Hereditary Renal Cancer Syndromes.

Familial kidney tumors represent a rare variety of hereditary cancer syndromes, although systematic gene sequencing studies revealed that as many as 5% of renal cell carcinomas (RCCs) are associated with germline pathogenic variants (PVs). Most instances of RCC predisposition are attributed to the loss-of-function mutations in tumor suppressor genes, which drive the malignant progression via somatic inactivation of the remaining allele. These syndromes almost always have extrarenal manifestations, for example, von Hippel-Lindau (VHL) disease, fumarate hydratase tumor predisposition syndrome (FHTPS), Birt-Hogg-Dubé (BHD) syndrome, tuberous sclerosis (TS), etc. In contrast to the above conditions, hereditary papillary renal cell carcinoma syndrome (HPRCC) is caused by activating mutations in the MET oncogene and affects only the kidneys. Recent years have been characterized by remarkable progress in the development of targeted therapies for hereditary RCCs. The HIF2aplha inhibitor belzutifan demonstrated high clinical efficacy towards VHL-associated RCCs. mTOR downregulation provides significant benefits to patients with tuberous sclerosis. MET inhibitors hold promise for the treatment of HPRCC. Systematic gene sequencing studies have the potential to identify novel RCC-predisposing genes, especially when applied to yet unstudied populations.

Ethnicity-specific BRCA1, BRCA2, PALB2, and ATM pathogenic alleles in breast and ovarian cancer patients from the North Caucasus.

BACKGROUND: Mountain areas of the North Caucasus host several large ethnic communities that have preserved their national identity over the centuries. METHODS: This study involved high-grade serous ovarian cancer (HGSOC) and breast cancer (BC) patients from Dagestan (HGSOC: 37; BC: 198), Kabardino-Balkaria (HGSOC: 68; BC: 155), North Ossetia (HGSOC: 51; BC: 104), Chechnya (HGSOC: 68; BC: 79), Ingushetia (HGSOC: 19; BC: 103), Karachay-Cherkessia (HGSOC: 13; BC: 47), and several Armenian settlements (HGSOC: 16; BC: 101). The group of BC patients was enriched by young-onset and/or family history-positive and/or bilateral and/or receptor triple-negative cases. The entire coding region of BRCA1, BRCA2, PALB2, and ATM genes was analyzed by next-generation sequencing. RESULTS: A significant contribution of BRCA1/2 pathogenic variants (PVs) to HGSOC and BC development was observed across all North Caucasus regions (HGSOC: 19-39%; BC: 6-13%). Founder alleles were identified in all ethnic groups studied, e.g., BRCA1 c.3629_3630delAG in Chechens, BRCA2 c.6341delC in North Ossetians, BRCA2 c.5351dupA in Ingush, and BRCA1 c.2907_2910delTAAA in Karachays. Some BRCA1/2 alleles, particularly BRCA2 c.9895C > T, were shared by several nationalities. ATM PVs were detected in 14 patients, with c.1673delG and c.8876_8879delACTG alleles occurring twice each. PALB2 heterozygosity was observed in 5 subjects, with one variant seen in 2 unrelated women. CONCLUSION: This study adds to the evidence for the global-wide contribution of BRCA1/2 genes to HGSOC and BC morbidity, although the spectrum of their PVs is a subject of ethnicity-specific variations. The data on founder BRCA1/2 alleles may be considered when adjusting the BRCA1/2 testing procedure to the ethnic origin of patients.

PCR-based analysis of PD-L1 RNA expression in lung cancer: comparison with commonly used immunohistochemical assays.

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.

Molecular predictors of the outcome of paclitaxel plus carboplatin neoadjuvant therapy in high-grade serous ovarian cancer patients.

BACKGROUND: Patients with advanced high-grade serous ovarian cancer (HGSOC) are usually treated with paclitaxel and carboplatin; however, predictive markers for this drug combination are unknown. METHODS: Tumor samples from 71 consecutive HGSOC patients, who received neoadjuvant chemotherapy with paclitaxel and carboplatin, were subjected to molecular analysis. RESULTS: BRCA1/2 germline mutation carriers (n = 22) had longer treatment-free interval (TFI) than non-carriers (n = 49) (9.5 months vs. 3.8 months; P = 0.007). Fifty-one HGSOCs had sufficient quality of tumor DNA for the next-generation sequencing (NGS) analysis by the SeqCap EZ CNV/LOH Backbone Design panel. All 13 tumors obtained from BRCA1/2 germline mutation carriers and 12 sporadic HGSOCs showed a high number of evenly spread chromosomal breaks, which was defined as a BRCAness phenotype; median TFI for this combined group approached 9.5 months. The remaining 26 HGSOCs had similarly high global LOH score (above 20%); however, in contrast to BRCAness tumors, LOH involved large chromosomal segments; these patients had significantly lower TFI (3.7 months; P = 0.006). All patients with CCNE1 amplification (n = 7), TP53 R175H substitution (n = 6), and RB1 mutation (n = 4) had poor response to paclitaxel plus carboplatin. CONCLUSION: This study describes a cost-efficient method of detecting the BRCAness phenotype, which is compatible with the laboratory-scale NGS equipment. Some molecular predictors allow the identification of potential non-responders to paclitaxel plus carboplatin, who may need to be considered for other treatment options.

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

Molecular profiles of BRCA1-associated ovarian cancer treated by platinum-based therapy: Analysis of primary, residual and relapsed tumors.

Our study aimed to analyze the evolution of molecular portraits of BRCA1-driven ovarian cancer (OC) during treatment. BRCA1 loss-of-heterozygosity status (LOH) and exome profiles were investigated in serial OC samples from 13 patients, which included primary tumors (n = 11) obtained before neoadjuvant therapy (NACT) or at primary debulking surgery, residual post-NACT cancer tissues (n = 13) and tumor relapses (16 samples from 13 patients). Loss of the wild-type BRCA1 allele was detected in 11/11 (100%) primary tumors, 6/13 (46%) residual post-NACT OC samples and 15/16 (94%) OC relapses. Full tumor triplets were available for four patients undergoing NACT; whereas primary carcinomas from these patients demonstrated BRCA1 LOH, the retention of the wild-type allele was detected in all four post-NACT residual tumors. These four women provided to the study 5 recurrent OC samples; 4 out of 5 tumor relapses had BRCA1 LOH thus resembling BRCA1 status observed in primary but not residual OC tissues. TP53 mutation was detected in 12 out of 13 patients and was retained across all serial samples. OC relapses tended to acquire additional intragenic mutations in genes involved in cell migration, adhesion and cell junction assembly. BRCA1-driven OCs demonstrate the plasticity of BRCA1 status during the treatment course. NACT results in rapid selection of pre-existing BRCA1-proficient cells. However, BRCA1 proficiency appears to be disadvantageous in the absence of platinum exposure, as tumor relapses usually re-acquire BRCA1 LOH during therapy holidays.

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

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.