Objective: to summarize existing information on hereditary types of colorectal cancer. Material and Methods . A literature search was conducted in the Medline, Cochrane Library, and Elibrary databases, including publications from January 2002 to October 2025. Out of 3000 studies found, 79 were used to write this systematic review. Results. Well-known hereditary colorectal cancer (CRC) varieties account for up to 4-5 % of all colorectal cancer cases. In addition to familial adenomatous polyposis, Lynch syndrome, and MUTYH-associated polyposis, at least 15 other, rarer nosological forms of hereditary CRC can be identified. Each of these diseases has a distinct clinical presentation and biological nature. These characteristics lead to differences in approaches to the prevention and treatment of various hereditary CRC subtypes. Unlike most hereditary tumor syndromes of other sites, which are typically autosomal dominant, some types of CRC are inherited via an autosomal recessive mechanism. The study of hereditary CRC contributes to the development of new approaches for treating sporadic colorectal tumors with somatic mutations in the same genes. Conclusion . This review provides detailed information on the genetic causes, mechanisms of carcinogenesis, and clinical features of both well-known and recently discovered types of hereditary CRC.

BACKGROUND:Several targeted drugs have been recently approved for the treatment of PIK3CA-mutated hormone receptor-positive (HR+)/HER2-negative (HER2-) breast cancer (BC). This study aimed at a comprehensive evaluation of the spectrum of PIK3CA alterations in Russian BC patients. METHODS:The tumor material from 1872 patients with ER+/HER2- BC was tested by a combination of PCR-based methods. RESULTS:Mutations were detected in 693/1872 (37%) cases, including 46 BC with two PIK3CA lesions. The three most common substitutions (E542K, E545K, and H1047R) were identified in 542/693 (78%) PIK3CA-mutated cases, while as many as 5.5-12% of identified mutations were not potentially detectable by common commercial kits. The study included patients of Slavic and non-Slavic ethnicities residing in regions with different climate conditions, however, these factors did not influence the distribution of PIK3CA mutations. The presence of PIK3CA variants was associated with older patient age at diagnosis (p = 0.0002), smaller tumor size (p = 0.005), lower grade (p = 0.005), Ki67 <20% (p = 0.0001) and progesterone receptor-positive status (p = 0.002) at the initial disease diagnosis, and fewer distant metastases at the time of the detection of BC spread (p = 0.0001). In a subgroup of 413 BC patients who received adjuvant tamoxifen or aromatase inhibitors, PIK3CA mutations were not associated with resistance to either type of treatment. CONCLUSIONS:The results of this study highlight the need to extend the PIK3CA testing beyond the hotspot regions of this gene. Although PIK3CA alterations contribute to the pathogenesis of HR+/HER2- BC and represent a target for several novel drugs, they are not intrinsically associated with unfavorable clinical characteristics of this subtype of cancer disease.

Homologous recombination deficiency (HRD) resulting from inactivating mutations in the BRCA1 and BRCA2 genes promotes increased chromosomal instability and renders tumor cells susceptible to platinum derivatives and PARP inhibitors. Hereditary and/or somatic mutations in BRCA2, ATM, CHEK2 and other loci involved in homologous recombination DNA repair (HRR) have been reported in up to 25% of metastatic prostate cancer (PC) cases. The contribution of alterations in HRR-related genes beyond BRCA1/2 to homologous recombination deficiency remains largely unknown. The aim of the current study was to compare the HRD scores in prostate tumors with alterations in different HRR genes. HRD scores were determined as the sum of genomic loss of heterozygosity (LOH), large-scale state transition (LST) and telomeric allelic imbalance (TAI) scores by targeted NGS using HiSNP Ultra Panel v1.0 (Nanodigmbio, China) in two PC groups. The first group consisted of 58 PC cases with germline or somatic mutations in any of 34 HRR genes, while the second group included 214 cases without HRR mutations. The cut-off for the presence of homologous recombination deficiency was set as an HRD score ≥ 42. HRD was observed more frequently in PCs with HRR mutations (9/58, 16%) than in cases without detectable HRR alterations (10/214, 5%, p = 0.008). In the HRR-mutated subgroup, high HRD scores were found in cases with BRCA2 (n = 4), ATM (n = 2), CDK12, NBN and FANCM mutations. The median HRD scores in PCs with mutations in BRCA2 (n = 9), ATM (n = 12), CHEK2 (n =8), NBN (n = 3), FANCM (n = 3), BRCA1 (n = 3), BLM (n = 3) were 41, 22.5, 7.5, 3, 10, 6, and 3, respectively. The comparison of HRD scores between BRCA2-mutant cases and ATM- (p = 0.046), CHEK2- (p = 0.005), or BLM-mutant PCs (p = 0.042) reached statistical significance. The presence of somatic TP53 mutations was associated with a higher degree of chromosomal instability and elevated HRD scores (p = 0.0001). A high HRD score is observed in a noticeable proportion of prostate tumors lacking mutations in the HRR genes. Prostate cancer cases with alterations in ATM, CHEK2, BLM, and possibly also NBN, FANCM genes are unlikely to have severe HRD. This work has been supported by the Russian Science Foundation (grant number 23-15-00262). Ekaterina Sh. Kuligina, Aglaya G. Iyevleva, Anna P. Sokolenko, Svetlana N. Aleksakhina, Maria V. Syomina, Ekaterina A. Otradnova, Evgeny N. Imyanitov. ATM, CHEK2 and BLM mutant prostate cancers do not have high homologous recombination deficiency scores [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1491.

