RESUMEN
We studied the state of the DNA repair system and apoptosis in young mice carrying heterozygous inactivating mutation in the NBS1 gene (c.1971insT, p.Arg658Stop). In the peripheral blood cells of 4-month-old NBS1insT males, the %DNA in the comet tail was higher by 10% than in wild-type mice (wt) (p<0.05). In hepatocytes of NBS1insT mice, the proportion of γH2AX+ nuclear regions marking DNA double-strand breaks was lower by 2 times than in wt mice (p<0.05), which can be an indicator of less efficient DNA repair. In the kidney tissue of NBS1insT mice, a tendency towards the proapoptotic ratio of Bax and Bcl-2 protein markers was revealed against the background of their reduced expression. Thus, the disturbances detected NBS1insT mice in young age suggest that this model is promising for further studies of carcinogenesis.
Asunto(s)
Proteínas de Unión al ADN , Proteínas Nucleares , Masculino , Ratones , Animales , Proteínas de Unión al ADN/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Daño del ADN/genética , Reparación del ADN/genética , ADN , Mutación , Apoptosis/genéticaRESUMEN
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. Systematic comparison with other relevant studies revealed that the founder effect observed in Belarus is among the highest estimates observed worldwide. These findings are surprising, given that the population of Belarus did not experience geographic or cultural isolation throughout history.
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Proteína BRCA1 , Proteína BRCA2 , Neoplasias de la Mama , Neoplasias Ováricas , Femenino , Humanos , Alelos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Efecto Fundador , Predisposición Genética a la Enfermedad , Mutación , Neoplasias Ováricas/genética , República de BelarúsRESUMEN
The aim of our trial was to evaluate the prognostic significance of qualitative ctDNA analysis on different stages of EGFR mutated non-small cell lung cancer (NSCLC) treatment. We included 99 patients amendable for the first line treatment with either gefitinib/erlotinib (n = 87), afatinib (n = 10) or osimertinib (n = 2). Sequential qualitative analysis of ctDNA with cobas® EGFR Mutation Test v2 were performed before first dose, after 2 and 4 months of treatment, and on progression. Our analysis showed clinically significant heterogeneity of EGFR-mutated NSCLC treated with 1st line tyrosine kinase inhibitors (TKIs) in terms of progression-free and overall survival. When treated with conventional approach, i.e. monotherapy with TKIs, the patients falls into three subgroups based on ctDNA analysis before and after 2 months of treatment. Patients without detectable ctDNA at baseline (N = 32) possess the best prognosis on duration of treatment (PFS: 24.07 [16.8-31.3] and OS: 56.2 [21.8-90.7] months). Those who achieve clearance after two months of TKI (N = 42) have indistinguishably good PFS (19.0 [13.7 - 24.2]). Individuals who retain ctDNA after 2 months (N = 25) have the worst prognosis (PFS: 10.3 [7.0 - 13.5], p = 0.000). 9/25 patients did not develop ctDNA clearance at 4 months with no statistical difference in PFS from those without clearance at 2 months. Prognostic heterogeneity of EGFR-mutated NSCLC should be taken into consideration in planning further clinical trials and optimizing the outcome of patients.
