Publications by authors named "Svetlana N Aleksakhina"

24 Publications

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Somatic loss of the remaining allele occurs approximately in half of CHEK2-driven breast cancers and is accompanied by a border-line increase of chromosomal instability.

Breast Cancer Res Treat 2022 Jan 12. Epub 2022 Jan 12.

N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758.

Purpose: Germline mutations in CHEK2 gene represent the second most frequent cause of hereditary breast cancer (BC) after BRCA1/2 lesions. This study aimed to identify the molecular characteristics of CHEK2-driven BCs.

Methods: Loss of heterozygosity (LOH) for the remaining CHEK2 allele was examined in 50 CHEK2-driven BCs using allele-specific PCR assays for the germline mutations and analysis of surrounding single-nucleotide polymorphisms (SNPs). Paired tumor and normal DNA samples from 25 cases were subjected to next-generation sequencing analysis.

Results: CHEK2 LOH was detected in 28/50 (56%) BCs. LOH involved the wild-type allele in 24 BCs, mutant CHEK2 copy was deleted in 3 carcinomas, while in one case the origin of the deleted allele could not be identified. Somatic PIK3CA and TP53 mutations were present in 13/25 (52%) and 4/25 (16%) tumors, respectively. Genomic features of homologous recombination deficiency (HRD), including the HRD score ≥ 42, the predominance of BRCA-related mutational signature 3, and the high proportion of long (≥ 5 bp) indels, were observed only in 1/20 (5%) BC analyzed for chromosomal instability. Tumors with the deleted wild-type CHEK2 allele differed from LOH-negative cases by elevated HRD scores (median 23 vs. 7, p = 0.010) and higher numbers of chromosomal segments affected by copy number aberrations (p = 0.008).

Conclusion: Somatic loss of the wild-type CHEK2 allele is observed in approximately half of CHEK2-driven BCs. Tumors without CHEK2 LOH are chromosomally stable. BCs with LOH demonstrate some signs of chromosomal instability; however, its degree is significantly lower as compared to BRCA1/2-associated cancers.
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http://dx.doi.org/10.1007/s10549-022-06517-3DOI Listing
January 2022

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives.

Int J Mol Sci 2021 Oct 10;22(20). Epub 2021 Oct 10.

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 Saint-Petersburg, Russia.

The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.
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http://dx.doi.org/10.3390/ijms222010931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536080PMC
October 2021

Efficacy of lorlatinib in lung carcinomas carrying distinct ALK translocation variants: The results of a single-center study.

Transl Oncol 2021 Aug 21;14(8):101121. Epub 2021 May 21.

I.P. Pavlov St.-Petersburg State Medical University, St.-Petersburg 197022, Russia; Institute of Medical Primatology, Sochi 354376, Russia; N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; St.-Petersburg State Pediatric Medical University, St.-Petersburg 194100, Russia; I.I. Mechnikov North-Western Medical University, St.-Petersburg 191015, Russia.

Background: Lorlatinib is a novel potent ALK inhibitor, with only a few studies reporting the results of its clinical use.

Methods: This study describes the outcomes of lorlatinib treatment for 35 non-small cell lung cancer patients with ALK rearrangements, who had 2 (n = 5), 1 (n = 26) or none (n = 4) prior tyrosine kinase inhibitors and received lorlatinib mainly within the compassionate use program.

Results: Objective tumor response (OR) and disease control (DC) were registered in 15/35 (43%) and 33/35 (94%) patients, respectively; brain metastases were particularly responsive to the treatment (OR: 22/27 (81%); DC: 27/27 (100%)). Median progression free survival (PFS) was estimated to be 21.8 months, and median overall survival (OS) approached to 70.1 months. Only 4 out of 35 patients experienced no adverse effects; two of them were the only subjects who had no clinical benefit from lorlatinib. PFS and OS in the no-adverse-events lorlatinib users were strikingly lower as compared to the remaining patients (1.1 months vs. 23.7 months and 10.5 months vs. not reached, respectively; p < 0.0001 for both comparisons). ALK translocation variants were known for 28 patients; there was no statistical difference between patients with V.1 and V.3 rearrangements with regard to the OS or PFS.

Conclusion: Use of lorlatinib results in excellent disease outcomes, however caution must be taken for patients experiencing no adverse effects from this drug.
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http://dx.doi.org/10.1016/j.tranon.2021.101121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144735PMC
August 2021

Revisiting multiple erroneous genetic testing results and clinical misinterpretations in a patient with Li-Fraumeni syndrome: lessons for translational medicine.

Hered Cancer Clin Pract 2021 Jan 6;19(1). Epub 2021 Jan 6.

N.N. Petrov Institute of Oncology, Pesochniy, Saint-Petersburg, 197758, Russia.