Kidney cancer (KC) is a common disease characterized by extreme heterogeneity. There are nine known monogenic diseases associated with a significantly elevated KC risk: von Hippel-Lindau disease, MET -associated papillary renal cancer, familial multiple leiomyomatosis and renal cell cancer, SDHx -associated familial pheochromocytoma/ paraganglioma, Birt-Hogg-Dube syndrome, tuberous sclerosis, Cowden syndrome, BAP1 - and MITF -associated melanoma-KC predisposition. These syndromes differ in the degree of cancer risk, the quantity, growth and progression rates of associated precancerous lesions, the morphology, and clinical presentations of malignancy itself, and in the response to therapy. Identification of causative germline lesion allows planning the surveillance of a mutation carrier, choosing the right time and extent of surgery, and optimizing treatment regimen. Hereditary KC research often brings forward novel approaches to the management of sporadic “phenocopies” of hereditary syndromes, i.e. sporadic cancers with somatic mutations in similar genes. The main directions for further study of genetic factors of KC are to find novel KC genes, to study risk modifiers in carriers of highly penetrant mutations, to clarify the involvement of hereditary nephropathies in the occurrence of renal cancers.

This study aimed to analyze clinical and regional factors influencing the distribution of actionable genetic alterations in a large consecutive series of colorectal carcinomas (CRCs). KRAS, NRAS and BRAF mutations, HER2 amplification and overexpression, and microsatellite instability (MSI) were tested in 8355 CRC samples. KRAS mutations were detected in 4137/8355 (49.5%) CRCs, with 3913 belonging to 10 common substitutions affecting codons 12/13/61/146, 174 being represented by 21 rare hot-spot variants, and 35 located outside the “hot” codons. KRAS Q61K substitution, which leads to the aberrant splicing of the gene, was accompanied by the second function-rescuing mutation in all 19 tumors analyzed. NRAS mutations were detected in 389/8355 (4.7%) CRCs (379 hot-spot and 10 non-hot-spot substitutions). BRAF mutations were identified in 556/8355 (6.7%) CRCs (codon 600: 510; codons 594–596: 38; codons 597–602: 8). The frequency of HER2 activation and MSI was 99/8008 (1.2%) and 432/8355 (5.2%), respectively. Some of the above events demonstrated differences in distribution according to patients’ age and gender. In contrast to other genetic alterations, BRAF mutation frequencies were subject to geographic variation, with a relatively low incidence in areas with an apparently warmer climate (83/1726 (4.8%) in Southern Russia and North Caucasus vs. 473/6629 (7.1%) in other regions of Russia, p = 0.0007). The simultaneous presence of two drug targets, BRAF mutation and MSI, was observed in 117/8355 cases (1.4%). Combined alterations of two driver genes were detected in 28/8355 (0.3%) tumors (KRAS/NRAS: 8; KRAS/BRAF: 4; KRAS/HER2: 12; NRAS/HER2: 4). This study demonstrates that a substantial portion of RAS alterations is represented by atypical mutations, KRAS Q61K substitution is always accompanied by the second gene-rescuing mutation, BRAF mutation frequency is a subject to geographical variations, and a small fraction of CRCs has simultaneous alterations in more than one driver gene.