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Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , ADN Tumoral Circulante/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del TratamientoRESUMEN
Purpose Endocrine therapy is a mainstay for the treatment of hormone receptor-positive breast cancer (BC); however, only a fraction of patients experience a pronounced response to antagonists of estrogen signaling. There is a need to identify predictors for efficacy of this treatment. Methods This study included 138 patients with newly diagnosed metastatic BC, who received upfront endocrine therapy. Archival biopsy specimens were tested for CCND1 and FGFR1 gene amplification and mRNA expression by PCR-based methods. Results CCND1 and FGFR1 amplification was detected in 24 (17.9%) and 28 (20.9%) of 134 evaluable cases, respectively; 9 carcinomas had concurrent alterations of these two genes. Presence of amplification in at least one locus was more common in tumors of higher grade (p = 0.018) and was associated with higher Ki-67 proliferation index (p = 0.036). CCND1 gene amplification was associated with shorter progression-free survival (PFS) in patients receiving aromatase inhibitors (AI) [16.0 months vs. 32.4 months, HR = 3.16 (95% CI 1.267.93), p = 0.014]. FGFR1 status did not significantly affect PFS of AI-treated women; however, objective response to AI was observed less frequently in FGFR1-amplified BC as compared to cases with normal FGFR1 copy number [2/15 (13.3%) vs. 22/46 (47.8%), p = 0.031]. Meanwhile, CCND1/FGFR1 gene status did not influence the outcome of tamoxifen-treated patients. Conclusion Presence of CCND1 and/or FGFR1 amplification is associated with worse outcomes of AI therapy in patients with metastatic BC (AU)
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Ciclina D1/genética , Amplificación de Genes , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Tamoxifeno/uso terapéuticoRESUMEN
The widespread introduction of genetic testing in recent years has made it possible to determine that more than a third of cases of pheochromocytomas and paragangliomas (PPPGs) are caused by germline mutations. Despite the variety of catecholamine-producing tumors manifestations, there is a sufficient number of clinical and laboratory landmarks that suggest a hereditary genesis of the disease and even a specific syndrome. These include a family history, age of patient, presence of concomitant conditions, and symptoms of the disease. Considering that each of the mutations is associated with certain diseases that often determine tactics of treatment and examination of a patient, e.g. high risk of various malignancies. Awareness of the practitioner on the peculiarities of the course of family forms of PPPGs will allow improving the tactics of managing these patients.The article provides up-to-date information on the prevalence of hereditary PPPGs. The modern views on the pathogenesis of the disease induced by different mutations are presented. The main hereditary syndromes associated with PPPGs are described, including multiple endocrine neoplasia syndrome type 2A and 2B, type 1 neurofibromatosis, von Hippel-Lindau syndrome, hereditary paraganglioma syndrome, as well as clinical and laboratory features of the tumor in these conditions. The main positions on the necessity of genetic screening in patients with PPPGs are given.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Neoplasia Endocrina Múltiple Tipo 2a , Paraganglioma , Feocromocitoma , Enfermedad de von Hippel-Lindau , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/genética , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/genética , Paraganglioma/diagnóstico , Paraganglioma/genética , Feocromocitoma/genética , Enfermedad de von Hippel-Lindau/diagnóstico , Enfermedad de von Hippel-Lindau/genéticaRESUMEN
PURPOSE: Endocrine therapy is a mainstay for the treatment of hormone receptor-positive breast cancer (BC); however, only a fraction of patients experience a pronounced response to antagonists of estrogen signaling. There is a need to identify predictors for efficacy of this treatment. METHODS: This study included 138 patients with newly diagnosed metastatic BC, who received upfront endocrine therapy. Archival biopsy specimens were tested for CCND1 and FGFR1 gene amplification and mRNA expression by PCR-based methods. RESULTS: CCND1 and FGFR1 amplification was detected in 24 (17.9%) and 28 (20.9%) of 134 evaluable cases, respectively; 9 carcinomas had concurrent alterations of these two genes. Presence of amplification in at least one locus was more common in tumors of higher grade (p = 0.018) and was associated with higher Ki-67 proliferation index (p = 0.036). CCND1 gene amplification was associated with shorter progression-free survival (PFS) in patients receiving aromatase inhibitors (AI) [16.0 months vs. 32.4 months, HR = 3.16 (95% CI 1.26-7.93), p = 0.014]. FGFR1 status did not significantly affect PFS of AI-treated women; however, objective response to AI was observed less frequently in FGFR1-amplified BC as compared to cases with normal FGFR1 copy number [2/15 (13.3%) vs. 22/46 (47.8%), p = 0.031]. Meanwhile, CCND1/FGFR1 gene status did not influence the outcome of tamoxifen-treated patients. CONCLUSION: Presence of CCND1 and/or FGFR1 amplification is associated with worse outcomes of AI therapy in patients with metastatic BC.
