GENETICS OF SUSCEPTIBILITY TO INFECTIOUS DISEASES

Genetic characteristics of host organism may cause susceptibility to a variety of bacteria, viruses and fungi, as well as influence the course of infectious diseases. Multiple studies indicate the existence of alleles predisposing to infections. Furthermore, there are about 300 nosological entities of primary immunodeficiencies (PID), i.e., inherited defects of immunity. Timely diagnosis of such conditions is quite challenging; however, it is vital for improving quality of patient care. Modern methods of DNA analysis allow establishing genetic causes of vulnerability to certain infectious agents in many individual

Молекулярная патология рака легкого: клинические аспекты

Discovery of tyrosine kinase inhibitor sensitizing mutations in lung cancer (LC) appears to be the main event in clinical oncology of the last decade. Activating lesions in epidermal growth factor receptor (EGFR) gene almost guarantee tumor response to gefitinib, erlotinib or afatinib.ALK translocations are strongly associated with efficacy of crizotinib or otherALK inhibitors. Instances of success of targeted therapy have been demonstrated for LC harboring mutations in ROS1, RET, HER2, BRAF and KRAS oncogenes. Whole genome sequencing of LC-derived DNAhas revealed a number of novel potentially druggable molecules. Rapid progress in understanding of lung cancer molecular pathogenesis allows to expect that several new targeted agents for LC treatment will become available already within this decade.Обнаружение мутаций, ассоциированных с беспрецедентной чувствительностью карцином лёгкого к ингибиторам тирозинкиназ, представляется наиболее важным событием клинической онкологии в прошедшем десятилетии. Активирующие повреждения в гене, кодирующем рецептор эпидермального фактора роста (EGFR), практически гарантируют ответ на лечение гефитинибом, эрлотинибом или афатинибом. Перестройки гена ALK ассоциированы с выраженным эффектом на терапию кризотинибом или другими ALK-ингибиторами. Продемонстрирована результативность таргетной терапии по отношению к опухолям, содержащим мутации в генах ROS1, RET, HER2, BRAF и KRAS. Изучение карцином лёгкого посредством полногеномного секвенирования позволило выявить новые перспективные мишени для лечебных воздействий. Тенденции накопления сведений о молекулярном патогенезе РЛ дают основания полагать, что спектр потенциально эффективных таргетных препаратов для лечения РЛ многократно расширится уже в этом десятилети

ГЕНЕТИКА ПРЕДРАСПОЛОЖЕННОСТИ К ИНФЕКЦИОННЫМ ЗАБОЛЕВАНИЯМ

Genetic characteristics of host organism may cause susceptibility to a variety of bacteria, viruses and fungi, as well as influence the course of infectious diseases. Multiple studies indicate the existence of alleles predisposing to infections. Furthermore, there are about 300 nosological entities of primary immunodeficiencies (PID), i.e., inherited defects of immunity. Timely diagnosis of such conditions is quite challenging; however, it is vital for improving quality of patient care. Modern methods of DNA analysis allow establishing genetic causes of vulnerability to certain infectious agents in many individualsГенетические особенности организма играют важную роль в развитии инфекционных заболеваний, обусловливая восприимчивость к разнообразным бактериям, вирусам и грибам, а также оказывая влияние на течение болезни. Многочисленные исследования свидетельствуют о существовании аллелей предрасположенности к инфекциям. Кроме того, в настоящее время известно около 300 нозологических форм первичных иммунодефицитов (ПИД), которые представляют собой наследственные дефекты иммунитета. Своевременная диагностика таких состояний представляет значительные трудности, однако она крайне необходима для повышения качества лечения пациентов. Использование современных методов ДНК-анализа во многих случаях позволяет установить генетическую причину уязвимости по отношению к тем или иным инфекционным агентам.

Лечение солидных опухолей ингибиторами контрольных точек на фоне сопутствующей ВИЧ-инфекции: стоит ли рисковать?

