RESUMO
Several breast cancer susceptibility genes have been discovered, but more are likely to exist. To identify additional breast cancer susceptibility genes, we used the founder population of Poland and performed whole-exome sequencing on 510 women with familial breast cancer and 308 control subjects. We identified a rare mutation in ATRIP (GenBank: NM_130384.3: c.1152_1155del [p.Gly385Ter]) in two women with breast cancer. At the validation phase, we found this variant in 42/16,085 unselected Polish breast cancer-affected individuals and in 11/9,285 control subjects (OR = 2.14, 95% CI = 1.13-4.28, p = 0.02). By analyzing the sequence data of the UK Biobank study participants (450,000 individuals), we identified ATRIP loss-of-function variants among 13/15,643 breast cancer-affected individuals versus 40/157,943 control subjects (OR = 3.28, 95% CI = 1.76-6.14, p < 0.001). Immunohistochemistry and functional studies showed the ATRIP c.1152_1155del variant allele is weakly expressed compared to the wild-type allele, and truncated ATRIP fails to perform its normal function to prevent replicative stress. We showed that tumors of women with breast cancer who have a germline ATRIP mutation have loss of heterozygosity at the site of ATRIP mutation and genomic homologous recombination deficiency. ATRIP is a critical partner of ATR that binds to RPA coating single-stranded DNA at sites of stalled DNA replication forks. Proper activation of ATR-ATRIP elicits a DNA damage checkpoint crucial in regulating cellular responses to DNA replication stress. Based on our observations, we conclude ATRIP is a breast cancer susceptibility gene candidate linking DNA replication stress to breast cancer.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Neoplasias da Mama , Proteínas de Ligação a DNA , Feminino , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Bancos de Espécimes Biológicos , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Dano ao DNA , Proteínas de Ligação a DNA/genética , Polônia/epidemiologia , Proteína de Replicação A/genética , Proteína de Replicação A/metabolismo , Reino Unido/epidemiologiaRESUMO
The SSU nuclear rDNA (encoding 18S ribosomal RNA) is one of the most frequently sequenced genes in the molecular analysis of insects. Molecular apomorphies in the secondary and tertiary structures of several 18S rRNA length-variable regions (LVRs) located within the V2, V4, and V7 hypervariable regions can be good indicators for recovering monophyletic groups within some heteropteran families. Among the LVRs that have been analysed, the LVR L in the V4 hypervariable region is the longest and most crucial for such assessments. We analysed the 18S rRNA V4 hypervariable region sequences of 45 species from the family Cydnidae, including all 6 subfamilies (Amaurocorinae, Amnestinae, Cephalocteinae, Cydninae, Garsauriinae, and Sehirinae) and three pentatomoid families (Parastrachiidae, Thaumastellidae, and Thyreocoridae), which have often been included in the broadly defined Cydnidae family. This is the first time that representatives of all Cydnidae subfamilies have been included in a molecular analysis. Only taxa from two subfamilies, Sehirinae and Cydninae, have been used in previous molecular studies. The secondary and tertiary structures of the LVR L were predicted for each species using the two-step procedure already accepted for such analyses to recover any molecular apomorphy essential for determining monophyly. The results of our comparative studies contradict the current understanding of the relationships among burrowing bugs and the current family classification.
Assuntos
Heterópteros , Humanos , Animais , Heterópteros/genética , RNA Ribossômico 18S/genética , DNA RibossômicoRESUMO
Ku70/80 protein inhibitors reduce the repair of DNA double-strand breaks via the Ku70/80 pathway, so they can be used to treat cancers with Ku70/80 overexpression. Since the association of Ku70/80 with germline CHEK2 mutations in breast cancer is unknown, in this study we evaluated the expression of Ku70/80 in breast cancers with germline CHEK2 mutations. Immunohistochemistry with a Ku70/80 antibody on tissue microarrays from 225 CHEK2-associated breast cancers was used and automatically assessed with computerized image analysis. We report that the vast majority of breast cancers expressed high level of nuclear Ku70/80 and a small percentage of tumors (3.5%) were negative for Ku70/80 expression. There was a significant difference between the nuclear Ku70/80 expression in CHEK2-associated vs. CHEK2-non-associated breast cancers in all tumors (p = 0.009), and in the estrogen receptor (ER) positive subgroup of breast cancers (p = 0.03). This study is the first reporting an association of Ku70/80 expression with CHEK2 germline mutations in breast cancer. The results suggest that evaluation of Ku70/80 expression in breast cancer may improve the selection of breast cancer patients for Ku70/80 inhibitor therapy, and point to CHEK2-associated breast cancer and a subset of ER-positive breast cancer as potential suitable targets for such therapy.
