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.
e13111 Background: First large Russian ovarian cancer observational study was conducted in 2014-2018. Methods: A total of 500 patients in 29 sites in Russia with newly diagnosed ovarian, peritoneal and fallopian tube cancer was enrolled (NCT02122588). The primary objective was to describe treatment approaches in the first line treatment. 141 patients (pts) with BRCA1/2 mutations (BRCA1/2mt) detected by NGS in blood and tissue were observed prospectively during at least 2 years. Results: Rate of BRCA1/2 mutations in Russian population is high – 28.4% (141 from 496 available for any testing). 77.6% (388/500) underwent biomarkers blood testing prior to treatment. CA-125 was positive in 99.7% (387/388), 15.2% (59/388) of pts had positive CA19-9, CA72-4 - in 2.3% (9/388). Positive CEA was presented in 15.2% (59/388). This marker was detected more frequently in BRCA2mt pts subgroup (28.0% (7/25)) than in BRCA1mt pts: 9.0% (8/90) (p = 0.05). 26.6% (133/500) of all study population had an oncology family history; 44.0% (62/141) BRCA1/2mt pts had relatives with oncological diseases and 19.7% (70/355) in BRCA wild type pts (p = 0.0001). 98.6% (139/141) of BRCA1/2mt pts received first line therapy. Objective response rate was registered in 79.8% (111/139) pts. Progression after platinum based regimens was observed in 53.6% (59/110) BRCA1mt pts and 44.8% (13/29) BRCA2mt pts. 35.6 % (21/59) of BRCA1mt pts had platinum-refractory and platinum-resistant relapses, while 15.4% in BRCA2mt subgroup (2/13) (p = 0.64). Platinum-sensitive relapses were in 64.4% (38/59) BRCA1mt pts and 84.6% BRCA2mt (11/13) (p = 0,64). Median PFS in BRCA1/2mt pts was 25.5 months. Among BRCA1/2mt pts underwent cytoreduction median PFS in subgroup without visible residual tumor was 36.4 months and in subgroup with residual tumor < 1 cm 15.3 months. Conclusions: In this large-scale prospective non-interventional study diagnostics and treatment approaches in Russian ovarian cancer pts were evaluated and high frequency of BRCA1/2mt was observed. Pts with BRCA1/2mt had better prognosis and most of them had platinum-sensitive relapses after first line chemotherapy that allowed platinum-based regimen rechallenge.
Abstract Pathogenic mutations in BRCA1 and BRCA2 genes are essential biomarkers of an increased breast and ovarian cancer risk and tumor sensitivity to poly ADP ribose (PARP) inhibitors. In many countries, their detection includes patient prescreening with quantitative PCR (qPCR) identifying several founder mutations. In Russia, eight mutations are included in such tests, among which c.5266dup (5382insC) is the most frequently identified one. Here, we showed the distribution of 1406 pathogenic or likely pathogenic mutations in BRCA1/2 genes identified in ovarian cancer patients recruited into the study from 72 Russian regions in 2015-2021. The most of mutations were detected with qPCR, for qPCR mutation negative samples, targeted next-generation sequencing (NGS) covering whole coding sequences of the genes was applied. As expected, the most abundant mutations were c.5266dupC (41.0%), c.4035delA (7.0%), c.1961delA (6.3%), c.181T>G (5.2%), c.3756_3759delGTCT (1.8%), c.3700_3704delGTAAA (1.5%), and c.68_69delAG (1.5%). However, we identified several mutations which were more frequent than the founder c.5946delT mutation (also known as 6174delT, 0.5% of participants): c.5152+1G>T (1.2%), c.1687C>T (1.0%), c.4689C>G (0.9%), c.1510delC (0.6%), c.2285_2286delGA (0.6%) in the BRCA1 gene; and c.5286T>G (1.2%), c.2808_2811delACAA (0.8%), c.658_659delGT (0.7%), c.7879A>T (0.6%), c.3847_3848delGT (0.6%) in the BRCA2 gene. Having developed an NGS-targeted panel on SNPs flanking BRCA2 c.5286T>G, we showed the founder effect for this mutation and suggested that it arose about 700 years ago that is twice later that it is thought for the c.5266dupC. The total occurrence of mutations identified in at least 10 participants (13 mutations) was only 70%. To our knowledge, eighty-nine mutations (identified in 8% of participants) have not been described previously. Thus, this study may help in improving prescreening qPCR tests and extend our knowledge about the BRCA1 and BRCA2 genes variability in ovarian cancer patients.
