A Systematic Review of the Prevalence of Germline BRCA mutations in North Asia Breast Cancer Patients.

OBJECTIVE: The BRCA1/2 mutation status testing is the global standard of care for breast cancer patients with a family history of cancer. BRCA1/2 mutations are known to be ethno-specific. For some ethnic groups of the Northern Asia (Buryats, Yakuts, Altaians, Tuvans, Khakasses, etc.) the founder mutations in the BRCA1/2 genes have not been revealed. This systematic review was conducted to assess the prevalence of BRCA1/2 mutation in breast cancer patients inhabiting Eastern Europe and Northern Asia (or Siberia). METHODS: A total of 23,561 studies published between 2014 and 2024 were analyzed, of which 55 were included in the review. The literature search was conducted using RusMed, Cyberleninka, Google Scholar, eLibrary, NCBI databases (n=5) and conference papers. RESULTS: The founder mutations (c.5266dupC and/or c.181T>G) of BRCA1 gene that were frequently observed in the Slav peoples were also identified in Chechens, Armenians, Bashkirs, Ukrainians, Mordovians, Mari, Kabardians, Tatars, Uzbeks, Kyrgyz, Ossetians, Khanty indigenous peoples and Adygs. For Chechens, Kabardians, Ingush, Buryats, Khakasses, Sakha, Tuvans and Armenians, rare pathogenic variants of the BRCA1/2, ATM, СНЕК2, BRIP1, NBN, PTEN, TP53, PMS1, XPA, LGR4, BRWD1 and PALB2 genes were found. No data are available about the frequency of pathogenic BRCA1/2 mutations for ethnic groups, such as the Udmurts, Komi, Tajiks, Tabasarans, and Nogais indigenous people. CONCLUSION: This is the first systematic review that provides the spectrum of BRCA mutations in ethnic groups of breast cancer patients inhabiting Eastern Europe and Northern Asia. It has been shown that the mutations are ethnospecific (varied widely within groups) and not all groups are equally well studied. Further studies on the ethnic specificity of BRCA gene mutations are required.

Long-term response with the atypical reaction to nivolumab in microsatellite stability metastatic colorectal cancer: A case report.

Immunotherapy has become an integral part of a comprehensive treatment approach to metastatic colorectal cancer (mCRC). Nivolumab (Opdivo) is a human immunoglobulin G4 monoclonal antibody that blocks the interaction between the programmed cell death 1 (PD-1) receptor and its ligands 1/2 (PD-L1/PD-L2), leading to inhibition of T-cell proliferation, cytokine secretion, and enhanced immune response. The US Food and Drug Administration (FDA) has approved this drug for use in high microsatellite instability (MSI-high)/deficiencies in mismatch repair (dMMR) advanced CRC patients. However, its efficacy is extremely limited in microsatellite stability (MSS)/mismatch repair proficient (pMMR) patients. We report a case of a 42-year-old man diagnosed with MSS/pMMR mCRC who has achieved a durable response to nivolumab after a progression under chemotherapy with antiangiogenic treatment. We observed for the first time an atypical response after 8 months of nivolumab treatment, with the regression of previous primary pulmonary lesions and the presence of new para-aortic lymph node lesions. This report demonstrates that a subset of pretreated mCRC patients with the MSS/pMMR phenotype may benefit from nivolumab and these patients need more attention.

Germline variants associated with breast cancer in Khakass women of North Asia.

INTRODUCTION: Variants in the BRCA1/2 genes are responsible for familial breast cancer. Numerous studies showed a different spectrum of BRCA variants among breast cancer patients of different Ethnicity origin. In the available literature, no previous research has focused on breast cancer-associated variants among the Khakass people (the indigenous people of the Russian Federation). METHODS: Twenty-six Khakass breast cancer patients were enrolled in the study. Genomic DNA was isolated from blood samples and used to prepare libraries using a Hereditary Cancer Solution kit. Next-generation sequencing (NGS) was performed using the MiSeq System (Illumina, USA). RESULTS: In our study, 12% of patients (3/26) carried a single pathogenic variant; 54% of patients (14/26) carried variants of uncertain significance (VUS) or conflicting variants; and 35% of patients (9/26) did not carry any clinically significant variants. Germline pathogenic variant in the ATM gene (rs780619951, NC_000011.10:g.108259022C > T) was identified in two unrelated patients with a family history of cancer (7.6%, 2/26). The pathogenic truncating variant in the ATM gene (p. R805* or c.2413C > T) leads to the nonfunctional version of the protein. This variant has been earlier reported in individuals with a family history of breast cancer. CONCLUSIONS: Our pilot study describes the germline variant in the ATM gene associated with breast cancer in Khakass women of North Asia.