Asunto(s)
Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Ciclina D1/genética , Amplificación de Genes , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Proliferación Celular , Resistencia a Antineoplásicos , Femenino , Humanos , Estimación de Kaplan-Meier , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Supervivencia sin Progresión , ARN Mensajero/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/uso terapéutico , Resultado del TratamientoRESUMEN
We report a patient with recurrent glioblastoma in eloquent brain area. Stereotactic fluorescence biospectroscopy and stereotactic photodynamic therapy of tumor in opercular area of the left frontal lobe under neurophysiological monitoring were carried out. Literature data on this issue were analyzed.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Fotoquimioterapia , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Fluorescencia , Glioblastoma/diagnóstico por imagen , Glioblastoma/tratamiento farmacológico , Glioblastoma/cirugía , Humanos , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
AIM OF STUDY: To determine a diagnostic algorithm for detecting translocation of the ALK gene and its frequency in the Moscow region. MATERIALS AND METHODS: During the priod between 2014 and 2018 (inclusive), 488 patients without activating mutations in the EGFR gene in the Moscow region were tested. To detect translocation of the ALK gene, fluorescence in situ hybridization (FISH) methods, an immunohistochemical method, and, in some cases, a polymerase chain reaction were used. RESULTS: Revealed ALK gene rearrangement in a population of patients with lung adenocarcinoma amounted to an average of 7.6% of cases. With this, the main method that we used was immunohistochemical method, applicable in more than 80% of cases. The use of other methods for verification of abnormalities in the ALK gene was found necessary in rare cases (3.3%). CONCLUSIONS: Using the algorithm presented in the article, it was possible to detect ALK gene rearrangement in a population of patients with lung adenocarcinoma in the Moscow region in an average of 7.6% of cases.
Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adenocarcinoma , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Reordenamiento Génico , Humanos , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , Moscú , Mutación , Proteínas Tirosina Quinasas ReceptorasRESUMEN
In contrast to other countries with predominantly white populations, Russian smoking-related lung cancers (LC) are mainly squamous cell carcinomas and approximately half lung adenocarcinomas (AdCa) are not related to tobacco consumption. Given that smoking significantly influences the probability of presence of actionable mutations in LC, one would expect that Russian lung AdCa patients would differ from other white populations in distribution of EGFR, ALK, KRAS and BRAF mutations. Herein, 2,336 consecutive lung AdCa cases, including 1,203 patients with known smoking status, were subjected to sequential testing for the above mutations. One quarter of lung AdCa patients carried either EGFR or ALK mutation with combined prevalence of 42% in those who had never smoked but only 8% in smokers. There was only a moderate difference in KRAS mutation frequency between ever- and never-smokers in EGFR/ALK-negative cases (31% vs. 23%), and this was mainly attributed to increased prevalence of G12C substitution in the former group. The occurrence of BRAF V600E mutation was 1.7% and 4% in EGFR/ALK/KRAS mutation-negative ever- and never-smokers, respectively. ALK testing of 470 EGFR-mutated tumors revealed only 1 (0.2%) instance of translocation. Similarly, KRAS testing identified 1 (1.25%) mutation in 80 EGFR-mutated AdCa and none in 48 ALK-rearranged AdCa. Therefore, concurrent actionable mutations in lung adenocarcinoma are exceptionally rare and sequential gene testing can be regarded as a reliable option.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Quinasa de Linfoma Anaplásico/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma , Análisis Mutacional de ADN , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares , Mutación , Reacción en Cadena de la Polimerasa , Federación de Rusia , FumarRESUMEN
Gemistocytic astrocytomas (GA) are a variant of diffuse astrocytomas GII (WHO, 2016). Like all diffuse astrocytomas, GA recur with time, which is often accompanied by malignant degeneretion into the anaplastic astrocytoma GIII or to the secondary glioblastoma GIV. However, the progression-free survival and overall survival in patients with GA is less than in patients with diffuse astrocytomas. Given that this group of patients, according to the WHO classification (2016), is classified as GII, patients with GA usually do not receive comprehensive treatment. We have conducted a thorough analysis of research on this problem for the period from 1956 to 2017. Differences in the histological pattern, immunohistochemical and molecular-genetic profiles, survival of patients with GA and diffuse astrocytomas GII are shown there. A clinical case of a patient with transformation of a diffuse astrocytoma in GA (GIII) and then into a secondary glioblastoma is presented.