Assuntos
Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Mutação em Linhagem Germinativa , Processamento de Imagem Assistida por ComputadorRESUMO
BACKGROUND: The objective of this study was to establish the contribution of PALB2 mutations to prostate cancer risk and to estimate survival among PALB2 carriers. METHODS: We genotyped 5472 unselected men with prostate cancer and 8016 controls for two Polish founder variants of PALB2 (c.509_510delGA and c.172_175delTTGT). In patients with prostate cancer, the survival of carriers of a PALB2 mutation was compared to that of non-carriers. RESULTS: A PALB2 mutation was found in 0.29% of cases and 0.21% of controls (odds ratio (OR) = 1.38; 95% confidence interval (CI) 0.70-2.73; p = 0.45). PALB2 mutation carriers were more commonly diagnosed with aggressive cancers of high (8-10) Gleason score than non-carriers (64.3 vs 18.1%, p < 0.0001). The OR for high-grade prostate cancer was 8.05 (95% CI 3.57-18.15, p < 0.0001). After a median follow-up of 102 months, the age-adjusted hazard ratio for all-cause mortality associated with a PALB2 mutation was 2.52 (95% CI 1.40-4.54; p = 0.0023). The actuarial 5-year survival was 42% for PALB2 carriers and was 72% for non-carriers (p = 0.006). CONCLUSION: In Poland, PALB2 mutations predispose to an aggressive and lethal form of prostate cancer.
Assuntos
Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Mutação , Neoplasias da Próstata/patologia , Análise de Sequência de DNA/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Polônia , Neoplasias da Próstata/genética , Análise de SobrevidaRESUMO
Methylation of the promoter of the BRCA1 gene in DNA derived from peripheral blood cells is a possible risk factor for breast cancer. It is not clear if this association is restricted to certain types of breast cancer or is a general phenomenon. We evaluated BRCA1 methylation status in peripheral blood cells from 942 breast cancer patients and from 500 controls. We also assessed methylation status in 262 paraffin-embedded breast cancer tissues. Methylation status was assessed using methylation-sensitive high-resolution melting and was categorized as positive or negative. BRCA1 methylation in peripheral blood cells was strongly associated with the risk of triple-negative breast cancer (TNBC) (odds ratio [OR] 4.70; 95% confidence interval [CI]: 3.13-7.07; p < 0.001), but not of estrogen-receptor positive breast cancer (OR 0.80; 95% CI: 0.46-1.42; p = 0.46). Methylation was also overrepresented among patients with high-grade cancers (OR 4.53; 95% CI: 2.91-7.05; p < 0.001) and medullary cancers (OR 3.08; 95% CI: 1.38-6.88; p = 0.006). Moreover, we detected a significant concordance of BRCA1 promoter methylation in peripheral blood and paired tumor tissue (p < 0.001). We found that BRCA1 promoter methylation in peripheral blood cells is associated with approximately five times greater risk of TNBC. We propose that BRCA1 methylation in blood-derived DNA could be a novel biomarker of increased breast cancer susceptibility, in particular for triple-negative tumors.
