CD55

Gene Summary

Gene:CD55; CD55 molecule, decay accelerating factor for complement (Cromer blood group)
Aliases: CR, TC, DAF, CROM
Location:1q32
Summary:This gene encodes a glycoprotein involved in the regulation of the complement cascade. Binding of the encoded protein to complement proteins accelerates their decay, thereby disrupting the cascade and preventing damage to host cells. Antigens present on this protein constitute the Cromer blood group system (CROM). Alternative splicing results in multiple transcript variants. The predominant transcript variant encodes a membrane-bound protein, but alternatively spliced transcripts may produce soluble proteins. [provided by RefSeq, Jul 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:complement decay-accelerating factor
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CD55 (cancer-related)

Feltes BC, Bonatto D
Overview of xeroderma pigmentosum proteins architecture, mutations and post-translational modifications.
Mutat Res Rev Mutat Res. 2015 Jan-Mar; 763:306-20 [PubMed] Related Publications
The xeroderma pigmentosum complementation group proteins (XPs), which include XPA through XPG, play a critical role in coordinating and promoting global genome and transcription-coupled nucleotide excision repair (GG-NER and TC-NER, respectively) pathways in eukaryotic cells. GG-NER and TC-NER are both required for the repair of bulky DNA lesions, such as those induced by UV radiation. Mutations in genes that encode XPs lead to the clinical condition xeroderma pigmentosum (XP). Although the roles of XPs in the GG-NER/TC-NER subpathways have been extensively studied, complete knowledge of their three-dimensional structure is only beginning to emerge. Hence, this review aims to summarize the current knowledge of mapped mutations and other structural information on XP proteins that influence their function and protein-protein interactions. We also review the possible post-translational modifications for each protein and the impact of these modifications on XP protein functions.

Fu D, Ren C, Tan H, et al.
Sox17 promoter methylation in plasma DNA is associated with poor survival and can be used as a prognostic factor in breast cancer.
Medicine (Baltimore). 2015; 94(11):e637 [PubMed] Related Publications
Aberrant DNA methylation that leads to the inactivation of tumor suppressor genes is known to play an important role in the development and progression of breast cancer. Methylation status of cancer-related genes is considered to be a promising biomarker for the early diagnosis and prognosis of tumors. This study investigated the methylation status of the Sox17 gene in breast cancer tissue and its corresponding plasma DNA to evaluate the association of methylation levels with clinicopathological parameters and prognosis.The methylation status of the Sox17 gene promoter was evaluated with methylation-specific polymerase chain reaction (MSP) in 155 paired breast cancer tissue and plasma samples and in 60 paired normal breast tissue and plasma samples. Association of Sox17 methylation status with clinicopathological parameters was analyzed by χ tests. Overall and disease-free survival (DFS) curves were calculated using Kaplan-Meier analysis, and the differences between curves were analyzed by log-rank tests.The frequency of Sox17 gene methylation was 72.9% (113/155) in breast cancer tissues and 58.1% (90/155) in plasma DNA. Sox17 gene methylation was not found in normal breast tissues or in their paired plasma DNA. There was a significant correlation of Sox17 methylation between corresponding tumor tissues and paired plasma DNA (r = 0.688, P < 0.001). Aberrant Sox17 methylation in cancer tissues and in plasma DNA was significantly associated with the tumor node metastasis stage (P = 0.035 and P = 0.001, respectively) and with lymph node metastasis (P < 0.001 and P = 0.001, respectively). Kaplan-Meier survival curves showed that aberrant Sox17 promoter methylation in cancer tissues and plasma DNA was associated with poor DFS (P < 0.005) and overall survival (OS) (P < 0.005). Multivariate analysis showed that Sox17 methylation in plasma DNA was an independent prognostic factor in breast cancer for both DFS (P = 0.020; hazard ratio [HR] = 2.142; 95% confidence interval [CI]: 1.128-4.067) and for OS (P = 0.001; HR = 4.737; 95% CI: 2.088-10.747).Sox17 gene promoter methylation may play an important role in breast cancer progression and could be used as a prognostic biomarker to identify patients at risk of developing metastasis or recurrence after mastectomy.

