Background:PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gain-of-function PPM1D with retained phosphatase activity. Their significance in carcinogenesis is unknown.Methods:The exon 6 of PPM1D was sequenced in blood DNA of 543 non-small-cell lung cancer patients (NSCLC). The functional significance of selected PPM1D alterations (Arg458X, Lys469Glu) was compared with the wild-type gene and examined by recombinant DNA techniques, immunoblotting and luciferase reporter assays.Results:The frameshift mutations were found in five NSCLC patients (5/543; 0.92%), all of them had squamous cell carcinomas (5/328; 1.5%). All patients with the mutations were exposed, before the blood collection, to the DNA damaging agents as a part of chemotherapeutic regimen. Functional tests demonstrated that truncating mutation Arg458X causes enhancement of dephosphorylation activity of PPM1D toward serine 15 of p53, whereas Lys469Glu version is equivalent to the wild-type. Neither version of PPM1D (wild-type, Arg458X, Lys469Glu) significantly modulated the ability of p53 to transactivate promoters of the examined p53-target genes (BAX and MDM2).Conclusions:The truncating mutations of PPM1D are present in blood DNA of NSCLC patients at frequency similar to percentage determined for ovarian cancer patients. Our findings raise a question if the detected lesions are a result of chemotherapy.
Polymorphisms in DNA repair genes may modulate not only an individual DNA repair capacity, DNA damage levels and cancer risk but also clinical outcome after DNA damage-inducing anticancer therapy. In this study, we analyzed the association between the XPA -4G>A, XPD Asp312Asn, hOGG1 Ser326Cys, XRCC1 Arg399Gln, XRCC2 -4234G>C, XRCC3 -4541A>G and Thr241Met polymorphisms and prognosis in 250 inoperable non-small cell lung cancer (NSCLC) patients treated with radiotherapy and platinum-based chemotherapy. In univariate model, the XPA-4A and XRCC1 399Gln alleles alone and in combination influenced survival only in stage III group. In multivariate analysis, the XPA-4 GA/AA was associated with poor survival (HR 1.55, p 5 0.011 overall and HR 1.72, p 5 0.008 in stage III). In chemoradiotherapy group, the XPA-4A carriers were at increased risk of death and progression (HR 1.73, p 5 0.013 and HR 1.65, p 5 0.016, respectively), especially in stage III (p 5 0.008). Moreover, individuals with ! 2 XPA/XRCC1 adverse alleles showed a higher risk of death (HR 1.46, p 5 0.036 overall; HR 1.85, p 5 0.004 in stage III and HR 1.71, p 5 0.022 in chemoradiotherapy group) and progression (HR 1.75, p 5 0.011 overall and HR 1.93, p 5 0.005 in stage III). The XPA-4 GA/AA genotype individually and together with the XRCC1 399Gln was an independent unfavorable prognostic factor in our study. Thus, our findings indicate a prognostic potential of the XPA-4G>A in unresected NSCLC treated with radiotherapy and chemoradiotherapy. The results require validation in an independent population.
Aim of the studyMetaplastic breast carcinomas (MBC) are a rare group of cancers, accounting for about 1% of all breast cancers. The study presents a case series of MBC patients diagnosed, treated and followed up in one healthcare center.Material and methodsThe study group comprised 18 women at the median age of 63 years. The most common carcinoma type in the study group was MBC with squamous epithelial differentiation (56%). Estrogen receptor expression was identified in one patient. No steroid or HER2 receptor expression was found in the remaining patients. We analyzed recurrence and survival rates in relation to clinical and therapeutic factors by using the Kaplan-Meier method.ResultsA significantly longer overall survival time was noted among patients treated with adjuvant radiation therapy, p = 0.018. No other factors had a significant influence on survival. Because of the small size of the study group, results obtained in the study should be treated with caution.