Objective. To present the available data regarding the tolerance of immune checkpoint inhibitors (ICIs) in cancer patients with concurrent HIV.Material and Methods. A literature search was conducted in the electronic databases PubMed, Cochrane Library and UpToDate up to February 2022.Results. The article outlines the background and experience of using ICIs for the treatment of malignant tumors in patients with concomitant HIV infection.Conclusions. Until recently, the presence of chronic infections, including HIV infection, was one of the key contraindications for prescribing immunotherapy. However, the recent scientific publications demonstrate the efficacy and good tolerability of ICIs in cancer patients with concurrent HIV. Future prospective clinical trials will help to predetermine the potential of immunotherapy in clinical practice in this patients.Цель исследования ‒ представить имеющиеся данные о переносимости ингибиторов контрольных точек (ИКТ) у онкологических пациентов, отягощенных ВИЧ-инфекцией.Материал и методы. Проведен поиск литературных источников, опубликованных в базах данных PubMed, Cochrane Library и UpToDate по февраль 2022 г.Результаты. В статье изложены предпосылки и опыт применения ИКТ для лечения злокачественных опухолей у больных с сопутствующей ВИЧ-инфекцией.Заключение. До недавнего времени наличие вирусных заболеваний, в т.ч. ВИЧ-инфекции, являлось одним из ключевых противопоказаний для назначения иммунотерапии. Однако последние научные публикации демонстрируют эффективность и хорошую переносимость ИКТ у онкологических пациентов, отягощенных ВИЧ-инфекцией. Дальнейшие проспективные исследования позволят определить потенциал иммунотерапии в клинической практике у данной категории больных

МОЛЕКУЛЯРНО-ГЕНЕТИЧЕСКИЙ «ПОРТРЕТ» РАКА МОЛОЧНОЙ ЖЕЛЕЗЫ

Understanding genetic mechanisms and detection of biological markers of tumor growth forms an individual molecular phenotype oftransformed cells that characterizes stage of tumor, the ability to metastasize, hormonal sensitivity, chemotherapyefficiencyetc. Mutations in proto- and anti-oncogenes controlling mitotic activity of cells and their ability to DNA reparation are often found in tumor cells in patients with cancer. Defects of classical tumor suppressor genes (BRCA1/2, CHEK2, ATM, PALB2, NBS1, TP53, etc.) determine the hereditary predisposition to breast cancer caused by genomic instability and appearance of «chimeric» genes, aneuploidies and chromosomal aberrations. Breast cancer is a genetically heterogeneous disease with various molecular, biological and clinical features. Identificationof the molecular phenotype of breast carcinomas is an important prognostic factor of the disease, and it helps to individualize the therapeutic approach for patients.Понимание генетических механизмов и выявление биологических маркеров опухолевого роста формируют индивидуальный молекулярный фенотип трансформированных клеток, который характеризует степень злокачественности опухоли, способность к метастазированию, гормональную чувствительность, эффективность химиотерапии и т. д. В опухолях пациентов с онкологическими заболеваниями обнаруживаются мутации прото- и антионкогенов, контролирующих митотическую активность клеток и их способность к репарации ДНК. Дефекты классических генов-супрессоров опухолевого роста (BRCA1/2, CHEK2, ATM, PALB2, NBS1, TP53 и др.) детерминируют наследственную предрасположенность к развитию рака молочной железы (РМЖ), обусловленную нарушением стабильности генома и возникновением «химерных» генов, анеуплоидий или хромосомных аберраций. РМЖ представляет собой генетически гетерогенное заболевание с различными молекулярно-биологическими и клиническими особенностями. Идентификация молекулярного фенотипа карцином молочной железы является важным прогностическим фактором заболевания и позволяет персонифицировать лечение больных

BRCA1 4153delA founder mutation in Russian ovarian cancer patients

The BRCA1 4153delA allele is frequently referred to as the Russian founder mutation, as it was initially detected in several cancer families from Moscow. Our earlier studies have demonstrated 1% occurrence of BRCA1 4153delA heterozygosity in familial and/or early-onset and/or bilateral Russian breast cancer (BC) patients. Since literature data suggest that the 4153delA variant is more associated with ovarian cancer (OC) than with BC, we expected to reveal a highly elevated frequency of this genotype in Russian ovarian cancer series. However, real-time allele-specific PCR genotyping has detected only two BRCA1 4153delA carriers out of 177 unselected OC patients (1.1%). Both these carriers were early-onset and had serous carcinomas of grade 3. Thus, our study supports neither the Russian origin of BRCA1 4153delA mutation, nor its selectivity towards ovarian versus breast cancer predisposition