Background: Many cancer patients undergo sophisticated laboratory testing, which requires proper interpretation and interaction between different specialists.

Case Presentation: We describe a patient with an extensive family history of cancer, who was diagnosed with bilateral breast cancer and two lung cancer lumps by the age of 40 years. She submitted a lung cancer specimen to a genetic profiling service, which reported the presence of the EGFR mutation (a combination of G719S and L833V substitutions) and the TP53 с.322_327del (p.G108_F109del) mutation in the tumor tissue. Possible therapeutic options were discussed at a medical conference, where one of the discussants raised a concern that the identified TP53 mutation may not necessarily be somatic, but reflect the germ-line status of the gene. Review of clinical records and follow-up dialog with the patient revealed, that she previously provided her blood for DNA analysis in two laboratories. The first laboratory utilized a custom NGS assay and did not detect the TP53 mutation, instead pointed to a potential pathogenic significance of the MSH6 c.2633 T > C (p.V878A) allele. The second laboratory revealed the TP53 с.322_327del (p.G108_F109del) allele but stated in the written report that it has an unknown pathogenic significance. To resolve the possible uncertainty regarding the role of the TP53 с.322_327del (p.G108_F109del) variant, we suggested that the patient invite her second cousin for genetic testing, as she was affected by neuroblastoma at the age of 3 years. This analysis revealed the presence of the same TP53 variant.

Conclusion: We provide point-by-point discussion, reviewing multiple laboratory mistakes and clinical misinterpretations occurred with this patient. This case report exemplifies the need to involve rigorous clinical expertise in the daily practice of medical laboratory facilities.
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http://dx.doi.org/10.1186/s13053-020-00157-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789132PMC
January 2021

Frequency and spectrum of founder and non-founder BRCA1 and BRCA2 mutations in a large series of Russian breast cancer and ovarian cancer patients.

Breast Cancer Res Treat 2020 Nov 9;184(1):229-235. Epub 2020 Aug 9.

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia.

Background: The spectrum of BRCA1 and BRCA2 mutations in Slavic countries is characterized by a high prevalence of founder alleles.

Methods: We analyzed a large data set of Russian breast cancer (BC) and ovarian cancer (OC) patients, who were subjected to founder mutation tests or full-length BRCA1 and BRCA2 analysis.

Results: The most commonly applied test, which included four founder mutations (BRCA1: 5382insC, 4153delA, 185delAG; BRCA2: 6174delT), identified BRCA1 or BRCA2 heterozygosity in 399/8533 (4.7%) consecutive BC patients, 230/2317 (9.9%) OC patients, and 30/118 (25.4%) women with a combination of BC and OC. The addition of another four recurrent BRCA1 mutations to the test (BRCA1 C61G, 2080delA, 3819del5, 3875del4) resulted in evident increase in the number of identified mutation carriers (BC: 16/993 (1.6%); OC: 34/1289 (2.6%); BC + OC: 2/39 (5.1%)). Full-length sequencing of the entire BRCA1 and BRCA2 coding region was applied to 785 women, very most of whom demonstrated clinical signs of BRCA-driven disease, but turned out negative for all described above founder alleles. This analysis revealed additional BRCA1 or BRCA2 mutation carriers in 54/282 (19.1%) BC, 50/472 (10.6%) OC, and 13/31 (42%) BC + OC patients. The analysis of frequencies of founder and "rare" BRCA1 and BRCA2 pathogenic alleles across various clinical subgroups (BC vs. OC vs. BC + OC; family history positive vs. negative; young vs. late-onset; none vs. single vs. multiple clinical indicators of BRCA1- or BRCA2-associated disease) revealed that comprehensive BRCA1 and BRCA2 analysis increased more than twice the number of identified mutation carriers in all categories of the examined women.

Conclusion: Full-length BRCA1 and BRCA2 sequencing is strongly advised to Slavic subjects, who have medical indications for BRCA1 and BRCA2 testing but are negative for recurrent BRCA1 and BRCA2 mutations.
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http://dx.doi.org/10.1007/s10549-020-05827-8DOI Listing
November 2020

Small fraction of testicular cancer cases may be causatively related to CHEK2 inactivating germ-line mutations: evidence for somatic loss of the remaining CHEK2 allele in the tumor tissue.

Fam Cancer 2021 01;20(1):49-53

N.N. Petrov Institute of Oncology, Leningradskaya, 68, Pesochny-2, St.-Petersburg, Russia, 197758.