Certain common inherited variations in genes involved in tumor angiogenesis, progression and metastasis may contribute to cancer therapy outcome and prognosis by altering the gene expression and protein activity. In this report, we examined the effect of functional polymorphisms in MMP-1, MMP-2, MMP-3, VEGF, VEGFR2, FGFR4 and COX-2 genes on overall (OS) and progression-free survival (PFS) of 350 Caucasian patients with inoperable non-small cell lung cancer (NSCLC). The results of multivariate analysis indicated that VEGFR2 -906C and COX-2 -1195G alleles were strongly associated with poor OS and PFS (p 5 0.002 and 0.015, respectively, for OS; p 5 0.009 and 0.015, respectively, for PFS), while MMP-2 -1306 T allele carriers had significantly reduced PFS (p 5 0.010). Moreover, an increased risk of death and progression was significantly associated with the number of adverse alleles for VEGFR2/COX-2 (p 5 0.0005 for OS and 0.0006 for PFS in >1 adverse allele carriers) and VEGFR2/COX-2/MMP-2 combinations (p 5 0.0003 for OS and 0.0001 for PFS in patients with >2 adverse alleles). Finally, VEGFR2 TC/CC, COX-2 AG/GG and MMP-2 CT/TT genotypes as well as "at risk" allele combinations were identified as independent predictors of unfavorable OS and PFS in the group. In conclusion, the data suggest that selected VEGFR2, COX-2 and MMP-2 polymorphisms may be potential prognostic markers in unresectable NSCLC treated with radiotherapy with or without chemotherapy, although further validation studies are warranted to confirm our observations.The majority of non-small cell lung cancers (NSCLC) are inoperable at initial diagnosis due to advanced stage and/or comorbidities. The choice of treatment in inoperable NSCLC depends mainly on clinical stage and, most frequently, is limited to radiation therapy, chemotherapy or a combination of both. The prognosis, however, remains unsatisfactory because of relatively low response rates and high metastatic potential. Large inter-individual variability is also observed in the clinical course and treatment outcomes, being a result of molecular heterogeneity of the tumor and host factors.1 Therefore, there is a need for novel prognostic and predictive markers that can be detected in blood and used in a large group of NSCLC patients for whom tumor tissue is not readily accessible.Lung cancer progression, including tumor growth, invasion and metastasis, depends on extracellular matrix (ECM) remodeling in which matrix metalloproteinases (MMPs) play an active role. They are multifunctional zinc endopeptidases being important regulators of the tumor microenvironment controlling cell proliferation, migration, inflammation and apoptosis.2 Some MMPs, such as MMP-1, -2, -3, -7 or -9, also contribute to angiogenesis, for example, MMP-2 and -9 are known to release vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) from ECM that, in turn, up-regulate the MMP expression. Angiogenesis is a complex, dynamic process of new blood vessels formation in which VEGF and VEGF receptor 2 (VEGF...
Polymorphism in signal-induced proliferation-associated 1 (SIPA1) gene may contribute to the development of metastasis in human cancers. In this preliminary study, we examined the association of the SIPA1 -313A>G (rs931127) polymorphism with overall survival (OS) and progression-free survival (PFS) in 351 inoperable patients with non-small cell lung cancer (NSCLC) treated with radiotherapy or radiochemotherapy (curative or palliative). The GG homozygotes had significantly shorter PFS under codominant and recessive models in all patients (hazard ratio (HR) 1.47, p = 0.035, and HR 1.47, p = 0.022, respectively) and in advanced stage subgroup (HR 1.49, p = 0.037, and HR 1.48, p = 0.023, respectively). The GG genotype was also associated with reduced OS and PFS (codominant model: HR 2.41, p = 0.020, and HR 2.34, p = 0.020, respectively; recessive model: HR 2.16, p = 0.026, and HR 2.18, p = 0.022, respectively) in radiotherapy alone subgroup. Moreover, the SIPA1 -313GG was identified as an independent adverse prognostic factor for PFS in the cohort. Our results indicate, for the first time, that the SIPA1 -313A>G may have a prognostic role in unresected NSCLC making it a potential predictor of poor survival due to earlier progression.
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