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p < 0.0001). Twelve pre-/post-NACT tissue pairs obtained from BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication.

Hereditary cancer syndromes (HCSs) are arguably the most frequent category of Mendelian genetic diseases, as at least 2% of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants (PVs). Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity; in addition, there are several dozen less frequent types of familial tumors. The development of the majority albeit not all hereditary malignancies involves two-hit mechanism, i.e. the somatic inactivation of the remaining copy of the affected gene. Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes; however, population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status. Hereditary cancer research initially focused mainly on cancer detection and prevention. Recent studies identified multiple HCS-specific drug vulnerabilities, which translated into the development of highly efficient therapeutic options.

The majority of NTRK1, NTRK2, and NTRK3 rearrangements result in increased expression of the kinase portion of the involved gene due to its fusion to an actively transcribed gene partner. Consequently, the analysis of 5′/3′-end expression imbalances is potentially capable of detecting the entire spectrum of NTRK gene fusions. Archival tumor specimens obtained from 8075 patients were subjected to manual dissection of tumor cells, DNA/RNA isolation, and cDNA synthesis. The 5′/3′-end expression imbalances in NTRK genes were analyzed by real-time PCR. Further identification of gene rearrangements was performed by variant-specific PCR for 44 common NTRK fusions, and, whenever necessary, by RNA-based next-generation sequencing (NGS). cDNA of sufficient quality was obtained in 7424/8075 (91.9%) tumors. NTRK rearrangements were detected in 7/6436 (0.1%) lung carcinomas, 11/137 (8.0%) pediatric tumors, and 13/851 (1.5%) adult non-lung malignancies. The highest incidence of NTRK translocations was observed in pediatric sarcomas (7/39, 17.9%). Increased frequency of NTRK fusions was seen in microsatellite-unstable colorectal tumors (6/48, 12.5%), salivary gland carcinomas (5/93, 5.4%), and sarcomas (7/143, 4.9%). None of the 1293 lung carcinomas with driver alterations in EGFR/ALK/ROS1/RET/MET oncogenes had NTRK 5′/3′-end expression imbalances. Variant-specific PCR was performed for 744 tumors with a normal 5′/3′-end expression ratio: there were no rearrangements in 172 EGFR/ALK/ROS1/RET/MET-negative lung cancers and 125 pediatric tumors, while NTRK3 fusions were detected in 2/447 (0.5%) non-lung adult malignancies. In conclusion, this study describes a diagnostic pipeline that can be used as a cost-efficient alternative to conventional methods of NTRK1–3 analysis.

The majority of NTRK1, NTRK2 and NTRK3 rearrangements result in the increased expression of the kinase portion of the gene due to its fusion to an actively transcribed gene partner. Consequently, the analysis of 5’-/3’-end expression imbalance is potentially capable of detecting the entire spectrum of NTRK gene fusions. Formalin-fixed tissue specimens were subjected to manual dissection of tumor cells, followed by DNA/RNA isolation and cDNA synthesis. 5’-/3’-end expression imbalance in NTRK genes was analyzed by real-time PCR. Further identification of gene rearrangements was performed by variant-specific multiplexed PCR for 42 common NTRK fusions, and, whenever necessary, by RNA-based next-generation sequencing (NGS). The study initially included 8075 tissue specimens; 651 (8.1%) of these samples failed to pass the quality control. NTRK rearrangements were detected in 7/6436 (0.1%) lung carcinomas, 11/137 (8.0%) pediatric tumors, and 13/851 (1.5%) adult non-lung malignancies. The highest incidence of NTRK translocations was observed in pediatric sarcomas (7/39, 17.8%). Relatively high frequency of NTRK fusions was seen in microsatellite-unstable colorectal tumors (6/48, 12.5%) and salivary gland carcinomas (5/93, 5.4%). None of 1293 lung carcinomas with driver alterations in EGFR/ALK/ROS1/RET/MET oncogenes had NTRK 5’/3’-end expression imbalance. Variant-specific PCR was performed for 744 tumors with normal 5’/3’-end expression ratio: there were no rearrangements in 172 EGFR/ALK/ROS1/RET/MET-negative lung cancers and 125 pediatric tumors, while NTRK fusions were detected in 2/447 (0.4%) non-lung adult malignancies. This study describes a robust pipeline for the detection of NTRK1, NTRK2 and NTRK3 gene fusions, which may be considered as a cost-efficient alternative to conventional methods of NTRK analysis.

