015). Studies suggest that germline variations in gene CHEK2 are diversified among different ethnic groups especially in patients negative for BRCAs Desrichard et al, 2011;Kuusisto et al, 2011).…”