A recent study suggested a role of CHEK2 loss-of-function germ-line pathogenic variants in the predisposition to testicular cancer (TC) (AlDubayan et al. JAMA Oncol 5:514-522, 2019). We attempted to validate this finding relying on the high population frequency of recurrent CHEK2 pathogenic variants in Slavic populations. CHEK2 pathogenic alleles (c.1100delC (p.Thr367Metfs); del5395 [del ex9-10]; IVS2 + 1G > A [c.444 + 1G > A]) were detected in 7/280 (2.5%) TC patients vs. 3/424 (0.7%) healthy men and 6/1007 (0.6%) healthy women [OR 4.0 (95% CI 1.5-11), p = 0.009 for pooled control groups]. Somatic CHEK2 loss-of-heterozygosity (LOH) was detected in 4 out of 6 tumors available for analysis; strikingly all these instances of LOH involved inactivation of the wild-type allele. The CHEK2 c.470T > C (p.Ile157Thr) variant was detected in 21/280 (7.5%) affected vs. 22/424 (5.2%) non-affected men [OR 1.5 (95% CI 0.8-2.7), p = 0.3]. Somatic CHEK2 LOH was revealed only in 6 out of 21 tumors obtained from CHEK2 c.470T > C (p.Ile157Thr) carriers, with the C-allele lost in two cases and T-allele deleted in four tumors. The results of comparison of allele frequencies in TC patients versus population controls coupled with the data on CHEK2 LOH status in tumor tissues support the association of CHEK2 pathogenic variants with TC risk.
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http://dx.doi.org/10.1007/s10689-020-00190-5DOI Listing
January 2021

Exome sequencing study of Russian breast cancer patients suggests a predisposing role for USP39.

Breast Cancer Res Treat 2020 Feb 21;179(3):731-742. Epub 2019 Nov 21.

Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Pesochny-2, St.-Petersburg, Russia, 197758.

Purpose: Germline variants in known breast cancer (BC) predisposing genes explain less than half of hereditary BC cases. This study aimed to identify missing genetic determinants of BC.

Methods: Whole exome sequencing (WES) of lymphocyte DNA was performed for 49 Russian patients with clinical signs of genetic BC predisposition, who lacked Slavic founder mutations in BRCA1, BRCA2, CHEK2, and NBS1 genes.

Results: Bioinformatic analysis of WES data was allowed to compile a list of 229 candidate mutations. 79 of these mutations were subjected to a three-stage case-control analysis. The initial two stages, which involved up to 797 high-risk BC patients, 1504 consecutive BC cases, and 1081 healthy women, indicated a potentially BC-predisposing role for 6 candidates, i.e., USP39 c.*208G > C, PZP p.Arg680Ter, LEPREL1 p.Pro636Ser, SLIT3 p.Arg154Cys, CREB3 p.Lys157Glu, and ING1 p.Pro319Leu. USP39 c.*208G > C was strongly associated with triple-negative breast tumors (p = 0.0001). In the third replication stage, we genotyped the truncating variant of PZP (rs145240281) and the potential splice variant of USP39 (rs112653307) in three independent cohorts of Russian, Byelorussian, and German ancestry, comprising a total of 3216 cases and 2525 controls. The data obtained for USP39 rs112653307 supported the association identified in the initial stages (the combined OR 1.72, p = 0.035).

Conclusions: This study suggests the role of a rare splicing variant in BC susceptibility. USP39 encodes an ubiquitin-specific peptidase that regulates cancer-relevant tumor suppressors including CHEK2. Further epidemiological and functional studies involving these gene variants are warranted.
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http://dx.doi.org/10.1007/s10549-019-05492-6DOI Listing
February 2020

The spectrum of Lynch syndrome-associated germ-line mutations in Russia.

Eur J Med Genet 2020 Mar 3;63(3):103753. Epub 2019 Sep 3.

St.-Petersburg Pediatric Medical University, 194100, Russia; N.N. Petrov Institute of Oncology, 197758, Russia; I.I. Mechnikov North-Western Medical University, 191015, Russia; St.-Petersburg State University, 199034, St.-Petersburg, Russia.

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome (LS), is a common cancer-predisposing syndrome. This study aimed to investigate the spectrum of germ-line mutations in Russian LS patients. LS-related mismatch repair (MMR) genes were analyzed in 16 patients, who were forwarded to genetic testing due to strong clinical features of LS and had high-level microsatellite instability (MSI-H) in the tumor (n = 14) or unknown MSI status (n = 2). In addition, 672 consecutive colorectal cancer (CRC) cases were screened for family history; 15 patients were younger than 50 years and reported 2 or more instances of LS-related cancers in 1st- or 2nd-degree relatives. Seven of these cases demonstrated MSI-H and therefore were subjected to DNA germ-line testing. Overall, 17/23 (74%) subjects carried LS-associated gene variants (MLH1: 10; MSH2: 4; MSH6: 2; PMS2: 1), with 2 alleles (MLH1 c.677G > T and MSH2 с.1906G > C) detected twice. Testing for recurrent mutations of 30 consecutive MSI-H CRCs led to the identification of 2 additional subjects with LS. The analysis of all relevant publications identified 28 unrelated LS patients presented in Russian medical literature and 3 unrelated Russian LS subjects described in international journals. Overall, 15/49 (31%) genetic defects revealed in Russian LS patients were represented by six recurrent alleles (MLH1: c.350C > T, c.677G > T, c.1852_1854del; MSH2: c.942+3A > T, c.1861C > T, с.1906G > C). We conclude that the founder effect for LS in Russia is seemingly less pronounced than the one for hereditary breast-ovarian cancer syndrome, however testing for recurrent LS mutations may be considered feasible in some circumstances.
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http://dx.doi.org/10.1016/j.ejmg.2019.103753DOI Listing
March 2020

Mechanisms of acquired tumor drug resistance.