Líbalová H, Krčková S, Uhlířová K, et al.
Analysis of gene expression changes in A549 cells induced by organic compounds from respirable air particles.
Mutat Res. 2014; 770:94-105 [PubMed] Related Publications
A number of toxic effects of respirable ambient air particles (genotoxic effects, inflammation, oxidative damage) have been attributed to organic compounds bound onto the particle surface. In this study, we analyzed global gene expression changes caused by the extractable organic matters (EOMs) from respirable airborne particles <2.5μm (PM2.5), collected at 3 localities from heavily polluted areas of the Czech Republic and a control locality with low pollution levels, in human lung epithelial A549 cells. Although the sampled localities differed in both extent and sources of air pollution, EOMs did not induce substantially different gene expression profiles. The number of transcripts deregulated in A549 cells treated with the lowest EOM concentration (10μg/ml) ranged from 65 to 85 in 4 sampling localities compared to the number of transcripts deregulated after 30μg/ml and 60μg/ml of EOMs, which ranged from 90 to 109, and from 149 to 452, respectively. We found numerous commonly deregulated genes and pathways related to activation of the aryl hydrocarbon receptor (AhR) and metabolism of xenobiotics and endogenous compounds. We further identified deregulation of expression of the genes involved in pro-inflammatory processes, oxidative stress response and in cancer and developmental pathways, such as TGF-β and Wnt signaling pathways. No cell cycle arrest, DNA repair or pro-apoptotic responses were identified at the transcriptional level after the treatment of A549 cells with EOMs. In conclusion, numerous processes and pathways deregulated in response to EOMs suggest a significant role of activated AhR. Interestingly, we did not observe substantial gene expression changes related to DNA damage response, possibly due to the antagonistic effect of non-genotoxic EOM components. Moreover, a comparison of EOM effects with other available data on modulation of global gene expression suggests possible overlap among the effects of PM2.5, EOMs and various types of AhR agonists.

Wang S, Lv C, Jin H, et al.
A common genetic variation in the promoter of miR-107 is associated with gastric adenocarcinoma susceptibility and survival.
Mutat Res. 2014; 769:35-41 [PubMed] Related Publications
BACKGROUND: Global miRNA expression profile has been widely used to characterize human cancers. It is well established that genetic variants in miRNAs can modulate miRNA biogenesis and disease risk.
METHODS: Genome-wide miRNA microarray was employed for assessment of miRNA expression profile of gastric adenocarcinoma (GAC). The variants of significantly dysregulated miRNA were genotyped in test (715 cases and 804 controls) and validation (940 cases and 1050 controls) subject sets.
RESULTS: MiRNA microarray revealed that 12 miRNAs including miR-107 significantly dysregulated in GAC tissues. The sequencing of the promoter of miR-107 identified 3 SNPs (rs11185777, rs78591545, and rs2296616) with minor allele frequency (MAF)>5%. Analyzing their association with GAC risk and prognosis revealed that the C allele of rs2296616 (T>C) was significantly associated with the decreased risk of GAC among the test, validation and combined sets (TC/CC vs. TT, adjusted OR=0.39, 95% CI=0.31-0.49 for the combined set). However, the C allele was related to an unfavorable prognosis of Cardia GAC (CGAC) (adjusted HR=1.49, 95% CI=1.01-2.20). In vivo evidence showed that the individuals with the rs2296616C allele had lower miR-107 expression compared with the homozygous T allele carriers.
CONCLUSION: miR-107 is dysregulated in GAC pathogenesis and the SNP rs2296616 may play a role in the process.