Asunto(s)
Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Adulto , Astrocitoma/clasificación , Astrocitoma/terapia , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/terapia , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Mutación , Proteínas de Neoplasias/genéticaRESUMEN
Distribution of cancer-predisposing mutations demonstrates significant interethnic variations. This study aimed to evaluate patterns of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. APC gene defects were identified in 26/38 (68%) subjects with colon polyposis; 8/26 (31%) APC mutations were associated with 2 known mutational hotspots (p.E1309Dfs*4 [n = 5] and p.Q1062fs* [n = 3]), while 6/26 (23%) mutations were novel (p.K73Nfs*6, p.S254Hfs*12, p.S1072Kfs*9, p.E1547Kfs*11, p.L1564X and p.C1263Wfs*22). Biallelic mutations in MUTYH gene were detected in 3/12 (25%) remaining subjects with polyposis and in 6/90 (6.7%) patients with colorectal cancer (CRC) carrying KRAS p.G12C substitution, but not in 231 early-onset CRC cases negative for KRAS p.G12C allele. In addition to known European founder alleles p.Y179C and p.G396D, this study revealed a recurrent character of MUTYH p.R245H germ-line mutation. Besides that, 3 novel pathogenic MUTYH alleles (p.L111P, p.R245S and p.Q293X) were found. Targeted next-generation sequencing of 7 APC/MUTYH mutation-negative DNA samples identified novel potentially pathogenic POLD1 variant (p.L460R) in 1 patient and known low-penetrant cancer-associated allele CHEK2 p.I157T in 3 patients. The analysis of 1120 healthy subjects revealed 15 heterozygous carriers of recurrent MUTYH mutations, thus the expected incidence of MUTYH-associated polyposis in Russia is likely to be 1:23 000.
Asunto(s)
Proteína de la Poliposis Adenomatosa del Colon/genética , Neoplasias Colorrectales/genética , ADN Glicosilasas/genética , Predisposición Genética a la Enfermedad , Adulto , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Análisis Mutacional de ADN , Femenino , Genotipo , Mutación de Línea Germinal/genética , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Federación de Rusia/epidemiologíaRESUMEN
Until recently the detection of carriers of mutations in hereditary cancer genes was aimed almost exclusively to the detection of subjects-at-risk, and consequently, personalized monitoring and preventive actions. However, it was revealed several years ago that some hereditary cancers are characterized by unique biological features and, therefore, unusual spectrum of drug sensitivity. For example, BRCA1/2-associated cancers usually demonstrate somatic loss of the remaining gene allele, and, hence, tumor-specific defects of DNA repair of double-strand breaks. This mechanism determines increased sensitivity of BRCA1/2-related cancers to cisplatin, mitomycin C and PARP inhibitors. Cancers arising as a part of Lynch syndrome can be effectively treated by the modulators of immune response. Tumors in patients with tuberous sclerosis often regress after administration of mTOR inhibitors. For the time being, there is already about a dozen of drugs demonstrating specific activity towards certain categories of hereditary cancers.
Asunto(s)
Cisplatino/uso terapéutico , Resistencia a Antineoplásicos , Mitomicina/uso terapéutico , Síndromes Neoplásicos Hereditarios , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Animales , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Humanos , Síndromes Neoplásicos Hereditarios/tratamiento farmacológico , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/metabolismo , Síndromes Neoplásicos Hereditarios/patologíaRESUMEN
Molecular genetic analysis has become a mandatory component of cancer diagnostics. Preanalytical step for DNA and RNA analysis is a complex process requiring tight interaction between surgeons, pathologists and molecular geneticists. This article discusses key aspects of handling of the tissues before DNA- and RNA-testing.