Assuntos
Proteína BRCA1/genética , Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Regiões Promotoras Genéticas/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Mama/patologia , Estudos de Casos e Controles , Metilação de DNA , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
In designing national strategies for genetic testing, it is important to define the full spectrum of pathogenic mutations in prostate cancer (PCa) susceptibility genes. To investigate the frequency of mutations in PCa susceptibility genes in Polish familial PCa cases and to estimate gene-related PCa risks and probability of aggressive disease, we analyzed the coding regions of 14 genes by exome sequencing in 390 men with familial prostate cancer and 308 cancer-free controls. We compared the mutation frequencies between PCa cases and controls. We also compared clinical characteristics of prostate cancers between mutation carriers and noncarriers. Of the 390 PCa cases, 76 men (19.5%) carried a mutation in BRCA1, BRCA2, NBN, ATM, CHEK2, HOXB13, MSH2 or MSH6 genes. No mutations were found in BRIP1, PTEN, TP53, MLH1, PMS2 and SPOP. Significant associations with familial PCa risk were observed for CHEK2, NBN, ATM, and HOXB13. High-grade (Gleason 8-10) tumors were seen in 56% of BRCA2, NBN or ATM carriers, compared to 21% of patients who tested negative for mutations in these genes (OR = 4.7, 95% CI 2.0-10.7, P = .0003). In summary, approximately 20% of familial prostate cancer cases in Poland can be attributed to mutations in eight susceptibility genes. Carriers of mutations in BRCA2, NBN and ATM develop aggressive disease and may benefit from intensified screening and/or chemotherapy.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA2/genética , Proteínas de Ciclo Celular/genética , Mutação , Proteínas Nucleares/genética , Neoplasias da Próstata/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Linhagem , Polônia , Neoplasias da Próstata/genética , Sequenciamento do ExomaRESUMO
One of the key parameters in the diagnosis of papillary thyroid carcinoma (PTC) are true nuclear pseudoinclusions (NPs), which constitute invaginations of the cytoplasm into the nucleus. On the other hand, strong cytoplasmic expression of CK19 is a well-known attribute of PTC tumor cells. We analyzed NPs using CK19 immunohistochemistry in histological sections of 52 PTCs and seven noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs). Strong CK19+ NPs were present in 77% of PTCs, whereas NPs in hematoxylin and eosin (HE)-stained slides (HE NPs) were identified in only 48% of PTCs. Detection of CK19+ NPs enabled easier and objective recognition of NPs and better discrimination of NPs from pseudo-pseudoinclusions than detection of HE NPs. In the 15 of the 27 (55.5%) PTCs in which we could not discern HE NPs, strong CK19+ NPs could be identified reliably, quickly and easily. Moreover, all NIFTPs were negative for both CK19+ NPs and HE NPs. Detection of CK19+ NPs may refine the assessment of this important diagnostic feature and, hence, the microscopic diagnostic criteria of PTC. Thus, these findings may have implications for the accurate diagnosis of PTC and NIFTP.
Assuntos
Queratina-19/análise , Câncer Papilífero da Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Biomarcadores Tumorais/análise , Núcleo Celular , Humanos , Imuno-Histoquímica , Corpos de Inclusão IntranuclearRESUMO
Membrane monocarboxylate transporter 1 (SLC16A1/MCT1) plays an important role in hepatocyte homeostasis, as well as drug handling. However, there is no available information about the impact of liver pathology on the transporter levels and function. The study was aimed to quantify SLC16A1 mRNA (qRT-PCR) and MCT1 protein abundance (liquid chromatography-tandem mass spectrometry (LC---MS/MS)) in the livers of patients diagnosed, according to the standard clinical criteria, with hepatitis C, primary biliary cirrhosis, primary sclerosing hepatitis, alcoholic liver disease (ALD), and autoimmune hepatitis. The stage of liver dysfunction was classified according to Child-Pugh score. Downregulation of SLC16A1/MCT1 levels was observed in all liver pathology states, significantly for ALD. The progression of liver dysfunction, from Child-Pugh class A to C, involved the gradual decline in SLC16A1 mRNA and MCT1 protein abundance, reaching a clinically significant decrease in class C livers. Reduced levels of MCT1 were associated with significant intracellular lactate accumulation. The MCT1 transcript and protein did not demonstrate significant correlations regardless of the liver pathology analyzed, as well as the disease stage, suggesting posttranscriptional regulation, and several microRNAs were found as potential regulators of MCT1 abundance. MCT1 membrane immunolocalization without cytoplasmic retention was observed in all studied liver pathologies. Overall, the study demonstrates that SLC16A1/MCT1 is involved in liver pathology, especially in ALD.