Nemati K, Golmoghaddam H, Hosseini SV, et al.
Interleukin-17FT7488 allele is associated with a decreased risk of colorectal cancer and tumor progression.
Gene. 2015; 561(1):88-94 [PubMed] Related Publications
BACKGROUND: IL-17 family of cytokines and human IL-23R play important and sometimes contradictory roles in autoimmune and inflammatory diseases as well as human malignancies. Different alleles of this cytokine family may differentially affect IL-17 secretion. We sought to investigate the association of IL-17A, IL-17F and IL-23R gene polymorphisms with the susceptibility to colorectal cancer (CRC).
METHODS: The IL-17A rs2275913 (G197A), IL-17F rs763780 (T7488C), IL-23R rs11209026 and IL-23R rs1088967 SNPs were detected in 202 patients with colorectal cancer and 203 healthy age/sex matched controls by PCR-RFLP method. For evaluation of the functional relevance of these SNPs with IL-17A and IL-17F production, the serum levels of IL-17A and IL-17F were investigated in 107 and 109 patients as well as 33 and 52 healthy individuals, respectively, by ELISA assays.
RESULTS: The IL-17F TT genotype [OR=0.44, 95% CI: 0.21-0.94, P=0.03] and T allele [OR=0.46, 95% CI: 0.21-1.1, P=0.03] were associated with a decreased risk of CRC compared with the TC genotype and C allele. Moreover, IL-17F TT genotype was significantly associated with well differentiation in tumors (P=0.02). We also observed a significant association between the AG genotype of IL-17A G197A SNP with increased risk of colorectal cancer as compared to AA genotype (P=0.001). The IL-17A concentrations in the sera of patients with CRC were significantly elevated compared to healthy individuals (P=0.008), and serum level of IL-17A was significantly related to tumor size (P=0.043). The A allele of IL-23R rs10889677 polymorphism was marginally associated with increased IL-17A levels in the sera of patients (P=0.08). The genotype distributions of IL-23R rs11209026 and IL-23R rs10889677 SNPs were not significantly different between CRC patients and controls. The haplotypes of IL-17A G197A/IL-17F T7488C and IL-23R were not significantly associated with CRC. No IL-17F was detected in the sera of patients and only one healthy individual had IL-17F in his serum.
CONCLUSION: Our findings suggest that the T allele of IL-17F T7488C polymorphism may be involved in reduced risk of CRC and IL-17A may be an attractive target for colorectal cancer immunotherapy.

Sofan MA, Elmasry S, Salem DA, Bazid MM
NPM1 gene mutation in Egyptian patients with cytogenetically normal acute myeloid leukemia.
Clin Lab. 2014; 60(11):1813-22 [PubMed] Related Publications
BACKGROUND: Nucleophosmin1 (NPM1) protein encoded from the NPM1 gene is a ubiquitously expressed nucleolar phoshoprotein which shuttles continuously between the nucleus and cytoplasm. NPM1 protein plays an important role in cell proliferation and apoptosis. NPM1 gene mutations at exon 12 represent the hallmark of a large sub-group of cytogenetically normal acute myeloid leukemia (CN-AML) patients worldwide.
METHODS: Genomic DNA from 53 CN-AML patients were amplified by PCR and followed by fragment analysis of post-PCR products using GeneMapper software for detection of NPM1 mutations.
RESULTS: NPM1 exon 12 mutations were found are 15/53 CN-AML patients (28.3%) including 3 of M1, 3 of M2, 5 of M4, 3 of M5, and 1 of M6 FAB subtypes. The NPM1 mutation was significantly associated with lower relapse rate (p < 0.05). The complete remission (CR) rate was significantly higher in the patients with high NPM1 mutation load (> 50%) than low NPM1 mutation load (< 50%) (87.5% vs. 28.6%; p = 0.02).
CONCLUSIONS: The aim of this study was to evaluate the NPM1 gene exon 12 mutation in Egyptian patients with CN-AML and its relation to clinical characteristics and patient outcome and survival.

Yang JJ, Landier W, Yang W, et al.
Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.
J Clin Oncol. 2015; 33(11):1235-42 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
PURPOSE: Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL.
PATIENTS AND METHODS: The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.
RESULTS: MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.
CONCLUSION: We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