Pathogenicity Reclassification of Genetic Variants Related to Early-Onset Breast Cancer among Women of Mongoloid Origin.

BACKGROUND: Germline alterations in BRCA1, BRCA2, and other genes are responsible for early-onset breast cancer. However, up to 20% of molecular tests report genetic variant of unknown significance (VUS) or novel variants that have never been previously described and their clinical significance are unknown. This study aimed to reclassify variant of unknown significance (VUS) or novel variants by using the ActiveDriveDB database that annotates variants through the lens of sites of post-translational modifications (PTM). METHODS: Our study included thirty-eighth young Buryat BC patients, belonging to the Mongoloid race and anthropologically to the Central Asia. Genomic DNA was extracted from the peripheral blood lymphocytes using the phenol/chloroform method. DNA library were prepared using the Hereditary Cancer SolutionTM kit (Sophia GENETICS, Switzerland) to cover 27 genes, such as ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. Paired-end sequencing (2 x 150 bp) was conducted using NextSeq 500 system (Illumina, USA). RESULTS: We re-examined 135 rare variants (41 VUS, 25 conflicting, 64 benign and 5 new variants). We identified 10 out of 135 (7.4%) mutations that affected the sites of post-translational modification in proteins. Of 135 rare mutations, 1 benign variant was reclassified as network-rewiring - motif loss mutation, 3 VUS and 1 new variant were reclassified as distal PTM- mutations, 2 new and 1 benign variant were classified as proximal PTM- mutations and 1 benign and 1 conflicting variant were classified as direct PTM- mutations. CONCLUSIONS: For the first time, 7.4% (10 out of 135) of mutations that affected the sites of post-translational modification in proteins were identified among early-onset breast cancer women of Mongoloid origin.

Role of TGF-ß signaling in the mechanisms of tamoxifen resistance.

The transforming growth factor beta (TGF-ß) signaling pathway plays complex role in the regulation of cell proliferation, apoptosis and differentiation in breast cancer. TGF-ß activation can lead to multiple cellular responses mediating the drug resistance evolution, including the resistance to antiestrogens. Tamoxifen is the most commonly prescribed antiestrogen that functionally involved in regulation of TGF-ß activity. In this review, we focus on the role of TGF-ß signaling in the mechanisms of tamoxifen resistance, including its interaction with estrogen receptors alfa (ERα) pathway and breast cancer stem cells (BCSCs). We summarize the current reported data regarding TGF-ß signaling components as markers of tamoxifen resistance and review current approaches to overcoming tamoxifen resistance based on studies of TGF-ß signaling.

Aberrant Methylation of LINE-1 Transposable Elements: A Search for Cancer Biomarkers.

Cancer remains one of the main causes of human mortality despite significant progress in its diagnostics and therapy achieved in the past decade. Massive hypomethylation of retrotransposons, in particular LINE-1, is considered a hallmark of most malignant transformations as it results in the reactivation of retroelements and subsequent genomic instability. Accumulating data on LINE-1 aberrant methylation in different tumor types indicates its significant role in cancer initiation and progression. However, direct evidence that LINE-1 activation can be used as a cancer biomarker is still limited. The objective of this review was to critically evaluate the published results regarding the diagnostic/prognostic potential of the LINE-1 methylation status in cancer. Our analysis indicates that LINE-1 hypomethylation is a promising candidate biomarker of cancer development, which, however, needs validation in both clinical and laboratory studies to confirm its applicability to different cancer types and/or stages. As LINE-1 is present in multiple cell-free copies in blood, it has advantages over single-copy genes regarding perspectives of using its methylation status as an epigenetic cancer biomarker for cell-free DNA liquid biopsy.