Abstract Background: This study is a first attempt to determine frequency of gBRCAm and share of sBRCAm in Russian ovarian cancer (OC) cancer patients (pts) using next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA). Russian population is known to have a sizable proportion of “frequent” germline mutations in BRCA genes, with occurrence in >2% of all BRCAm cases. Methods: 498 pts with primary serous and endometrioid OC were enrolled in noninterventional study OVATAR (NCT02122588). NGS testing of BRCAm in genomic DNA (gDNA) from leukocytes and primary tumor tissue was performed. MLPA assay for large rearrangements (LGR) was used on gDNA from leukocytes. Results: Interim analysis includes pairs of tumor and blood samples from 400 pts. The total rate of BRCA1/2 mutations was 35% (140/400 pts) including 29.8% (119/400) of germline mutations (gBRCAm) and 5.2% (21/400) of somatic mutations. Alterations reported hereby were either classified as deleterious/pathogenic in public databases, or identified as “likely pathogenic” (e.g., loss-of-function). VUS were not included. Frequent gBRCAm were detected in 49.3% of gBRCAm cases (69/140). BRCAm were counted as rare: in 30.7% (43/140) pts, including LGR in 3.6% (5/140) pts. sBRCAm: in 15% (21/140) pts. Although previously counted as frequent, 6174delT in BRCA2 was not detected. 4 pts carried pathogenic germline BRCA2 c.T5286G:p.Y1762* nonsense mutation, with prevalence 2.9% among BRCAm carriers, which makes it the new and only potential “hot-spot” in BRCA2 gene. Large deletions comprise 5% of all BRCAm and mostly occur in BRCA1 gene. Conclusion: The overall rate of both somatic and germline BRCA variations in Russian OC population is in line with global data, with high percent of 8 frequent gBRCAm (49.3%). Use of MLPA is limited by blood samples with low rate of germline LGR. NGS is becoming a method of choice to hit both small variations and LGR in BRCA genes. gene/mutation# of pts (n=140) and % of BRCAmgBRCAmFrequent mutations n=69 (49,3%)BRCA15382insC3726,4%4154delA75,0%2080delA64,3%C61G53,6%185delAG42,9%3819del532,1%3875del432,1%BRCA2T5286G (c.T5286G:p.Y1762*)42,9%Rare mutations n=43 (30,7%)BRCA12417,1%BRCA21913,6%Exons deletions n=7 (5%)BRCA164,3%BRCA210,7%sBRCAmn=21 (15%)BRCA1139,3%BRCA285,7% Citation Format: Alexandra Tyulyandina, Vera Gorbunova, Svetlana Khokhlova, Larisa Kolomiets, Maksim Filipenko, Evgeny Imyanitov, Irina Demidova, Yuri Moliaka, Nadezhda Cherdyntseva, Dmitriy Vodolajskiy, Ludmila Lyubchenko, Sergei Tjulandin, Ilya Tsimafeyeu, Olga Vedrova, Vera Karaseva, Sergei Andreev, Tatiana Kekeeva. Profile of BRCA1/BRCA2 mutations in Russian ovarian cancer population detected by NGS and MLPA analysis: Interim results of OVATAR study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1241.
The problem of translation of modern achievements of personalized medicine into everyday clinical practice is actively discussed, but far from being resolved. The authors presented the clinical case of adverse course of juvenile myoclonic epilepsy in a 63-year-old woman. The authors emphasized that after the correction of antiepileptic therapy, taking into account the position of personalized medicine, not only achieved pharmacoinduced remission of epileptic seizures, but also significantly improved the quality of life of the patient.
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