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. A Osorio1, R L Milne2, G Pita3, P Peterlongo4,5, T Heikkinen6, J Simard7, G Chenevix-Trench8, A B Spurdle8, J Beesley8, X Chen8, S Healey8, KConFab9, S L Neuhausen10, Y C Ding10, F J Couch11,12, X Wang11, N Lindor13, S Manoukian4, M Barile14, A Viel15, L Tizzoni5,16, C I Szabo17, L Foretova18, M Zikan19, K Claes20, M H Greene21, P Mai21, G Rennert22, F Lejbkowicz22, O Barnett-Griness22, I L Andrulis23,24, H Ozcelik24, N Weerasooriya23, OCGN23, A-M Gerdes25, M Thomassen25, D G Cruger26, M A Caligo27, E Friedman28,29, B Kaufman28,29, Y Laitman28, S Cohen28, T Kontorovich28, R Gershoni-Baruch30, E Dagan31,32, H Jernström33, M S Askmalm34, B Arver35, B Malmer36, SWE-BRCA37, S M Domchek38, K L Nathanson38, J Brunet39, T Ramón y Cajal40, D Yannoukakos41, U Hamann42, HEBON37, F B L Hogervorst43, S Verhoef43, EB Gómez García44,45, J T Wijnen46,47, A van den Ouweland48, EMBRACE37, D F Easton49, S Peock49, M Cook49, C T Oliver49, D Frost49, C Luccarini50, D G Evans51, F Lalloo51, R Eeles52, G Pichert53, J Cook54, S Hodgson55, P J Morrison56, F Douglas57, A K Godwin58, GEMO59,60,61, O M Sinilnikova59,60, L Barjhoux59,60, D Stoppa-Lyonnet61, V Moncoutier61, S Giraud59, C Cassini62,63, L Olivier-Faivre62,63, F Révillion64, J-P Peyrat64, D Muller65, J-P Fricker65, H T Lynch66, E M John67, S Buys68, M Daly69, J L Hopper70, M B Terry71, A Miron72, Y Yassin72, D Goldgar73, Breast Cancer Family Registry37, C F Singer74, D Gschwantler-Kaulich74, G Pfeiler74, A-C Spiess74, Thomas v O Hansen75, O T Johannsson76, T Kirchhoff77, K Offit77, K Kosarin77, M Piedmonte78, G C Rodriguez79, K Wakeley80, J F Boggess81, J Basil82, P E Schwartz83, S V Blank84, A E Toland85, M Montagna86, C Casella87, E N Imyanitov88, A Allavena89, R K Schmutzler90, B Versmold90, C Engel91, A Meindl92, N Ditsch93, N Arnold94, D Niederacher95, H Deißler96, B Fiebig97, R Varon-Mateeva98, D Schaefer99, U G Froster100, T Caldes101, M de la Hoya101, L McGuffog49, A C Antoniou49, H Nevanlinna6, P Radice4,5 and J Benítez1,3 on behalf of CIMB

Resolution on the results of Advisory Board “Searching the effective methods of testing and treating patients with NSCLC caused by <i>NTRK</i> gene fusions“

The Advisory Board was held on December 24, 2021. The molecular genetic research lead specialists and national lead oncologists discussed issues of diagnosis of NTRK gene translocations in patients with non-small cell lung cancer (NSCLC), as well as current opportunities for the treatment of patients with NSCLC caused by NTRK gene fusions. The experts reaffirmed the necessity to identify timely patients with NSCLC caused by NTRK gene fusions, as the correct diagnosis of the disease, including the use of modern diagnostic methods of NTRK gene fusion (NGS is the most sensitive and specific method) determines the success of patient treatment. In this regard, it is critical that physicians know the advantages and disadvantages of each molecular diagnostic method used to have the opportunity to choose the best approach in each clinical case. In order to have a clear, well-functioning strategy for managing patients with suspected NSCLC caused by NTRK gene fusion, it is necessary to use molecular genetic tests, as well as include TRK inhibitors (in particular, the drug larotrectinib; at the time publication of the Resolution, the drug larotrectinib is not registered in the territory of the Russian Federation) in the clinical guidelines for the treatment of lung cancer. Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor. The clinical studies on larotrectinib have demonstrated high response rates and durable responses in adults and children with tumours associated with NTRK gene fusions, including primary CNS tumours and brain metastases. The objective response rate observed with larotrectinib was 79%, with 16% achieving a complete response and 64% achieving a partial response. At the same time, the median progression-free survival on larotrectinib was 28.3 months, and the median overall survival was 44.4 months