Biochim Biophys Acta Rev Cancer 2019 12 20;1872(2):188310. Epub 2019 Aug 20.

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia; Department of Oncology, I.I. Mechnikov North-Western Medical University, St.-Petersburg 195067, Russia. Electronic address:

Systemic therapy often results in the reduction of tumor size but rarely succeeds in eradicating all cancer cells. Drug efflux, persistence of cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) and down-regulation of apoptosis are the most known general causes of therapy failure. Tumor escape from targeted compounds often involves pathway-specific mechanisms, which result in the restoration of the affected signaling cascade. The acquisition of drug resistance is mediated by mutations, changes in gene expression, alternative splicing, post-translational protein modifications, etc. Development of resistance to therapy may not necessary involve the emergence of new tumor clones: multiple studies demonstrate that even chemonaive neoplasms already have a small population of cells, which are capable of surviving therapeutic pressure and facilitating the disease progression. Use of combinations of cancer drugs, sequential therapy, adaptive therapy and topical ablation of drug-resistant malignant lumps may help to prolong the time to treatment failure. Many studies on mechanisms of drug resistance rely on the use of cell cultures and animal models. The development of approaches that allow efficient monitoring of the evolution of tumor phenotype in clinical setting presents a challenge.
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http://dx.doi.org/10.1016/j.bbcan.2019.188310DOI Listing
December 2019

Lack of Response to Vemurafenib in Melanoma Carrying BRAF K601E Mutation.

Case Rep Oncol 2019 May-Aug;12(2):339-343. Epub 2019 May 16.

N.N. Petrov Institute of Oncology, Saint Petersburg, Russian Federation.

Vemurafenib has been developed to target common BRAF mutation V600E. It also exerts activity towards some but not all rare BRAF substitutions. Proper cataloguing of drug-sensitive and -insensitive rare mutations remains a challenge, due to low occurrence of these events and inability of commercial PCR-based diagnostic kits to detect the full spectrum of BRAF gene lesions. We considered the results of BRAF exon 15 testing in 1872 consecutive melanoma patients. BRAF mutation was identified in 1,090 (58.2%) cases. While drug-sensitive codon 600 substitutions constituted the majority of BRAF gene lesions (V600E: 962 [51.4%]; V600K: 86 [4.6%]; V600R: 17 [0.9%]), the fourth common BRAF allele was K601E accounting for 9 (0.5%) melanoma cases. The data on BRAF inhibitor sensitivity of tumors with K601E substitution are scarce. We administered single-agent vemurafenib to a melanoma patient carrying BRAF K601E mutation as the first-line treatment. Unfortunately, this therapy did not result in a tumor response. Taken together with already published data, this report indicates lack of benefit from conventional BRAF inhibitors in patients with BRAF K601E mutated melanoma.
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http://dx.doi.org/10.1159/000500481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547278PMC
May 2019

Lack of Response to Imatinib in Melanoma Carrying Rare Mutation p.T632I.

Case Rep Oncol 2019 Jan-Apr;12(1):109-112. Epub 2019 Jan 23.

Department of Tumor Growth Biology, N.N. Petrov National Medical Research Center of Oncology, Saint Petersburg, Russian Federation.

Approximately 15% of acral and mucous melanomas carry activating mutations in oncogene. There is a diversity of spectrum of mutations, with some of them rendering tumors responsive to imatinib, while others being imatinib-resistant or not studied yet. Here we present an acral melanoma patient with р.T632I mutation, who failed to respond to imatinib.
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http://dx.doi.org/10.1159/000495782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477486PMC
January 2019

Exome-based search for recurrent disease-causing alleles in Russian population.

Eur J Med Genet 2019 Jul 24;62(7):103656. Epub 2019 Apr 24.

St. Petersburg Pediatric Medical University, 194100, St. Petersburg, Russia; N.N. Petrov Institute of Oncology, 197758, St. Petersburg, Russia; I.I. Mechnikov North-Western Medical University, 191015, St. Petersburg, Russia; St. Petersburg State University, 199034, St. Petersburg, Russia.