RET-kinase-activating gene rearrangements occur in approximately 1–2% of non-small-cell lung carcinomas (NSCLCs). Their reliable detection requires next-generation sequencing (NGS), while conventional methods, such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) or variant-specific PCR, have significant limitations. We developed an assay that compares the level of RNA transcripts corresponding to 5′- and 3′-end portions of the RET gene; this test relies on the fact that RET translocations result in the upregulation of the kinase domain of the gene and, therefore, the 5′/3′-end expression imbalance. The present study included 16,106 consecutive NSCLC patients, 14,449 (89.7%) of whom passed cDNA quality control. The 5′/3′-end unbalanced RET expression was observed in 184 (1.3%) tumors, 169 of which had a sufficient amount of material for the identification of translocation variants. Variant-specific PCR revealed RET rearrangements in 155/169 (91.7%) tumors. RNA quality was sufficient for RNA-based NGS in 10 cases, 8 of which carried exceptionally rare or novel (HOOK1::RET and ZC3H7A::RET) RET translocations. We also applied variant-specific PCR for eight common RET rearrangements in 4680 tumors, which emerged negative upon the 5′/3′-end unbalanced expression test; 33 (0.7%) of these NSCLCs showed RET fusion. While the combination of the analysis of 5′/3′-end RET expression imbalance and variant-specific PCR allowed identification of RET translocations in approximately 2% of consecutive NSCLCs, this estimate approached 120/2361 (5.1%) in EGFR/KRAS/ALK/ROS1/BRAF/MET-negative carcinomas. RET-rearranged tumors obtained from females, but not males, had a decreased level of expression of thymidylate synthase (p < 0.00001), which is a known predictive marker of the efficacy of pemetrexed. The results of our study provide a viable alternative for RET testing in facilities that do not have access to NGS due to cost or technical limitations.

Gene fusions involving protein kinases are druggable targets characteristic for a subset of NSCLCs. NGS analysis for 650 kinase genes was performed for 38 RNA lung adenocarcinomas obtained from young-onset patients (age range: 33-50 years; median age: 44 years; 22 males and 16 females). All these tumors were negative for activating events involving EGFR, ALK, ROS1, RET, MET, NTRK1/2/3, BRAF, HER2 and KRAS genes. Kinome RNAseq revealed 67 chimeric transcripts in 38 NSLC cases. Five of these chimeras were recurrent, being a result of large intrachromosomal rearrangements and observed in 2-19 tumors each; however, none of these translocations predicted for a protein product. The majority of aberrations were frameshift mutations. 18 fusion variants were in-frame, but only four rearrangements preserved the entire kinase domain within a chimeric transcript: BCR-PKHD1 t(22;6)(q11.23;p12.3), CLTC-RPS6KB1 17q23.1del0.2Mb, CDC42BPG-ATG2A 11q13.1del0.05Mb and MAPRE1-DGKB t(20;7)(q11.21;p21.2). By the time of the abstract submission, BCR-PKHD1 and recently reported CLIP1-LTK [Izumi et al., 2021, PMID 34819663] gene fusions were analyzed in 2754 NSCLCs, which were negative for all known actionable mutations, however no new instances of these translocations have been observed. This study has not replicated the data on the frequent involvement of CLIP1-LTK fusions in NSCLCs, however identified a number of other kinase gene fusions deserving further investigation.