New germline mutations in non-BRCA genes among breast cancer women of Mongoloid origin.

In accordance with the Asian BRCA Consortium data, there is a significant difference in incidence rate of breast cancer depending on age, as well as spectrum and prevalence of BRCA1/2 mutations between Mongoloid (East Asian) and Caucasoid (European) people. However, European strategies to identify familial BC are still applied to the Asian population, including Russian Mongoloids (Khakas, Buryats, Tyvans and Yakuts and others). The main purpose of the study was to identify molecular changes associated with hereditary BC in Russian Mongoloid BC patients (Buryats). Thirty-nine patients were included in the study. Genomic DNA extracted from lymphocytes was used to prepare DNA-libraries. Target sequencing was designed to cover 27 genes, such as ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2 and others. Paired-end sequencing (2 × 150 bp) was conducted on a NextSeq 500 system (Illumina, USA). Three pathogenic mutations in non-BRCA genes were found (prevalence of 8%). The pathogenic mutations were found in the RAD51D and PTEN genes. The pathogenic variant in the RAD51D gene (rs137886232, NC_000017.10:g.33428366G>A, p.R141X) was observed in two unrelated individuals aged under 40. One of these patients had a family history of late-onset stomach cancer in second-degree relatives. The pathogenic mutation in the PTEN gene (rs786201044, NC_000010.10:g.89692922T>C, p.C136R) was observed in a 38 years old breast cancer patient with no family history. In our study, we first describe pathogenic mutations in RAD51D and PTEN genes found in young Buryat patients.

Premalignant lesions of squamous cell carcinoma of the lung: The molecular make-up and factors affecting their progression.

Squamous cell carcinoma (SCC), one of the most common forms of lung cancer, shows accelerated progression and aggressive growth and usually is observed at advanced stages. SCC originates from morphological changes in the bronchial epithelium that occur during chronic inflammation: basal cell hyperplasia, squamous metaplasia, and dysplasia I-III. However, the process is not inevitable; it can be stopped at any stage, remain in the stable state indefinitely and either progress or regress. The reasons and mechanisms of different scenarios of the evolution of premalignant lesions in the respiratory epithelium are not fully understood. In this review, we summarized the literature data (including our own data) regarding genetic, epigenetic, transcriptomic and proteomic profiles of the premalignant lesions and highlighted factors (environmental causes, inflammation, and gene polymorphism) that may govern their progression or regression. In conclusion, we reviewed strategies for lung cancer prevention and proposed new models and research directions for studying premalignant lesions and developing new tools to predict the risk of their malignant transformation.

New germline BRCA2 gene variant in the Tuvinian Mongol breast cancer patients.

To date, there are a limited number of reports on inherited gene mutations associated with breast cancer (BC) among Mongoloid indigenous people in Russia. The present study aimed at identifying the BC-associated genes in 26 Russian Mongoloid BC patients (Buryats, Tuvinians and others). The median age of the patients at the time of breast cancer diagnosis was 41 years (range 25-51 years). Genomic DNA isolated from blood samples was used to prepare libraries using a capture-based target enrichment kit (Hereditary Cancer Solution™, SOPHiA GENETICS, Switzerland) covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). Next-generation sequencing (NGS) was performed on an Illumina NextSeq 500 System (Illumina, USA). In our study, we found 1 Indel and 11 SNPs that passed filters during variant calling. We identified a highly pathogenic germline rs483353122 (c.8208_8209insAG, p.Leu2737Serfs*2) in the BRCA2 gene in six unrelated Tuvinian Mongol BC patients. We also identified a likely damaging germline rs35352891 in the MUTYH gene (c.1118C>T, p.Ala373Val) in one Buryat Mongol BC patient. Other SNPs were classified as variants of uncertain significance. To the best of our knowledge, this report is the first to describe the highly pathogenic variant in the BRCA2 gene (rs483353122) and the likely damaging germline variant in the MUTYH gene (rs35352891) in Russian Mongoloid BC patients with young-onset and/or bilateral and/or familial BC. Further studies are therefore necessary to evaluate the contributions of novel sequence variants to hereditary BC.