Exomes of 27 Russian subjects were analyzed for the presence of medically relevant alleles, such as protein-truncating variants (PTVs) in known recessive disease-associated genes and pathogenic missense mutations included in the ClinVar database. 36 variants (24 PTVs and 12 amino acid substitutions) were identified and then subjected to the analysis in 897 population controls. 9/36 mutations were novel, however only two of them (POLH c.490delG associated with xeroderma pigmentosum variant (XPV) and CATSPER1 c.859_860delCA responsible for spermatogenic failure) were shown to be recurrent. 27 out of 36 pathogenic alleles were already described in prior genetic studies; seven of them occurred only in the index cases, while 20 demonstrated evidence for persistence in Russian population. In particular, non-random occurrence was revealed for SERPINA1 c.1096G > A (alpha-1 antitrypsin deficiency), C8B c.1282C > T and c.1653G > A (complement component 8B deficiency), ATP7B c.3207C > A (Wilson disease), PROP1 c.301_302delAG (combined pituitary hormone deficiency), CYP21A2 c.844G > T (non-classical form of adrenogenital syndrome), EYS c.1155T > A (retinitis pigmentosa), HADHA c.1528G > C (LCHAD deficiency), SCO2 c.418G > A (cytochrome c oxidase deficiency), OTOA c.2359G > T (sensorineural deafness), C2 c.839_866del (complement component 2 deficiency), ACADVL c.848T > C (VLCAD deficiency), TGM5 c.337G > T (acral peeling skin syndrome) and VWF c.2561 G > A (von Willebrand disease, type 2N). These data deserve to be considered in future medical genetic activities.
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http://dx.doi.org/10.1016/j.ejmg.2019.04.013DOI Listing
July 2019

First-Line Cetuximab Monotherapy in KRAS/NRAS/BRAF Mutation-Negative Colorectal Cancer Patients.

Clin Drug Investig 2018 Jun;38(6):553-562

City Cancer Center, Saint Petersburg, 197758, Russia.

Background: Colorectal carcinomas (CRCs) are sensitive to treatment by anti-epidermal growth factor receptor (EGFR) antibodies only if they do not carry activating mutations in down-stream EGFR targets (KRAS/NRAS/BRAF). Most clinical trials for chemo-naive CRC patients involved combination of targeted agents and chemotherapy, while single-agent cetuximab or panitumumab studies included either heavily pretreated patients or subjects who were not selected on the basis of molecular tests. We hypothesized that anti-EGFR therapy would have significant efficacy in chemo-naive patients with KRAS/NRAS/BRAF mutation-negative CRC.

Methods: Nineteen patients were prospectively included in the study.

Results: Two (11%) patients experienced partial response (PR) and 11 (58%) subjects showed stable disease (SD). Median time to progression approached 6.1 months (range 1.6-15.0 months). Cetuximab efficacy did not correlate with RNA expression of EGFR and insulin-like growth factor 2 (IGF2). Only one tumor carried PIK3CA mutation, and this CRC responded to cetuximab. Exome analysis of patients with progressive disease (PD) revealed 1 CRC with high-level microsatellite instability and 1 instance of HER2 oncogene amplification; 3 of 4 remaining patients with PD had allergic reactions to cetuximab, while none of the subjects with PR or SD had this complication. Comparison with 19 retrospective KRAS/NRAS/BRAF mutation-negative patients receiving first-line fluoropyrimidines revealed no advantages or disadvantages of cetuximab therapy.

Conclusions: Cetuximab demonstrates only modest efficacy when given as a first-line monotherapy to KRAS/NRAS/BRAF mutation-negative CRC patients. It is of question, why meticulous patient selection, which was undertaken in the current study, did not result in the improvement of outcomes of single-agent cetuximab treatment.
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http://dx.doi.org/10.1007/s40261-018-0629-1DOI Listing
June 2018

Survival Outcomes in EGFR Mutation-Positive Lung Cancer Patients Treated with Gefitinib until or beyond Progression.

Oncol Res Treat 2016 15;39(10):605-614. Epub 2016 Sep 15.

City Cancer Center, St.-Petersburg, Russia.

Background: Discontinuation of gefitinib treatment is often accompanied by a disease flare. Some studies have demonstrated a benefit of the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) beyond progression; however, long-term results of these investigations remain limited.

Patients And Methods: We observed 70 patients with EGFR-mutated (EGFR-M+) non-small cell lung cancer (NSCLC) receiving single-agent gefitinib in a routine clinical setting; 56 patients were experiencing RECIST progression at the time of the analysis.