Asunto(s)
Pruebas Genéticas , Neoplasias , Manejo de Especímenes/métodos , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
Whole exome sequencing (WES) has become a leading tool for genetic analysis right after its invention. This approach permits the detection of mutations spread within coding regions of the entire genome. For cancer patients WES is particularly effective for the search of hereditary cancer mutations and identification of somatically mutated druggable genes. Use of WES already resulted in significant advances in understanding for molecular mechanisms of cancer.
Asunto(s)
Exoma , Genes Relacionados con las Neoplasias , Mutación , Neoplasias/genética , Análisis Mutacional de ADN , HumanosRESUMEN
CHEK2 is classified as a moderate-penetrance gene for hereditary breast cancer (BC). In Russia, CHEK2 mutations hold second position in the list of BC-predisposing gene defects after BRCAl, and include CHEK2 1100deIC, de15395, and IVS2+lG>A gene-inactivating alleles. CHEK2-driven breast carcinomas are generally characterized by poor prognosis and low sensitivity to the conventional therapeutic regimens. CHEK2 testing needs to be incorporated into routine clinical practice owing its overt clinical significance.
Asunto(s)
Neoplasias de la Mama/genética , Quinasa de Punto de Control 2/genética , Enfermedades Genéticas Congénitas/genética , Mutación , Penetrancia , Proteína BRCA1/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Femenino , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/mortalidad , Enfermedades Genéticas Congénitas/terapia , Humanos , Pronóstico , Federación de Rusia/epidemiologíaRESUMEN
This review is aimed at the analysis the current state of acral lentiginous melanoma. This tumor has rather aggressive course and is the main cause of death in skin cancer patients. In Russia the incidence of melanoma during the period 2000-2010 increased from 3.18 to 3.95 cases per 100000 of population. The average annual growth rate was 1.99% and the total growth rate was 21.81%. Although skin melanoma is a visual tumor, more than one third of patients visit oncologists at advanced stages of the disease. Primary melanoma with localizations on the skin of fingers, interdigital spaces, soles, palms and nail plates is especially difficult for early diagnostics.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/diagnóstico , Melanoma/epidemiología , Melanoma/etiología , Melanoma/genética , Melanoma/terapia , Pronóstico , Factores de Riesgo , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/terapia , Terminología como AsuntoRESUMEN
OBJECTIVE: to comparatively study the immunohistochemical profile and to analyze mutations in the BRAF and N-RAS genes. MATERIAL AND METHODS: The spindle cell melanomas taken from the Institute's archives were divided into 6 groups according to the results of clinical and morphological analyses and follow-up studies. Immunohistochemical examination was conducted in 58 cases, including 19 nodular spindle cell melanomas, 10 superficial spreading melanomas, 4 combined melanomas, 8 sarcoma- toid melanomas, 13 mixed desmoplastic melanomas, and 4 pure desmoplastic melanomas. RESULTS: All tumors of the spectrum in question expressed S100, SOX10, KBA.62, nestin, and cyclin D1. The rate of positive staining was 80% for MITF, 69% for PNL2, 61% for HMB45, 58% for Melan A, 36% for CD117, and 35% for SMA. The expression of HMB45 and Melan A was diffuse and marked in the groups of nodular and superficial spreading melanomas; sarcomatoid and mixed desmoplastic melanomas showed only scattered stained cells; pure desmoplastic melanomas were negative to these markers. SMA immunoexpression was observed in only sarcomatoid and desmoplastic types. Dual S100 staining showed a separate actin-positive myofibroblast-like population disappearing in more cellular zones. EMA, claudin 1, and DOG1 were negative in all cases. BRAFV expression was detected in 14% (in 2 nodular and 1 superficial spreading melanomas) and correlated with the presence of mutation. NRAS mutation was found in 1 nodular spindle cell melanoma. Desmoplastic melanomas did not harbor the above mutations. CONCLUSION: This study indicates the variant heterogeneity of spindle cell melanomas, as confirmed by clinical, morphological, immunohistochemical, and molecular examinations. The findings may be useful in the differential diagnosis of these tumors.