New variants in the BRCA1 gene in Buryat Mongol breast cancer patients: Report from two families.

BACKGROUND: The BRCA1 mutations that are endemic to the Slavic population of Russia have not been identified among indigenous peoples, including the Buryats, Tuvinians and Altaians with hereditary breast cancer. OBJECTIVE: This study was aimed to identify the mutations that are responsible for the occurrence of hereditary breast cancer in the indigenous population of the Republic of Buryatia. METHODS: Mutations in the BRCA1 gene were identified in blood samples by Sanger-based sequencing. RESULTS: We identified 11 polymorphisms (10 SNPs and 1 Indel) and 6 new unclassified sequence variants in the BRCA1 gene. In our study three new sequence variants (c.321T>A, c.366T>A, c.4357+2T>A) were found in position of previously described polymorphisms in dbSNPs: rs80357544 (c.321delT), rs190900046 (c.366T>G), and rs80358152 (c.4357+2T>C), respectively. Other three new sequence variants (c.3605A>G, c.1998A>C, and c.80+13A>C) have not been previously described in dbSNP, BIC and Human Gene Mutation Databases. CONCLUSIONS: We described six new sequence variants that have never been published in the literature or databases. Further studies are required to confirm the impact of new sequence variants on the risk of breast cancer in the Buryat Mongol population.

Distribution of EGFR Mutations in 10,607 Russian Patients with Lung Cancer.

INTRODUCTION: This study was aimed to evaluate distribution of epidermal growth factor receptor (EGFR) mutations in a large series of Russian lung cancer (LC) patients. METHODS: 10,607 LC samples were considered for EGFR analysis; EGFR status was successfully determined in 10,426 cases (98.3 %), indicating relatively low failure rate. RESULTS: EGFR mutations (ex19del and L858R) were detected in 1759/8716 (20.2 %) adenocarcinomas, 28/669 (4.2 %) squamous cell carcinomas (SCC) and 8/119 (6.7 %) large cell carcinomas. The occurrence of EGFR mutations in adenocarcinomas gradually increased with age, being attributed mainly to the increment of the L858R frequency in non-smokers (patients aged 18-30 years: 1/27 (3.7 %); 31-40 years: 5/98 (5.1 %); 41-50 years: 18/276 (6.5 %); 51-60 years: 102/944 (10.8 %); 61-70 years: 138/1011 (13.7 %); 71-80 years: 85/496 (17.1 %); 81-100 years: 5/27 (18.5 %); p < 0.0001). The EGFR mutation was detected in 804/2107 (38.2 %) non-smoking women versus 125/806 (15.5 %) non-smoking men (p < 0.0001), while the corresponding figures for smokers were 60/273 (22.0 %) versus 147/2214 (6.6 %) (p < 0.0001). The obtained gender-related data differ from the estimates obtained in Asian studies; they indicate that increased prevalence of EGFR mutations in white females may not be entirely attributed to the low prevalence of smoking, but is likely to be related to gender factors per se. CONCLUSION: Biological causes of distinct age- and gender-related distribution of EGFR mutations in LC deserve further investigation.

Regulatory single nucleotide polymorphisms at the beginning of intron 2 of the human KRAS gene.

There are two regulatory single nucleotide polymorphisms (rSNPs) at the beginning of the second intron of the mouse K-ras gene that are strongly associated with lung cancer susceptibility. We performed functional analysis of three SNPs (rs12228277: T greater than A, rs12226937: G greater than A, and rs61761074: T greater than G) located in the same region of human KRAS. We found that rs12228277 and rs61761074 result in differential binding patterns of lung nuclear proteins to oligonucleotide probes corresponding two alternative alleles; in both cases, the transcription factor NF-Y is involved. G greater than A substitution (rs12226937) had no effect on the binding of lung nuclear proteins. However, all the nucleotide substitutions under study showed functional effects in a luciferase reporter assay. Among them, rs61761074 demonstrated a significant correlation with allele frequency in non-small-cell lung cancer (NSCLC). Taken together, the results of our study suggest that a T greater than G substitution at nucleotide position 615 in the second intron of the KRAS gene (rs61761074) may represent a promising genetic marker of NSCLC.