Background: PD-L1 testing is currently performed by immunohistochemistry (IHC). We questioned whether the results of PCR-based measurement of PD-L1 RNA expression correlate with IHC scores obtained by different commercial assays. Materials and methods: 167 consecutive non-squamous non-small cell lung carcinomas (NSCLCs) were analyzed for PD-L1 RNA expression and 22C3, SP263, and SP142 IHC scoring using recommended cut-offs. RNA expression was divided into low, moderate, and high categories. Results: RNA and protein expression demonstrated moderate correlation as continuous variables. Using prespecified RNA cut-offs, PCR testing showed a high negative predictive value towards the IHC analysis: the share of PD-L1 protein-negative tumors among cases classified as PD-L1-low by the PCR test reached 92-99% for all three antibodies. Meanwhile, about half of cases with moderate to high PD-L1 RNA expression had IHC staining in less than 1% tumor cells as determined by 22C3 or SP263 antibodies. Among the 51 discordant cases, which had <1% tumor staining by both 22C3 and SP263 clones but high RNA level, 29 (57%) showed >= 1% positive immune cells by SP263 and/or 22C3, 14 cases (27%) had detectable IHC expression in 0.1-0.9% tumor or immune cells by SP263 and/or 22C3, and 8 (16%) were entirely negative by IHC. Conclusion: Some NSCLCs demonstrate readily detectable PD-L1 expression on the level of RNA, but fall below commonly accepted cut-offs by IHC. It remains to be studied whether these discrepancies are attributed to technical or biological reasons. Clinical sensitivity of these tumors to immune therapy deserves additional investigations.

Chemotherapy constitutes the backbone of cancer treatment. Several predictive assays assist personalized administration of cytotoxic drugs and are recommended for use in a clinical setting. The deficiency of DNA repair by homologous recombination (HRD), which is caused by inactivation of BRCA1/2 genes or other genetic events, is associated with high tumor responsiveness to platinum compounds, bifunctional alkylating agents and topoisomerase II poisons. Low activity of MGMT predicts the efficacy of nitrosoureas and tetrazines. Some clinically established pharmacogenetic tests allow for the adjustment of drug dosage, for example, the analysis of DPYD allelic variants for administration of fluoropyrimidines and UGT1A1 genotyping for the use of irinotecan. While there are promising molecular predictors of tumor sensitivity to pemetrexed, gemcitabine and taxanes, they remain in the investigational stage and require additional validation. Comprehensive molecular analysis of tumors obtained from drug responders and non-responders is likely to reveal new clinically useful predictive markers for cytotoxic therapy.

Background Despite the progress in the development of next-generation sequencing (NGS), diagnostic PCR assays remain to be utilized in clinical routine due to their simplicity and low cost. Tests for 5 '-/3 '-end mRNA unbalanced expression can be used for variant-independent detection of translocations, however, many technical aspects of this methodology require additional investigations. Methods Known ALK/ROS1 fusions and 5 '-/3 '-end unbalanced expression were analyzed in 2009 EGFR mutation-negative non-small cell lung cancer (NSCLC) samples with RT-PCR tests, which were optimized for the use with FFPE-derived RNA. Results Variant-specific PCR tests for 4 common ALK and 15 common ROS1 translocations detected 115 (5.7%) and 44 (2.2%) rearrangements, respectively. Virtually all samples with common ALK fusions demonstrated some level of 5 '/3 ' mRNA ends unbalanced expression, and 8 additional NSCLCs with rare ALK fusions were further identified by PCR or NGS among 48 cases selected based on ALK expression measurements. Interestingly, NSCLCs with unbalanced 5 '-/3 '-end ALK expression but without identified ALK translocations had elevated frequency of RAS mutations (21/40, 53%) suggesting the role of RAS activation in the alternative splicing of ALK gene. In contrast to ALK, only a minority of ROS1 translocation-positive cases demonstrated unbalanced gene expression, with both 5 '- and 3 '-end mRNA expression being elevated in most of the samples with translocations. Surprisingly, high ROS1 expression level was also found to be characteristic for NSCLCs with activating mutations in other tyrosine kinases such as EGFR, ALK, or MET. Conclusions Comprehensive ALK analysis can be performed by the test for 5 '-/3 '-end unbalanced expression with minimal risk of missing an ALK rearrangement. In contrast, the use of the test for 5 '-/3 '-end unbalanced expression for the detection of ROS1 fusions is complicated; hence, the utilization of variant-specific PCR assays for ROS1 testing is preferable.

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. 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. 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). 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.

lymphocyte levels (p¼0.001) and higher immune cell type percentages (p¼0.006).This BRCA1-like subgroup was characterised by a gene expression profile that strongly associates with a number of cell-mediated immunity related pathways, such as the PD-L1/PD-1 pathway (p<0.001) and natural killer cell mediated cytotoxicity (p<0.001).Conclusions: By analysing multiomics data from n ¼ 192 patients with BRCA1-like triple-negative breast cancer, we found indications for the presence of distinct subgroups of which one has immunomodulatory features.How these BRCA1-like, TNBC subgroups may direct immunotherapy strategies will be addressed in follow-up studies.