Results: There was a significant increase (p = 0.00001) in overall survival (OS) in patients continuing on gefitinib beyond progression (n = 21; median duration of continued gefitinib use: 4.2 months; median OS: not reached; expected OS: 29.7 months) as compared to those who stopped gefitinib treatment upon disease progression (n = 35; median OS: 14.0 months). The association between extended gefitinib use and improved OS remained true in multivariate Cox regression analysis (hazard ratio = 4.49, 95% confidence interval 1.25-16.09; p = 0.021). Patient selection bias constitutes an essential limitation of this clinical observational study, given that patients with a more favorable disease course and/or high initial tumor sensitivity to TKI treatment were more likely to be considered for prolonged gefitinib use.

Conclusion: This study confirms that continued administration of gefitinib beyond progression is a viable treatment option for some patients with EGFR-M+ NSCLC, in particular those who cannot be rescued by novel EGFR mutation-specific inhibitors such as osimertinib.
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http://dx.doi.org/10.1159/000449024DOI Listing
March 2017

BRAF and NRAS mutations in Russian melanoma patients: results of a nationwide study.

Melanoma Res 2016 10;26(5):442-7

aDepartment of Pathology, Russian Medical Academy for Postgraduate Education, Moscow bDepartment of Tumor Growth Biology, N.N. Petrov Research Institute of Oncology cBiological and Medical Faculties, St-Petersburg State University dDepartment of Clinical Genetics, St-Petersburg Pediatric Medical University eDepartment of Oncology, I.I. Mechnikov North-Western Medical University, St-Petersburg, Russia.

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http://dx.doi.org/10.1097/CMR.0000000000000278DOI Listing
October 2016

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

Mol Diagn Ther 2016 08;20(4):401-6

N.N. Blokhin Cancer Center, Moscow, 115478, Russia.

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.
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http://dx.doi.org/10.1007/s40291-016-0213-4DOI Listing
August 2016

High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation.

Cancer Lett 2015 Dec 2;369(2):363-7. Epub 2015 Sep 2.

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St. Petersburg 197758, Russia; Department of Medical Genetics, St. Petersburg Pediatric Medical University, St. Petersburg 194100, Russia; Department of Oncology, I.I. Mechnikov North-Western Medical University, St. Petersburg 191015, Russia; Department of Oncology, St. Petersburg State University, St. Petersburg 199034, Russia. Electronic address:

Preoperative therapy provides an advantage for clinical drug assessment, as it involves yet untreated patients and facilitates access to the post-treatment biological material. Testing for Slavic founder BRCA mutations was performed for 225 ovarian cancer (OC) patients, who were treated by platinum-based neoadjuvant therapy. 34 BRCA1 and 1 BRCA2 mutation carriers were identified. Complete clinical response was documented in 12/35 (34%) mutation carriers and 8/190 (4%) non-carriers (P = 0.000002). Histopathologic response was observed in 16/35 (46%) women with the germ-line mutation versus 42/169 (25%) patients with the wild-type genotype (P = 0.02). Somatic loss of heterozygosity (LOH) for the remaining wild-type BRCA1 allele was detected only in 7/24 (29%) post-neoadjuvant therapy residual tumor tissues as compared to 9/11 (82%) BRCA1-associated OC, which were not exposed to systemic treatment before the surgery (P = 0.009). Furthermore, comparison of pre- and post-treatment tumor material obtained from the same patients revealed restoration of BRCA1 heterozygosity in 2 out of 3 sample pairs presenting with LOH at diagnosis. The obtained data confirm high sensitivity of BRCA-driven OC to platinating agents and provide evidence for a rapid selection of tumor cell clones without LOH during the course of therapy.
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http://dx.doi.org/10.1016/j.canlet.2015.08.028DOI Listing
December 2015

BRAF-mutated clear cell sarcoma is sensitive to vemurafenib treatment.

Invest New Drugs 2015 Oct 20;33(5):1136-43. Epub 2015 Aug 20.

Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Pesochny-2, 197758, St.-Petersburg, Russia.

We report a patient with a metastatic relapse of clear cell sarcoma, whose tumor harbored BRAF V600E mutation. Standard chemotherapy with doxorubicin and ifosfamide failed to slow the disease progression. Subsequent administration of vemurafenib (960 mg twice a day) resulted in complete tumor response after 8 weeks of treatment. Literature data on the use of vemurafenib and dabrafenib in non-melanoma BRAF-mutated tumors are reviewed.
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http://dx.doi.org/10.1007/s10637-015-0280-0DOI Listing
October 2015

Novel ALK fusion partners in lung cancer.

Cancer Lett 2015 Jun 23;362(1):116-21. Epub 2015 Mar 23.