Slomovitz BM, Jiang Y, Yates MS, et al.
Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma.
J Clin Oncol. 2015; 33(8):930-6 [PubMed] Article available free on PMC after 10/03/2016 Related Publications
PURPOSE: The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregulated in endometrial cancer (EC). Hormonal manipulation leads to response in some patients with EC, but resistance derived from PI3K pathway activation has been documented. Targeting mammalian target of rapamycin (mTOR) may overcome endocrine resistance. We conducted a two-institution phase II trial of everolimus and letrozole in women with recurrent EC.
PATIENTS AND METHODS: Patients were considered incurable, had measurable disease, and were treated with up to two prior cytotoxic regimens. Everolimus was administered orally at 10 mg daily and letrozole was administered orally at 2.5 mg daily. Each cycle consisted of 4 weeks of therapy. Patients were treated until progression, toxicity, or complete response (CR). The primary end point was the clinical benefit rate (CBR), which was defined as CR, partial response, or stable disease (≥ 16 weeks) by RECIST 1.0 criteria. Translational studies were performed to correlate biomarkers with response.
RESULTS: Thirty-eight patients were enrolled (median age, 62 years; range, 24 to 82 years). Thirty-five patients were evaluable for response. The CBR was 40% (14 of 35 patients); the median number of cycles among responders was 15 (range, seven to 29 cycles). The confirmed objective response rate (RR) was 32% (11 of 35 patients; nine CRs and two partial responses; median, 15 cycles; range, eight to 29 cycles). Twenty percent of patients (seven of 35 patients) were taken off treatment after a prolonged CR and at the discretion of the treating clinician. None of the patients discontinued treatment as a result of toxicity. Serous histology was the best predictor of lack of response. Patients with endometrioid histology and CTNNB1 mutations responded well to everolimus and letrozole.
CONCLUSION: Everolimus plus letrozole results in a high CBR and RR in patients with recurrent EC. Further development of this combination in recurrent endometrioid EC is under way.

Rybka J, Butrym A, Wróbel T, et al.
The expression of Toll-like receptors in patients with acute myeloid leukemia treated with induction chemotherapy.
Leuk Res. 2015; 39(3):318-22 [PubMed] Related Publications
Toll-like receptors play an important role in the host defense against microorganisms. TLRs are mainly expressed in human immune-related cells, such as monocytes, neutrophils, macrophages, dendritic cells, T cells, B cells and NK cells. The expression or up-regulation of TLRs has been demonstrated in some tumors and tumor cell lines but the role of TLRs in pathogenesis and development of acute leukemias remains unclear. The aim of this study was to evaluate the expression of TLR2, TLR4 and TLR9 and their significance as prognostic factors in patients with acute leukemias treated with induction chemotherapy. 103 patients with newly diagnosed acute myeloid leukemia (AML) were evaluated (47 females and 56 males). The median age of patients was 51 years. Using quantitative reverse transcriptase PCR, the mRNA expression of genes TLR2, TLR4 and TLR9 was measured. The mRNA expression of TLR2 and TLR4 was significantly higher in patients with NR than in patients with CR and CRi. We especially observed that mRNA expression of TLR2 and TLR4 was significantly higher in patients with myelomonocytic and monoblastic acute leukemia than in patients with other types of AML. The mRNA expression of TLR2 and TLR4 was higher in AML patients than in healthy individuals, although there was no statistically significant difference. Patients with higher mRNA expression of TLR2 and TLR4 had significantly shorter OS than patients with lower mRNA expression of TLR2 and TLR4. Multivariate analysis showed that mRNA expression of TLR2 and the age of patients were independent factors associated with treatment response. Our results suggest that TLRs could be an independent prognostic factor for response rate after induction therapy in patients with acute myeloid leukemias.