Assuntos
Fígado/metabolismo , Fígado/patologia , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/metabolismo , Adulto , Idoso , Animais , Regulação para Baixo , Feminino , Regulação da Expressão Gênica , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/genética , RNA Mensageiro , Espectrometria de Massas em TandemRESUMO
To optimize genetic testing, it is necessary to establish the spectrum of breast cancer-predisposing mutations in particular ethnic groups. We studied 1,018 women with a strong family history for breast cancer (families with hereditary breast cancer; HBC) from genetically homogenous population of Poland, which is populated by ethnic Slavs, for mutations in 14 cancer susceptibility genes. Additionally, we compared the frequency of candidate pathogenic variants in breast cancer cases and controls. Germline mutations were detected in 512 of 1,018 probands with breast cancer (50.3%), including BRCA1/2 mutations detected in 420 families and non-BRCA mutations seen in 92 families. Thirteen BRCA1/2 founder mutations represented 84% of all BRCA1/2-positive cases. Seven founder mutations of CHEK2, PALB2, NBN and RECQL represented 73% of all non-BRCA-positive cases. Odds ratios for hereditary breast cancer were 87.6 for BRCA1, 15.4 for PALB2, 7.2 for CHEK2, 2.8 for NBN and 15.8 for RECQL. Odds ratios for XRCC2, BLM and BARD1 were below 1.3. In summary, we found that 20 founder mutations in six genes (BRCA1/2, CHEK2, PALB2, NBN and RECQL) are responsible for 82% of Polish hereditary breast cancer families. A simple test for these 20 mutations will facilitate genetic testing for breast cancer susceptibility in Poland. It may also facilitate genetic testing for breast cancer susceptibility in other Slavic populations and women of Slavic descent worldwide.
Assuntos
Neoplasias da Mama/genética , Mutação em Linhagem Germinativa/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Humanos , Pessoa de Meia-Idade , PolôniaRESUMO
BACKGROUND: XRCC2 participates in homologous recombination and in DNA repair. XRCC2 has been reported to be a breast cancer susceptibility gene and is now included in several breast cancer susceptibility gene panels. METHODS: We sequenced XRCC2 in 617 Polish women with familial breast cancer and found a founder mutation. We then genotyped 12,617 women with breast cancer and 4599 controls for the XRCC2 founder mutation. RESULTS: We identified a recurrent truncating mutation of XRCC2 (c.96delT, p.Phe32fs) in 3 of 617 patients with familial breast cancer who were sequenced. The c.96delT mutation was then detected in 29 of 12,617 unselected breast cancer cases (0.23%) compared to 11 of 4599 cancer-free women (0.24%) (OR = 0.96; 95% CI 0.48-1.93). The mutation frequency in 1988 women with familial breast cancer was 0.2% (OR = 0.84, 95% CI 0.27-2.65). Breast cancers in XRCC2 mutation carriers and non-carriers were similar with respect to age of diagnosis and clinical characteristics. Loss of the wild-type XRCC2 allele was observed only in one of the eight breast cancers from patients who carried the XRCC2 mutation. No cancer type was more common in first- or second-degree relatives of XRCC2 mutation carriers than in relatives of the non-carriers. CONCLUSION: XRCC2 c.96delT is a protein-truncating founder variant in Poland. There is no evidence that this mutation predisposes to breast cancer (and other cancers). It is premature to consider XRCC2 as a breast cancer-predisposing gene.
Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Adulto , Idoso , Alelos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Estudos de Associação Genética , Testes Genéticos , Genótipo , Humanos , Pessoa de Meia-Idade , Mutação , Taxa de Mutação , Polônia/epidemiologiaRESUMO
The contribution of DNA damage repair mechanisms to the progression of normal breast to ductal carcinoma in situ (DCIS) and invasive ductal carcinoma is largely unknown. The purpose of this report was to assess the mRNA expression levels of two important genes associated with DNA repair, BRCA1 and PARP1, in normal breast tissue, DCIS G1, G2 and G3, and co-existing adjacent invasive ductal carcinoma. BRCA1 and PARP1 mRNA expression was assessed in 32 ductal carcinomas in situ of the breast using a laser microdissection and pressure catapulting system and quantitative real-time PCR. The relative expression of BRCA1 mRNA was significantly increased in DCIS G2 and DCIS G3 relative to normal breast tissue (p = 0.02, p = 0.001, respectively). Significant differences in BRCA1 expression were observed between DCIS G1 and G2 (p = 0.02) and between DCIS G1 and G3 (p = 0.0007). No significant differences in BRCA1 expression were observed between normal breast tissue and DCIS G1 and between DCIS component and adjacent invasive ductal carcinoma. No significant differences in the relative expression of PARP1 mRNA were observed between groups. Increased BRCA1 mRNA expression (but not PARP1 mRNA) occurs early in the development of breast cancer, i.e. at the noninvasive (DCIS) stage, suggesting a demand for increased activity of a DNA double-strand break repair by homologous recombination. DCIS G1 and normal breast tissue share highly similar BRCA1 and PARP1 expression level. This finding supports the idea that DCIS G1 belongs to a separate family of precursor lesions with low malignant potential.
Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal não Infiltrante/genética , Poli(ADP-Ribose) Polimerase-1/genética , Humanos , Microdissecção e Captura a Laser , RNA MensageiroRESUMO
BRCA1/2-associated breast cancers are sensitive to poly(ADPribose) polymerase (PARP) inhibitors and platinum compounds mainly due to their deficiency in DNA repair via homologous recombination (HR). However, approximately only 15% of triple-negative breast cancers (TNBCs) are BRCA1/2-associated. TNBCs that exhibit BRCAness (a phenotype reflecting impaired HR in BRCA1/2-negative tumors) are also regarded sensitive to PARP inhibitors and platinum compounds. Thus, we hypothesized that hereditary BRCA1/2-negative TNBCs may exhibit BRCAness. To find a subset of hereditary BRCA1/2-negative TNBCs among 360 TNBCs, we first identified a group of 41 hereditary TNBCs by analyzing the family histories of the patients. Next, we tested this group for the presence of germline BRCA1/2 mutations, and finally, we compared the expression levels of 120 genes involved in HR and five other major mechanisms of DNA damage repair between BRCA1/2-associated and BRCA1/2-negative subgroups of hereditary TNBCs using real-time PCR arrays. Approximately 73% of the hereditary TNBCs were BRCA1/2-associated and 27% were BRCA1/2-negative. The expression levels of the analyzed genes showed no significant differences between these two subgroups indicating the BRCAness of the BRCA1/2-negative hereditary TNBCs and thereby distinguishing a novel subset of TNBCs as a potential target for PARP inhibitors or platinum-based therapy. The results show the significance of family history in selecting patients with TNBC for therapies directed at incompetent DNA repair (e.g., PARP inhibitors and/or platinum-based therapies) and indicate that a relatively simple strategy for broadening the target group for these modes of treatment is to identify patients with hereditary TNBCs.
Assuntos
Genes BRCA1 , Genes BRCA2 , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Dano ao DNA , Reparo do DNA , Feminino , Mutação em Linhagem Germinativa , Recombinação Homóloga , Humanos , Pessoa de Meia-Idade , Fenótipo , Inibidores de Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Sistema de Registros , Inquéritos e Questionários , Adulto JovemRESUMO
Several single nucleotide polymorphisms (SNPs) have been associated with an elevated risk of prostate cancer risk. It is not established if they are useful in predicting the presence of prostate cancer at biopsy or if they can be used to define a low-risk group of men. In this study, 4,548 men underwent a prostate biopsy because of an elevated prostate specific antigen (PSA; ≥4 ng/mL) or an abnormal digital rectal examination (DRE). All men were genotyped for 11 selected SNPs. The effect of each SNP, alone and in combination, on prostate cancer prevalence was studied. Of 4,548 men: 1,834 (40.3%) were found to have cancer. A positive association with prostate cancer was seen for 5 of 11 SNPs studied (rs1800629, rs1859962, rs1447295, rs4430796, rs11228565). The cancer detection rate rose with the number of SNP risk alleles from 29% for men with no variant to 63% for men who carried seven or more risk alleles (OR = 4.2; p = 0.002). The SNP data did not improve the predictive power of clinical factors (age, PSA and DRE) for detecting prostate cancer (AUC: 0.726 vs. 0.735; p = 0.4). We were unable to define a group of men with a sufficiently low prevalence of prostate cancer that a biopsy might have been avoided. In conclusion, our data do not support the routine use of SNP polymorphisms as an adjunct test to be used on the context of prostate biopsy for Polish men with an abnormal screening test.