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia; Department of Oncology, I.I. Mechnikov North-Western Medical University, St.-Petersburg 191015, Russia. Electronic address:

Detection of ALK rearrangements in patients with non-small cell lung cancer (NSCLC) presents a significant technical challenge due to the existence of multiple translocation partners and break-points. To improve the performance of PCR-based tests, we utilized the combination of 2 assays, i.e. the variant-specific PCR for the 5 most common ALK rearrangements and the test for unbalanced 5'/3'-end ALK expression. Overall, convincing evidence for the presence of ALK translocation was obtained for 34/400 (8.5%) cases, including 14 EML4ex13/ALKex20, 12 EML4ex6/ALKex20, 3 EML4ex18/ALKex20, 2 EML4ex20/ALKex20 variants and 3 tumors with novel translocation partners. 386 (96.5%) out of 400 EGFR mutation-negative NSCLCs were concordant for both tests, being either positive (n = 26) or negative (n = 360) for ALK translocation; 49 of these samples (6 ALK+, 43 ALK-) were further evaluated by FISH, and there were no instances of disagreement. Among the 14 (3.5%) "discordant" tumors, 5 demonstrated ALK translocation by the first but not by the second PCR assay, and 9 had unbalanced ALK expression in the absence of known ALK fusion variants. 5 samples from the latter group were subjected to FISH, and the presence of translocation was confirmed in 2 cases. Next generation sequencing analysis of these 2 samples identified novel translocation partners, DCTN1 and SQSTM1; furthermore, the DCTN1/ALK fusion was also found in another NSCLC sample with unbalanced 5'/3'-end ALK expression, indicating a recurrent nature of this translocation. We conclude that the combination of 2 different PCR tests is a viable approach for the diagnostics of ALK rearrangements. Systematic typing of ALK fusions is likely to reveal new NSCLC-specific ALK partners.
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http://dx.doi.org/10.1016/j.canlet.2015.03.028DOI Listing
June 2015

Candidate gene analysis of BRCA1/2 mutation-negative high-risk Russian breast cancer patients.

Cancer Lett 2015 Apr 22;359(2):259-61. Epub 2015 Jan 22.

N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia; I.I. Mechnikov North-Western Medical University, St-Petersburg 191015, Russia. Electronic address:

Twenty one DNA repair genes were analyzed in a group of 95 BC patients, who displayed clinical features of hereditary disease predisposition but turned out to be negative for mutations in BRCA1 and BRCA2 entire coding region as well as for founder disease-predisposing alleles in CHEK2, NBN/NBS1 and ATM genes. Full-length sequencing of CHEK2 and NBN/NBS1 failed to identify non-founder mutations. The analysis of TP53 revealed a woman carrying the R282W allele; further testing of additional 108 BC patients characterized by a very young age at onset (35 years or earlier) detected one more carrier of the TP53 germ-line defect. In addition, this study confirmed non-random occurrence of PALB2 truncating mutations in Russian hereditary BC patients. None of the studied cases carried germ-line defects in recently discovered hereditary BC genes, BRIP1, FANCC, MRE11A and RAD51C. The analysis of genes with yet unproven BC-predisposing significance (BARD1, BRD7, CHEK1, DDB2, ERCC1, EXO1, FANCG, PARP1, PARP2, RAD51, RNF8, WRN) identified single women carrying a protein-truncating allele, WRN R1406X. DNA sequencing of another set of 95 hereditary BC cases failed to reveal additional WRN heterozygous genotypes. Since WRN is functionally similar to the known BC-predisposing gene, BLM, it deserves to be analyzed in future hereditary BC studies. Furthermore, this investigation revealed a number of rare missense germ-line variants, which are classified as probably protein-damaging by online in silico tools and therefore may require further consideration.
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http://dx.doi.org/10.1016/j.canlet.2015.01.022DOI Listing
April 2015

Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations.

Breast Cancer Res Treat 2014 Jun 7;145(2):553-62. Epub 2014 May 7.

Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Pesochny-2, 197758, St.-Petersburg, Russia.

17 double heterozygous (DH) breast cancer (BC) patients were identified upon the analysis of 5,391 affected women for recurrent Slavic mutations in BRCA1, CHEK2, NBN/NBS1, ATM, and BLM genes. Double heterozygosity was found for BRCA1 and BLM (4 patients), BRCA1 and CHEK2 (4 patients), CHEK2 and NBS1 (3 patients), BRCA1 and ATM (2 patients), CHEK2 and BLM (2 patients), CHEK2 and ATM (1 patient), and NBS1 and BLM (1 patient). DH BC patients were on average not younger than single mutation carriers and did not have an excess of bilateral BC; an additional non-breast tumor was documented in two BRCA1/BLM DH patients (ovarian cancer and lymphoplasmacytic lymphoma). Loss-of-heterozygosity (LOH) analysis of involved genes was performed in 5 tumors, and revealed a single instance of somatic loss of the wild-type allele (LOH at CHEK2 locus in BRCA1/CHEK2 double heterozygote). Distribution of mutations in patients and controls favors the hypothesis on multiplicative interaction between at least some of the analyzed genes. Other studies on double heterozygosity for BC-predisposing germ-line mutations are reviewed.
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http://dx.doi.org/10.1007/s10549-014-2971-1DOI Listing
June 2014

High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients.