Asunto(s)
Melanoma/genética , Melanoma/patología , Nevo de Células Fusiformes/genética , Nevo de Células Fusiformes/patología , Diagnóstico Diferencial , GTP Fosfohidrolasas/genética , Humanos , Inmunohistoquímica , Melanoma/clasificación , Melanoma/metabolismo , Proteínas de la Membrana/genética , Mutación , Nevo de Células Fusiformes/clasificación , Nevo de Células Fusiformes/metabolismo , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
Discovery of activating EGFR mutations led to dramatic modification of treatment schemes for nonsquamous lung cancer. 70 patients with activating EGFR mutations were treated by gefitinib being either a part of prospective phase II trial (n = 25) or, subsequently, subjected to routine clinical management (n = 45). Objective response rate approached to 32.7%. Median time to disease progression was 14 months, and median overall survival was 26.1 months. Subgroup analysis revealed statistically longer time to disease progression (p < 0,0001) and overall survival (p = 0,001) in latter vs. former group, despite the lower rate of objective response (22% vs 48%). Possible explanations include more relaxed standards for routine gefitinib use, i.e. inclusion of the patients with non-measurable tumor lumps, continuation of gefitinib uptake upon slow disease progression, and increasing availability and quality of radiosurgery for brain metastases.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Supervivencia sin Enfermedad , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Molecular genetic analysis of lung tumors is often essential for the proper choice of therapy. EGFR mutation is a well-known marker of sensitivity to gefitinib, erlotinib and afatinib; ALK-translocations make tumor sensitive to several ALK inhibitors; low intratumoral expression of DNA repair genes (ERCC1, BRCA1, etc.) may increase the therapeutic index of platinum-based drugs. Usually these markers are evaluated using formalin-fixed paraffin-embedded tumor tissues. The goal of this work was to assess utility of archived cytological lung cancer specimens as an alternative source of material for molecular genetic testing. We analyzed paired histological and cytological lung adenocarcinoma specimens. Comparison of results within the pairs showed that cytological material can be used instead of histological material for qualitative analyses (detection of EGFR mutations or ALK-translocations); however, gene expression measurements, obtained by quantitative real-time PCR, may differ significantly in histological and cytological samples from the same patient.
Asunto(s)
Adenocarcinoma/genética , Antineoplásicos/farmacología , Bancos de Muestras Biológicas , Receptores ErbB/genética , Pruebas Genéticas , Neoplasias Pulmonares/genética , Biología Molecular , Mutación , Proteínas Tirosina Quinasas Receptoras/genética , Translocación Genética , Adenocarcinoma del Pulmón , Quinasa de Linfoma Anaplásico , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Terapia Molecular Dirigida , Reacción en Cadena en Tiempo Real de la Polimerasa , Federación de Rusia , Manejo de EspecímenesRESUMEN
Two groups of breast cancer patients (53±2 years) in clinical remission receiving no specific therapy were examined: group 1, with BRCA1 gene mutations (N=11) and group 2, without mutations of this kind (N=11). The two groups did not differ by insulinemia and glycemia, insulin resistance index, blood levels of thyrotropic hormone, sex hormone-binding globulin, insulin-like growth factor-1, triglycerides, or lipoproteins. In group 1, blood estradiol level was higher. Intensive glucose-induced generation of reactive oxygen species in these patients was associated with a decrease of cholesterolemia, of the C-peptide/insulin proportion, and a trend to higher urinary excretion of 4-hydroxyestrone, one of the most genotoxic catecholestrogens. BRCA1 gene mutations in breast cancer patients were associated with signs of estrogenization and a pro-genotoxic shift in the estrogen and glucose system, which could modulate the disease course and requires correction.