Whole exome sequencing (WES) is a powerful tool for the cataloguing of population-specific genetic diseases. Within this proof-of-concept study we evaluated whether analysis of a small number of individual exomes is capable of identifying recurrent pathogenic alleles. We considered 106 exomes of subjects of Russian origin and revealed 13 genetic variants, which occurred more than twice and fulfilled the criteria for pathogenicity. All these alleles turned out to be indeed recurrent, as revealed by the analysis of 1045 healthy Russian donors. Eight of these variants (NAGA c.973G>A, ACADM c.985A>C, MPO c.2031-2A>C, SLC3A1 c.1400T>C, LRP2 c.6160G>A, BCHE c.293A>G, MPO c.752T>C, FCN3 c.349delC) are non-Russian-specific, as their high prevalence was previously demonstrated in other European populations. The remaining five disease-associated alleles appear to be characteristic for subjects of Russian origin and include CLCN1 c.2680C>T (myotonia congenita), DHCR7 c.453G>A (Smith-Lemli-Opitz syndrome), NUP93 c.1162C>T (steroid-resistant nephrotic syndrome, type 12), SLC26A2 c.1957T>A (multiple epiphyseal dysplasia) and EIF3F c.694T>G (mental retardation). These recessive disease conditions may be of particular relevance for the Russian Federation and other countries with a significant Slavic population.

Transl Lung Cancer Res 2021;10(10):4035-4038 | https://dx.doi.org/10.21037/tlcr-21-680 Lung cancer (LC) is the most common oncological disease worldwide. Its incidence currently exceeds 2 million cases per year, with 1.8 million subjects dying from this malignancy. LC accounts for 11.6% of total cancer diagnoses and 18.4% cancer-related deaths (1). Early-stage LC usually does not cause specific symptoms; consequently, more than 70% LCs are diagnosed at advanced stages (2,3). Recent breakthroughs in targeted and immune therapy resulted in dramatic improvement of LC outcomes (4,5). Nevertheless, LC is a direct cause of death in the majority of patients with this diagnosis (1). LC is often characterized in the scientific literature as a highly aggressive disease; nevertheless, patients diagnosed at stage IA have approximately 80% probability of being cured (6). Furthermore, 5-year overall survival rate for stage IA lung cancer may be close to 90%. In contrast, stage IV LC is associated with dismal prognosis, with 5-year overall survival rate falling below 20% (7). These data suggest that early diagnosis of LC is a key for reducing mortality from this disease. LC screening studies largely support this hypothesis: for example, it was shown that lowdose computed tomography (LDCT) reduces LC mortality by at least 20% in persons at-risk (i.e., in smokers) (8-10). The major problem of LDCT screening i s an unacceptably high rate of false-positive findings. Indeed, many healthy people, particularly elderly subjects and smokers, present with so-called lung “nodules”, i.e., some lumps detected by X-rays. These lumps reflect topical increase of the density of lung tissue due to alterations in its structure. The most ominous cause of these nodules is the LC. However, many benign processes, e.g., inflammatory infiltrates caused by smoking-related irritation of bronchi, infections, autoimmune processes etc., manifest with lumps which are largely indistinguishable from LC by imaging. Great efforts have been invested to improve radiographic procedures and their interpretation in order to discriminate between LC and non-LC nodules. Besides careful visual analysis of appearance of these nodules, to be performed by highly-trained specialists with the support of various electronic tools, it is suggested to consider some probability factors, e.g., age of the patient and his/her smoking history. This «clinical» approach, although being wise and intuitively attractive, has a high risk of missing malignant disease at a curable stage. Consequently, many subjects with LDCT-detected nodules end up with invasive procedures aimed to obtain a piece of suspected nodule and to subject it to a morphological analysis. Collection of tissue samples from thoracic cavity is obviously associated with suffering of examined subjects and often results in serious complications, particularly bleeding. Unfortunately, even this invasive intervention cannot guarantee right diagnosis: there are many instances of LC, where tissue biopsy produces false-negative results die to actual failure to obtain tumor sample (11-14). Liang et al. (15) recently presented a test called PulmoSeek, which is based on the detection of LCspecific methylation signatures in circulating tumor DNA Editorial Commentary