Int J Cancer 2014 May 27;134(10):2352-8. Epub 2014 Jan 27.

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg, Russia.

In a search for new breast cancer (BC) predisposing genes, we performed a whole exome sequencing analysis using six patient samples of familial BC and identified a germline inactivating mutation c.183delG [p. Arg61fs] in an orphan G protein-coupled receptor GPRC5A. An extended case-control study revealed a tenfold enrichment for this mutation in BC patients carrying the 5382insC allele of BRCA1, the major founder mutation in the Russian population, compared to wild-type BRCA1 BC cases [6/117 (5.1%) vs. 8/1578 (0.5%), p = 0.0002]. In mammary tumors (n = 60), the mRNA expression of GPRC5A significantly correlated with that of BRCA1 (p = 0.00018). In addition, the amount of GPRC5A transcript was significantly lower in BC obtained from BRCA1 mutation carriers (n = 17) compared to noncarriers (n = 93) (p = 0.026). Accordingly, a siRNA-mediated knockdown of either BRCA1 or GPRC5A in the MDA-MB-231 human BC cell line reduced expression of GPRC5A or BRCA1, respectively. Knockdown of GPRC5A also attenuated radiation-induced BRCA1- and RAD51-containing nuclear DNA repair foci. Taken together, these data suggest that GPRC5A is a modifier of BC risk in BRCA1 mutation carriers and reveals a functional interaction of these genes.
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http://dx.doi.org/10.1002/ijc.28569DOI Listing
May 2014

Pattern of clinically relevant mutations in consecutive series of Russian colorectal cancer patients.

Med Oncol 2013 14;30(3):686. Epub 2013 Aug 14.

Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia.

One hundred and ninety-five consecutive surgically treated Russian colorectal cancer (CRC) patients were retrospectively analyzed for the presence of mutations in KRAS, NRAS, BRAF and PIK3CA genes as well as for the microsatellite instability status. Comparison between high-resolution melting analysis, co-amplification at lower denaturation temperature PCR, DNA sequencing and allele-specific PCR for the detection of KRAS codon 12/13 mutations revealed that none of these methods alone provided satisfactory results in 100 % of the analyzed cases; this experience supports the use of more than one mutation-detecting technique at least in some circumstances. KRAS codon 12/13 substitutions were detected in 70 (35.9 %) CRC cases. Other mutations in the RAS/RAF genes occurred in 22 (11.3 %) cases and included rare KRAS (n = 6), NRAS (n = 8) and BRAF (n = 8) alterations. 5 BRAF mutations affected codon 600, while the remaining 3 potentially functional substitutions were located in the position 594. Twenty-four (12.3 %) CRC cases carried mutations in the PIK3CA, and 18 of these tumors also contained activating alteration in the RAS/RAF genes (p = 0.007). Only 3 (1.5 %) CRC cases showed high-level microsatellite instability (MSI-H) as determined by a panel of mononucleotide markers. Overall, the distribution of potentially predictive mutations in Russian CRC cases is similar to the one observed in other patient series of European descent. Noticeable occurrence of D594G mutation in BRAF oncogene and low frequency of MSI-H may deserve specific attention.
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http://dx.doi.org/10.1007/s12032-013-0686-5DOI Listing
April 2014

Evidence for angiogenesis-independent contribution of VEGFR1 (FLT1) in gastric cancer recurrence.

Med Oncol 2013 26;30(3):644. Epub 2013 Jun 26.

N.N. Petrov Institute of Oncology, 197758 St. Petersburg, Russia.

Angiogenesis plays an important role in cancer progression and involves activation of multiple signaling cascades. This study investigated the relationships between microvessel density, expression of VEGF and VEGFR1 (FLT1), and gastric cancer (GC) recurrence. Twenty-nine surgically treated GC cases with similar initial clinical presentation were selected for the study; 11 of these cases recurred within 3 years, while the remaining 18 did not. Microvessel density correlated with VEGF mRNA content, but neither of these parameters was associated with the disease outcome. When tumors were ranked according to the level of expression of angiogenic molecules, 9 out of 10 cases with the highest VEGFR1 expression belonged to the recurrence group, while none of the 10 GC with the lowest content of VEGFR1 mRNA had the disease relapse (p = 0.000). VEGFR1 expression did not show even a trend to correlation with the level of cancer tissue vascularization. Immunofluorescent staining by anti-VEGFR1 antibody revealed VEGFR1 expression in tumor cells but not in other cell types. Our data provide indirect support to the evidence for a non-angiogenic contribution of VEGFR1 in cancer pathogenesis.
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http://dx.doi.org/10.1007/s12032-013-0644-2DOI Listing
April 2014
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