Assuntos
Polimorfismo de Nucleotídeo Único , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Área Sob a Curva , Biópsia , Exame Retal Digital , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
BACKGROUND: The G84E mutation in the HOXB13 gene has been associated with a high lifetime risk of prostate cancer in North America (about 20-fold). The geographical and ethnic extent of this recurrent allele has not yet been determined. METHODS: We assayed for the presence of the G84E mutation in 3,515 prostate cancer patients and 2,604 controls from Poland and estimated the odds ratio for prostate cancer associated with the allele. RESULTS: The G84E mutation was detected in 3 of 2,604 (0.1%) individuals from the general population in Poland and in 20 of 3,515 (0.6%) men with prostate cancer (Odds ratio [OR] = 5.0; 95% CI: 1.5-16.7; P = 0.008). The allele was present in 4 of 416 (1.0%) men with familial prostate cancer (OR = 8.4, 95% CI: 1.9-37.7; P = 0.005). CONCLUSIONS: The G84E mutation predisposes to prostate cancer in Poland, but accounts for only a small proportion of cases. We expect that the G84E founder mutation might be present in other Slavic populations.
Assuntos
Proteínas de Homeodomínio/genética , Mutação Puntual/genética , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Linhagem , Polônia/epidemiologia , Fatores de Risco , População Branca/genética , População Branca/estatística & dados numéricosRESUMO
Pleurozium schreberi is a common and widespread species that has been the object of many studies, and its biology and ecology are well known. However, genetic studies on this species are limited or even absent. Because of the lack of any data about the genetic diversity of the moss species P. schreberi in Poland, the present paper describes the results of the studies carrying out for the first time this kind of research based on the atpB-rbcL spacer sequences of chloroplast DNA. A total of 35 specimens of P. schreberi from 19 locations in Poland were sampled. Total genomic DNA was extracted, amplified, and sequenced, and all obtained sequences were analyzed. Our findings suggest the low genetic diversity of P. schreberi in Poland. We detected four different haplotypes, shared between different populations.
RESUMO
The lace bug tribe Acalyptaini (Tingidae: Tinginae) includes five genera, Acalypta, Derephysia, Dictyonota, Kalama, and Recaredus, and it was recently resurrected based on morphological and karyological characters. We aimed to validate the distinctiveness of this tribe using 18S rDNA sequences, which have not been used in previous Tingidae phylogenomic studies. Our results confirmed the monophyly of the tribe. Moreover, the monophyly of the subfamily Cantacaderinae and its basal position within the family Tingidae were indicated, as well as the position of the tribe Litadeini as sister to all other Tinginae. In addition, we attempted to determine the apomorphic morpho-molecular characters in the secondary and tertiary structures of length-variable regions of the 18S rRNA sequences of the analysed species. The results showed that two LVRs (LVR X and LVR L) of the hypervariable region V4 exhibited significant variability in the number of nucleotides and could be considered for apomorphic recognition.
RESUMO
Germline mutations in BRCA1 were already linked to basal-like subtype of immunophenotypic molecular classification of breast cancer (BC). However, it is not known whether mutations in other BC susceptibility genes are associated with molecular subtypes of this cancer. We tested the hypothesis that distinct mutations in another BC susceptibility gene involved in DNA repair, i.e., CHEK2 may be associated with particular immunophenotypic molecular subtypes of this cancer. Two groups of patients: 1255 with BCs and 5496 healthy controls were genotyped for four CHEK2 mutations (I157T and three truncating mutations: 1100delC, IVS2 + 1G > A, del5395). BCs were tested by immunohistochemistry on tissue microarrays for ER, PR, HER-2, EGFR, and CK5/6 and were assigned to appropriate subtypes of immunophenotypic molecular classification. There was a significant association between CHEK2 mutations and the immunophenotypic molecular classification (P = 0.004). CHEK2-associated cancers were predominantly luminal (108/117 = 92.3%). CHEK2-I157T variant was associated with the luminal A subtype (P = 0.01), whereas CHEK2-truncating mutations were associated with the luminal B subtype (P = 0.005). Comparing the prevalence of CHEK2 mutations in BC with controls revealed that carriers of an I157T variant had OR of 1.80 for luminal A subtype and carriers of truncating mutations had OR of 6.26 for luminal B subtype of BC. To our knowledge, this is the first study showing that specific mutations in the same susceptibility gene are associated with different immunophenotypic molecular subtypes of BC. This association represents independent evidence supporting the biological significance of immunophenotypic molecular classification of BC.
Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Mutação em Linhagem Germinativa , Proteínas Serina-Treonina Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Estudos de Casos e Controles , Quinase do Ponto de Checagem 2 , Códon sem Sentido , Dispneia , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Recém-Nascido , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Fenótipo , Adulto JovemRESUMO
Identifying targets for personalized targeted therapy is the pathologist's domain and a treasure. For decades, pathologists have had to learn, understand, adopt and implement many new laboratory techniques as they arrived on the scene. Pathologists successfully integrate the results of those tests into final pathology reports that were, and still are, the basis of clinical therapeutic decisions. The molecular methods are different but no more difficult to comprehend in the era of "kit procedures". In recent years, the development of targeted therapies has influenced routine practices in pathology laboratories because the use of molecular techniques is required to include clinically useful predictive information in the pathology report. Pathologists have the knowledge and expertise to identify particular gene mutations using the appropriate molecular tests currently available. This review focuses on the most important recent developments in KRAS mutation testing in metastatic colorectal cancer (CRC), and shows that a pathologist is involved in 10 stages of this procedure. Recent studies have shown that highly sensitive, simple, reliable and rapid assays may significantly improve the identification of CRC patients resistant to anti-EGFR therapy. Thus, direct sequencing does not seem to be an optimal procedure of KRAS testing for clinical purposes. Twelve currently available high-sensitivity diagnostic assays (with the CE-IVD mark) for KRAS mutation testing are briefly described and compared. The suggested pathology report content for somatic mutation tests is described. In conclusion, evidence is presented that sending away paraffin blocks with tumor tissue for KRAS mutation testing may not be in the best interest of patients. Instead, an evidence-based approach indicates that KRAS mutation testing should be performed in pathology departments, only with the use of CE-IVD/FDA-approved KRAS tests, and with the obligatory, periodic participation in the KRAS EQA scheme organized by the European Society of Pathology as an independent international body.
Assuntos
Neoplasias Colorretais/genética , Testes Genéticos/métodos , Mutação , Medicina de Precisão/métodos , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Neoplasias Colorretais/tratamento farmacológico , Humanos , Terapia de Alvo Molecular/métodos , Proteínas Proto-Oncogênicas p21(ras)RESUMO
Recent findings raise the possibility of PARP inhibitor therapy in colorectal cancers (CRCs). However, the extent of PARP-1 protein expression in clinical specimens of CRC is not known. Using immunohistochemistry we assessed PARP-1 protein expression in tissue microarrays of 151 CRCs and its association with the patient's age, sex, Astler-Coller stage, grade and site of the tumor. High PARP nuclear immunoreactivity was found in 68.2% (103/151) of all cases. In turn, 31.8% (48/151) of tumors showed low PARP expression, including 9 (6%) PARP-1 negative CRCs. There was a significant association of PARP-1 expression with the site of CRC and Astler-Coller stage. A high PARP expression was noted in 79.1% of colon vs. 53.9% of rectal tumors (p = 0.001). The mean PARP-1 score was 1.27 times higher in colon vs. rectal cancers (p = 0.009) and it was higher in stage B2 vs. stage C of CRCs (p = 0.018). In conclusion, the level of PARP-1 protein nuclear expression is associated with the tumor site and heterogeneous across clinical specimens of CRC, with the majority of CRCs expressing a high level but minority - low or no PARP-1 expression. These findings may have a clinical significance because the assessment of PARP-1 expression in tumor samples may improve selection of patients with CRC for PARP inhibitor therapy.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Poli(ADP-Ribose) Polimerases/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/análise , Análise Serial de TecidosRESUMO
The Old World swallowtail Papilio machaon Linnaeus, 1758 is one of the most well-known and most characteristic members of the family Papilionidae. Over the past two centuries, the butterfly has been the subject of many studies. P. machaon is characterised by a tendency to change the wing colour pattern. In turn, due to the great interest of collectors and amateur entomologists, these studies have been converted into the description of over 100 colour forms, aberrations and subspecies. In this study, mitochondrial DNA (mtDNA), 16S rDNA and cytochrome b sequences were used to examine the correlation between the intraspecific classification and genetic structure of P. machaon. The study used 87 specimens from 59 different localities covering the geographic distribution of this species in the Palaearctic. The phylogenetic relationships within and between the Old World swallowtail subspecies showed that the intraspecific classification proposed by various authors does not correlate with the variability in mitochondrial DNA sequences. In addition, populations occurring at the species distribution borders in the Palaearctic Region (i.e., Japan, Kamchatka, Morocco and Sakhalin) are genetically distinct from other species.