Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients

One of the factors providing the diversity and heterogeneity of malignant tumors, particularly breast cancer, are genetic variations, due to gene polymorphism, and, especially, the phenomenon of loss of heterozygosity (LOH). It has been shown that LOH in some genes could be a good prognostic marker. Aim: To perform genome-wide study on LOH in association with metastasisfree survival in breast cancer. Materials and Methods: The study involved 68 patients with breast cancer. LOH status was detected by microarray analysis, using a high density DNA-chip CytoScanTM HD Array (Affymetrix, USA). The Chromosome Analysis Suite 3.1 (Affymetrix, USA) software was used for result processing. Results: 13,815 genes were examined, in order to detect LOH. The frequency of LOH varied from 0% to 63%. The association analysis identified four genes: EDA2R, PGK1, TAF9B and CYSLTR1 that demonstrated the presence of LOH associated with metastasis-free survival (log-rank test, p < 0.03). Conclusions: The presence of LOH in EDA2R, TAF9B, and CYSLTR1 genes is associated with metastasis-free survival in breast cancer patients, indicating their potential value as prognostic markers

ЭТНИЧЕСКИЕ АСПЕКТЫ НАСЛЕДСТВЕННОГО РАКА МОЛОЧНОЙ ЖЕЛЕЗЫ В РЕГИОНЕ СИБИРИ

Background: Ethnic diversity of the population in the region of Siberia suggests the existence of different germline mutations in the BRCA1/2 genes associated with breast and ovarian cancer in different ethnic populations, but spectrum of these mutations has not been studied. Objective: Our aim was to evaluate the frequency of the most common mutations BRCA1 / 2 (BRCA1 5382insC, BRCA1 185delAG, BRCA1 4153delAG, BRCA1 T300G, BRCA2 6174delT) in women diagnosed with breast cancer among indigenous people and newcomers living in Siberia. Methods: We tested 1281 genomic DNA samples for the presence of BRCA1 5382insC mutation in patients diagnosed with breast cancer considering no family history. 72 patients having hereditary cancer signs were tested for the mutations BRCA1 185delAG, BRCA1 4153delAG, BRCA1 T300G, BRCA2 6174delT. Results: Out of 765 patients of Slavic ethnic group, 27 women (3.5%) were carriers of allele BRCA1 5382insC. The frequencies of mutations in patients with signs of hereditary cancer were: 8.3% in group of young patients (under 40 years), 20.0% in patients with bilateral cancer and 5.7% in patients with family history of breast or ovarian cancers. We tested 516 BC patients residing on the territory of the Buryat-Aginsky district, Republics of Tyva and Altai. Out of them, there were 197 patients among the indigenous population (buryats, tuvinians, altaians), and 319 patients among newcomers (Slavic ethnics). Mutations BRCA1 5382insC were detected only in women from Slavic ethnic groups. The frequency of BRCA1 5382insC mutation was 6% in the group where family history was excluded and 14% in the group of patients with characteristics of family cancer. Allele BRCA1 5382insC was not found in indigenous breast cancer patients, although 59 patients had signs of hereditary cancer. In women from Slavic ethnic group, the BRCA1 185delAG, BRCA1 4153delAG and BRCA1 T300G mutations were detected in 9.1% of cases and were not found in patients among the indigenous population. Conclusion: studies of mutations in the BRCA1 gene in breast cancer patients from Siberia confirmed data on the high frequency of «founder mutation» BRCA1 5382insC in Slavic population and indicate the advisability of further studies to identify the genes responsible for the occurrence of hereditary breast cancer in the indigenous population. Обоснование: этническая разнородность населения Сибири предполагает наличие разных наследственных мутаций в генах BRCA1/2, ассоциированных с раком молочной железы (РМЖ) и раком яичников в различных популяциях, спектр которых не изучен. Цель исследования: оценить частоту встречаемости наиболее распространенных в РФ мутаций BRCA1/2 (BRCA1 5382insC, BRCA1 185delAG, BRCA1 4153delAG, BRCA1 T300G, BRCA2 6174delT) у представительниц коренного и пришлого населения Сибири. Методы: протестирован 1281 образец геномной ДНК на наличие распространенных мутаций у больных с диагнозом РМЖ. Результаты: из 765 больных РМЖ славянской принадлежности 27 человек (3,5%) были носителями аллеля BRCA1 5382insC. Частота мутации у пациенток с признаками наследственного рака составила: у молодых пациенток до 40 лет — 8,3%, у пациенток с билатеральным раком — 20,0%, при отягощенном семейном анамнезе — 5,7%. На наличие мутации BRCA15382insC протестировано 516 больных РМЖ из Агинского бурятского автономного округа, республик Тыва и Алтай, из них 319 женщин пришлого населения (славянки) и 197 представительниц коренного населения (бурятки, тувинки, алтайки). Мутации обнаружены только у славянок, частота без учета семейного анамнеза составила 6%, с учетом признаков семейного рака — около 14%. У больных РМЖ коренного населения мутация не обнаружена, хотя 59 пациенток имеют признаки наследственного рака. Мутации BRCA1 185delAG, BRCA1 4153delAG и BRCA1 T300G выявлены у славянок в 6,7% случаев и не выявлены у представительниц коренного населения. Заключение: получены данные о высокой частоте встречаемости «мутации-основателя» 5382insC у больных РМЖ славянской популяции и отсутствии «славянских» мутаций у больных РМЖ женщин монголоидного происхождения. Актуальны исследования по выявлению генов наследственного рака молочной железы у представительниц коренного населения.

Genome-wide methylotyping resolves breast cancer epigenetic heterogeneity and suggests novel therapeutic perspectives

Aim: To provide a breast cancer (BC) methylotype classification by genome-wide CpG islands bisulfite DNA sequencing. Materials & methods: XmaI-reduced representation bisulfite sequencing DNA methylation sequencing method was used to profile DNA methylation of 110 BC samples and 6 normal breast samples. Intrinsic DNA methylation BC subtypes were elicited by unsupervised hierarchical cluster analysis, and cluster-specific differentially methylated genes were identified. Results & conclusion: Overall, six distinct BC methylotypes were identified. BC cell lines constitute a separate group extremely highly methylated at the CpG islands. In turn, primary BC samples segregate into two major subtypes, highly and moderately methylated. Highly and moderately methylated superclusters, each incorporate three distinct epigenomic BC clusters with specific features, suggesting novel perspectives for personalized therapy. © 2019 Alexander Tanas et al