Balkan Journal of Medical Genetics

CLINICAL RELEVANCE OF CHEK2 AND NBN MUTATIONS IN THE MACEDONIAN POPULATION
Maleva Kostovska I, Jakimovska M, Kubelka-Sabit K, Karadjozov M, Arsovski A, Stojanovska L, Plaseska-Karanfilska D1,
*Corresponding Author: Dijana Plaseska-Karanfilska, M.D., Ph.D., Research Centre for Genetic Engineering and Biotechnology “Geogi D. Efremov,” Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia. Tel: +389-2-3235-410. Fax: +389-2-3155-434. E-mail: dijana@manu.edu.mk
page: 47

RESULTS

We analyzed 300 patient and 283 control individuals for the presence of 1100delC, IVS2+1G>A, I157T, del 5395 in CHEK2 and 657del5, R215W mutations in NBN to determine their frequencies in the Macedonian population. The results are summarized in Table 2. Our primer extension design provides a very fast and highly accurate one-tube screening method for detection of five mutations in a single reaction (Figure 1). The identified mutations were validated by Sanger sequencing using BigDye chemistry. The 5395 bp deletion in CHEK2 was assayed by PCR. The truncation mutation 1100delC in CHEK2 was detected in one patient (0.3%) and in none of the control cohort. The patient was a 31-year-old woman diagnosed with invasive third stage ductal carcinoma, with positive lymph nodes (pN1a), but no metastases. Her mother was diagnosed with breast cancer at age 40 and died 2 years later. The IVS2+1G>A and the 5395 bp deletion were not observed in our analyzed groups. The I157T missense mutation was the most frequent variant identified in our study. It was detected in 10 patients (3.33%) and four controls (1.4%). Statistically significant association was not observed [p = 0.176, odds ratio (OR) = 1.91; 95% confidence interval (CI): 0.64 to 5.68), although there was a significant association when familial vs. non familial breast cancer patients (p = 0.041, OR = 3.91; 95% CI: 0.99 to 15.44) were compared. All patient carriers were of Macedonian descent, median age at first diagnosis was 53 years and all had ductal carcinoma. The NBN 657del5 mutation was identified in one patient (0.3%) and in none of the controls. The patient was a 42-year-old woman diagnosed with invasive ductal carcinoma reporting no relatives diagnosed with breast cancer. The R215W mutation was observed in one patient (0.3%) and one control individual (0.35%). It was interesting to note that the patient carried both the R215W and I157T mutations. She was diagnosed with invasive ductal carcinoma at the age of 43, stage IA and was negative for lymph node and metastasis. She reported a family history of breast cancer from her mother’s and father’s side of the family. Her mother was diagnosed with breast cancer at the age of 54 and her mother’s cousin at age 39, who died 2 years later. Both of her father’s sisters had been diagnosed with breast cancer at ages 50 and 62, and they died a few years after.

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