Frequency of EGFR mutations in non-small cell lung cancer patients: screening data from West Siberia.

BACKGROUND: Incorporation of molecular analysis of the epidermal growth factor receptor (EGFR) gene into routine clinical practice has shown great promise to provide personalized therapy of the non-small cell lung cancer (NSCLC) in the developed world. However, the genetic testing of EGFR mutations has not yet become routine clinical practice in territories remote from the central regions of Russia. Therefore, we aimed to study the frequency of major types of activating mutations of the EGFR gene in NSCLC patients residing in West Siberia. MATERIALS AND METHODS: We examined EGFR mutations in exons 19 and 21 in 147 NSCLC patients (excluding squamous cell lung carcinomas) by real time polymerase chain reaction. RESULTS: EGFR mutations were detected in 28 of the 147 (19%) patients. There were 19 (13%) cases with mutations in exon 19 and 9 cases (6%) in exon 21. Mutations were more frequently observed in women (42%, p=0.000) than in men (1%). A significantly higher incidence of EGFR mutations was observed in bronchioloalveolar carcinomas (28%, p=0.019) and in adenocarcinomas (21%, p=0.024) than in large cell carcinomas, mixed adenocarcinomas, and NOS (4%). The EGFR mutation rate was much higher in never-smokers than in smokers: 38% vs. 3% (p=0.000). The frequency of EGFR mutations in the Kemerovo and Tomsk regions was 19%. CONCLUSIONS: The incorporation of molecular analysis of the EGFR gene into routine clinical practice will allow clinicians to provide personalised therapy, resulting in a significant increase in survival rates and improvement in life quality of advanced NSCLC patients.

The effect of folate-related SNPs on clinicopathological features, response to neoadjuvant treatment and survival in pre- and postmenopausal breast cancer patients.

This study aimed to investigate the relationship of ten single nucleotide polymorphisms (SNPs) in the MTHFR, MTR, MTRR, DHFR, MTHFD1, TS, RFC1 and DNMT3b genes with cancer survival, therapeutic response to neoadjuvant chemotherapy and clinicopathological characteristics in 300 pre- and postmenopausal breast cancer patients of a Russian Western Siberian population. We found that the MTHFR 677CT genotype as well as combination of MTHFR 677CT and 677TT genotype was related to tumor size and estrogen-positive status in postmenopausal group. The RFC1 80А allele was associated with an increased risk of lymph node metastases among postmenopausal women. The MTHFR 677TT genotype was significantly correlated with a better progression-free survival in premenopausal patients. In contrast, a worse outcome was observed in this group patient with MTHFD1 1958AA genotype. In the multivariate analysis, the MTHFD1 1958AA genotype was identified as an independent prognostic factor for premenopausal breast cancer survival. Our findings provide evidence for associations of breast cancer survival with folate-related SNPs in a population of Western Siberian region of Russia and the MTHFD1 (1958G>A) may have additional prognostic value especially among premenopausal patients.

Effect of tocopherol-monoglucoside (TMG), a water-soluble glycosylated derivate of vitamin E, on hematopoietic recovery in irradiated mice.

A preparation of alpha-tocopherol monoglucoside (TMG) administered i.p. at a dose of 600 mg/kg immediately after whole body gamma irradiation was examined for its radioprotective efficacy towards bone marrow and peripheral blood nucleated cells. When mice received X-rays at a dose of 5,6 Gy, a marked decrease in bone marrow karyocytes and a reduction of peripheral leukocytes within the early post-irradiated period were observed. However these changes were attenuated in TMG-treated mice. Significant protection of blood lymphocytes was found for the TMG group of mice. The return to normal value of the reduced blood leukocyte count starting from the 8th day was more rapid in TMG-treated mice than in untreated irradiated mice. TMG administration was found to enhance hematopoietic recovery, as measured by the exceeded nucleated bone marrow cell count due to elevated amount of both lymphoid and granulocytic elements in the TMG-group, in comparison with that of both control irradiated and non-irradiated animals. These findings indicate that the radioprotective effect of TMG is apparently realized through its influence on hematopoietic system.