Резюме

Рибченко Л.А., Клименко С.В. Визначення імовірних носіїв мутацій BRCA1 та BRCA2 серед жінок з раком молочної залози та без нього.

Проаналізована дискримінаційна здатність алгоритмів BOADICEA, Penn II, Myriad та Манчестерської бальної системи щодо прогнозування ризику BRCA1 та BRCA2 мутацій у пацієнтів з РМЗ та без нього. Доказана ефективність використання моделей BOADICEA та Манчестерської бальної системи серед досліджуваної когорти осіб.

Ключові слова: алгоритми визначення ризику BRCA1 і BRCA2 мутацій, BOADICEA, Манчестерська бальна система, Penn II, Myriad.

Резюме

Рыбченко Л.А., Клименко С.В. Определение вероятных носителей мутаций BRCA1 та BRCA2 среди женщин с раком молочной железы и без него

Проанализирована дискриминационная способность алгоритмов BOADICEA, Penn II, Myriad и Манчестерской балльной системы относительно прогнозирования риска BRCA1 и BRCA2 мутаций у пациентов с РМЖ и без него. Доказана эффективность применения моделей BOADICEA и Манчестерской балльной системы среди исследуемой когорты лиц.

Ключевые слова: алгоритмы определения риска BRCA1 и BRCA2 мутаций, BOADICEA, Манчестерская балльная система, Penn II, Myriad.

Summary

Rybchenko L.A., Klymenko S.V. Identification of possible carriers of BRCA1 and BRCA2 mutations among women with breast cancer and healthy women.

Discriminatory ability of algorithms BOADICEA, Penn II, Myriad and the Manchester scoring system for prediction of possible carriers of BRCA1 and BRCA2 mutations in patients with and without breast cancer was analyzed. The effectiveness of use of BOADICEA and Manchester scoring system was proved among the individuals of study cohort.

Key words: algorithms, determination the risk of BRCA1 and BRCA2 mutations, BOADICEA, Manchester scoring system, Penn II, Myriad.

Рецензент: д.мед. наук, проф. М.А. Пілінська

UDC 618.19-006:616-001. 28:575 (083.13)

DETECTION OF PROBABLE BRCA1 AND BRCA2 MUTATIONS IN WOMEN WITH AND WITHOUT BREAST CANCER

L.A.Rybchenko, S.V.Klymenko

National Research Center for Radiation Medicine

rybchenkol@i.ua

Introduction. Mutations in genes BRCA1 and BRCA2 cause high risk of breast cancer (BC) and ovarian cancer (OC). It is required before genetic study of genes data to evaluate probability of carriage of mutations using algorithms of prognosis of BRCA1/2 pathological alleles. It will ensure examination of significant number of individuals with lowest expenses.

The aim of the study was to determine discriminatory capacity of algorithms BOADICEA, Penn II, Myriad and Manchester Scoring System (MSS) for prognosis of carriage of BRCA1 and BRCA2 mutations in patients with BC and without this disease.

Material and methods. Four hundred twenty five women have been enrolled in the study: 146 women with BC and 279 almost healthy women. Patients have been selected for the study according to the principles of Declaration of Helsinki after study has been approved by Committee of Ethics of NRCRM of NAMSU. In order to determine probable carriers of BRCA1 and BRCA2 mutations, firstly, the genealogical study concerning oncologic pathology in pedigrees of probands has been carried out emphasizing the cases of BC and OC. Secondly, the risks of carriage of mutations using algorithms BOADICEA, Penn II, Myriad and MSS, have been calculated. Thirdly, molecular-genetic test of BRCA1 and BRCA2 genes with the help of polymerase chain reaction using conditions of DNA amplification and sequence of the primers for identification of mutations, which has been published by Chan et al., has been carried out. Sections of tumor tissues fixed in formalin and embedded in paraffin have been taken as material of study in groups of BC patients. In group of patients without BC, peripheral blood has been used as material of study. Fourthly, discriminatory analysis of studied models using statistical program MedCalc has been carried out.

Results and discussion. When carrying out genealogical study in group of BC patients, ≥2 cases of BC and/or OC among relatives have been found in 24.6% of individuals. Moreover, 3 women without compromised family history of cancer had bilateral BC. Women without BC had compromised family history of cancer in 1.8% of cases. Molecular-genetic study of genes BRCA1/2 has detected 7.1% (10 out of 141) mutations in BC patients. In one woman, mutation 185delAG in gene BRCA1 has been detected, in nine women ‒ mutation 5382insC in gene BRCA1.

In cancer-free women has been found 1.1% (3 out of 279) of mutations, all cases were represented by allele variant 5382insC. Mutation 6174delT in gene BRCA2 has not been detected in any women. Significant difference in frequency of mutations between group of BC-patients and group of BC-free individuals has been determined (p=0.0015). Discriminatory analysis of models has been conducted for patients, whose pedigrees contained ≥2 cases of BC and/or OC – 44 individuals: 39 patients, among whom 9 patients had mutations and 5 women without BC, among whom 2 women had pathological alleles (Table 1). For visualization of effectiveness of algorithms, the ROC-curves have been constructed (Fig.1). For determination of discriminatory capacity of models for differentiation of individuals with mutations and without them, area under curve (AUC) of each algorithm has been compared with neutral value (0.50). Predicative significance has been determined only for model BOADICEA and MSS both for prognosis of BRCA1 and combined risk of BRCA1/2 mutations (Table 2). Algorithms BOADICEA with the best discriminatory threshold ≥ 6.7% (AUC‒ 0.79; 95% CI ‒ 0.65-0.90, р=0.0002) and MSS ‒ ≥6 scores (AUC ‒ 0.76; 95% CI ‒ 0.60-0.87, р=0.0003) correspond with good level of prognosis of BRCA1 mutations. Discriminatory capacity of algorithms BOADICEA (AUC ‒ 0.74; 95% CI ‒ 0.59-0.86, р=0.0054) and MSS (0.76; 95% CI ‒ 0.61-0.88, р=0.0004) indicates good level of prognosis of combined risk of BRCA1/2 mutations with maximum possible operational features at thresholds ≥7.7% and ≥12 scores correspondingly.

Conclusion. One should apply the BOADICEA and MSS models for testing the BRCA1 and BRCA2 mutation risks in BC patients and individuals without malignant tumors of mammary gland with compromised family history of BC and/or OC.