Hereditary cancer syndromes.

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, the somatic inactivation of the remaining copy of the affected gene.

Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in -Driven Breast Cancer Patients.

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells.

Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAF mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study.

Background: Primary analysis of the phase 3 IMspire150 study showed improved investigator-assessed progression-free survival with first-line atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF mutation-positive melanoma. With a median follow-up of 18·9 months (IQR 10·4-23·8) at the primary analysis, overall survival data were immature. Here, we report the results from the second, prespecified, interim overall survival analysis.

Integrative Genomic Tests in Clinical Oncology.

Many clinical decisions in oncology practice rely on the presence or absence of an alteration in a single genetic locus, be it a pathogenic variant in a hereditary cancer gene or activating mutation in a drug target. In addition, there are integrative tests that produce continuous variables and evaluate complex characteristics of the entire tumor genome. Microsatellite instability (MSI) analysis identifies tumors with the accumulation of mutations in short repetitive nucleotide sequences.

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation.

Strong founder effect for BRCA1 c.3629_3630delAG pathogenic variant in Chechen patients with breast or ovarian cancer.

Coding sequences of BRCA1, BRCA2, ATM, TP53, and PALB2 genes were analyzed in 68 consecutive Chechen patients with high-grade serous ovarian cancer (HGSOC). Pathogenic BRCA1/2 variants were identified in 15 (22%) out of 68 HGSOC cases. Nine out of ten patients with BRCA1 pathogenic alleles carried the same deletion (c.

Simultaneous Onset of Pediatric Systemic Lupus Erythematosus in Twin Brothers: Case Report.

Unlabelled: There are hundreds of twin adult patients with systemic lupus erythematosus (SLE), but male children with SLE are rarely affected. Two monozygotic twin brothers developed SLE at the age of 11 years during 1 month. The index brother manifested with Henoch-Shonlein purpura, accompanied by ANA positivity, and later developed critical left femoral arterial stenosis with high levels of anti-dsDNA, antiphospholipid antibodies, hypocomplementemia, and Coombs-positive hemolytic anemia.

Deep Learning Analysis of the Adipose Tissue and the Prediction of Prognosis in Colorectal Cancer.

Research has shown that the lipid microenvironment surrounding colorectal cancer (CRC) is closely associated with the occurrence, development, and metastasis of CRC. According to pathological images from the National Center for Tumor diseases (NCT), the University Medical Center Mannheim (UMM) database and the ImageNet data set, a model called VGG19 was pre-trained. A deep convolutional neural network (CNN), VGG19CRC, was trained by the migration learning method.

Founder vs. non-founder BRCA1/2 pathogenic alleles: the analysis of Belarusian breast and ovarian cancer patients and review of other studies on ethnically homogenous populations.

The spectrum of BRCA1/2 mutations demonstrates significant interethnic variations. We analyzed for the first time the entire BRCA1/2 coding region in 340 Belarusian cancer patients with clinical signs of BRCA1/2-related disease, including 168 women with bilateral and/or early-onset breast cancer (BC), 104 patients with ovarian cancer and 68 subjects with multiple primary malignancies involving BC and/or OC. BRCA1/2 pathogenic alleles were detected in 98 (29%) women, with 67 (68%) of these being represented by founder alleles.

Preparation of Duplex Sequencing Libraries for Archival Paraffin-Embedded Tissue Samples Using Single-Strand-Specific Nuclease P1.

DNA from formalin-fixed paraffin-embedded (FFPE) tissues, which are frequently utilized in cancer research, is significantly affected by chemical degradation. It was suggested that approaches that are based on duplex sequencing can significantly improve the accuracy of mutation detection in FFPE-derived DNA. However, the original duplex sequencing method cannot be utilized for the analysis of formalin-fixed paraffin-embedded (FFPE) tissues, as FFPE DNA contains an excessive number of damaged bases, and these lesions are converted to false double-strand nucleotide substitutions during polymerase-driven DNA end repair process.

Evaluation of conformational transitions of h-BRCA2 functional domain and unclassified variant Arg2502Cys using multimodal approach.

Breast cancer type 2 susceptibility (BRCA2) protein plays an essential role in the repair mechanism of DNA double-strand breaks and interstrand cross-links by Homologous recombination. Germline mutations identified in the BRCA2 gene confer an increased risk of hereditary breast and ovarian cancer. Missense mutations are identified all over the gene, including the DNA binding region of BRCA2 that interacts with FANCD2.

Comprehensive evaluation of the test for 5'-/3'-end mRNA unbalanced expression as a screening tool for ALK and ROS1 fusions in lung cancer.

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.

Changes in the concentration of EGFR-mutated plasma DNA in the first hours of targeted therapy allow the prediction of tumor response in patients with EGFR-driven lung cancer.

Purpose: This study aimed to analyze changes in the plasma concentration of EGFR-mutated circulating tumor DNA (ctDNA) occurring immediately after the start of therapy with EGFR tyrosine kinase inhibitors (TKIs).

Methods: Serial plasma samples were collected from 30 patients with EGFR-driven non-small cell lung cancer before intake of the first tablet and at 0.5, 1, 2, 3, 6, 12, 24, 36 and 48 h after the start of the therapy.

Tumor irradiation may facilitate the detection of tumor-specific mutations in plasma.

Background: The mutation-based analysis of circulating tumor DNA (ctDNA) is a promising diagnostic tool for clinical oncology. However, it has low success rate because many cancer patients do not have detectable ctDNA in the bloodstream.

Aim: To evaluate whether preoperative tumor irradiation results in a transient increase of plasma ctDNA concentration due to the induction of apoptosis in radiation-exposed cells.

Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction.

Identification of recurrent pathogenic alleles using exome sequencing data: Proof-of-concept study of Russian subjects.

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.

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.

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).

Molecular tests for prediction of tumor sensitivity to cytotoxic drugs.

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.

Molecular testing for colorectal cancer: Clinical applications.

Molecular genetic analysis is an integral part of colorectal cancer (CRC) management. The choice of systemic therapy for CRC is largely based on the results of tumor molecular testing. Evaluation of the and gene status is mandatory for consideration of anti-epidermal growth factor receptor (EGFR) therapy.

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

The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g.