Cui L, Gao C, Zhang RD, et al.
Low expressions of ARS2 and CASP8AP2 predict relapse and poor prognosis in pediatric acute lymphoblastic leukemia patients treated on China CCLG-ALL 2008 protocol.
Leuk Res. 2015; 39(2):115-23 [PubMed] Related Publications
ARS2 protein is important to early development and cell proliferation, in which ARS2-CASP8AP2 interaction is implicated. However, the predictive significance of ARS2 in childhood acute lymphoblastic leukemia (ALL) is unknown. Here we evaluate the predictive values of ARS2 expression and combined ARS2 and CASP8AP2 expression in relapse. We showed that ARS2 expression in ALL bone marrow samples at initial diagnosis was markedly lower than that in complete remission (CR). Likewise, the levels of ARS2 expression in the patients suffering from relapse were significantly lower than that of patients in continuous CR. Furthermore, low expression of ARS2 was closely correlated to poor treatment response including poor prednisone response and high minimal residual disease (MRD), and the patients with high MRD (≥10(-4)) and low ARS2 were more subject to relapse. The multivariate analyses for relapse free survival and event free survival revealed that ARS2 expression remained an independent prognostic factor after adjusting other risk factors. In addition, combined assessment of ARS2 and CASP8AP2 expression was more accurate to predict relapse, based on which an algorithm composed of ARS2 and CASP8AP2 expression, prednisone response and MRD (day 78) was proposed. Together, ARS2 and CASP8AP2 expressions can precisely predict high-risk of relapse and ALL prognosis.

Garzon R, Volinia S, Papaioannou D, et al.
Expression and prognostic impact of lncRNAs in acute myeloid leukemia.
Proc Natl Acad Sci U S A. 2014; 111(52):18679-84 [PubMed] Article available free on PMC after 30/06/2015 Related Publications
Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis, and cell cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged ≥60 y) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. An independent set of 71 untreated older patients with CN-AML was used to validate the outcome scores using RNA sequencing. Distinctive lncRNA profiles were found associated with selected mutations, such as internal tandem duplications in the FLT3 gene (FLT3-ITD) and mutations in the NPM1, CEBPA, IDH2, ASXL1, and RUNX1 genes. Using the lncRNAs most associated with event-free survival in a training cohort of 148 older patients with CN-AML, we derived a lncRNA score composed of 48 lncRNAs. Patients with an unfavorable compared with favorable lncRNA score had a lower complete response (CR) rate [P < 0.001, odds ratio = 0.14, 54% vs. 89%], shorter disease-free survival (DFS) [P < 0.001, hazard ratio (HR) = 2.88] and overall survival (OS) (P < 0.001, HR = 2.95). The validation set analyses confirmed these results (CR, P = 0.03; DFS, P = 0.009; OS, P = 0.009). Multivariable analyses for CR, DFS, and OS identified the lncRNA score as an independent marker for outcome. In conclusion, lncRNA expression in AML is closely associated with recurrent mutations. A small subset of lncRNAs is correlated strongly with treatment response and survival.

ten Broeke SW, Brohet RM, Tops CM, et al.
Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk.
J Clin Oncol. 2015; 33(4):319-25 [PubMed] Related Publications
PURPOSE: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers.
METHODS: Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers.
RESULTS: The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis.
CONCLUSION: CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.

Hsia TC, Chang WS, Liang SJ, et al.
Interleukin-10 (IL-10) promoter genotypes are associated with lung cancer risk in Taiwan males and smokers.
Anticancer Res. 2014; 34(12):7039-44 [PubMed] Related Publications
Interleukin-10 (IL-10) is an immunosuppressive cytokine involved in carcinogenesis via immune escape. The present study aimed at evaluating the contribution of IL-10 promoter A-1082G (rs1800896), T-819C (rs3021097), A-592C (rs1800872) genetic polymorphisms to the risk of lung cancer in Taiwan. Associations of three IL-10 polymorphic genotypes with lung cancer risk were investigated among 358 lung cancer patients and 716 age- and gender-matched healthy controls. In addition, the genetic-lifestyle interaction was also examined. The results showed that the percentages of TT, TC and CC for IL-10 T-819C genotypes were differentially represented as 59.2%, 35.8% and 5.0% in the lung-cancer patient group and 52.0%, 37.0% and 11.0% in the non-cancer control group, respectively (p for trend=0.0025). The CC genotype carriers were of lower risk for lung cancer (OR=0.4, 95% CI=0.23-0.69, p=0.0005). Further stratification of the population by gender and smoking behavior showed that the IL-10 T-819C genotype conducted a protective effect on lung cancer susceptibility, which was obvious among males and smokers (p=0.0003 and 0.0004, respectively). The CC and TC genotypes of IL-10 T-819C compared to the TT genotype may have a protective effect on lung cancer risk in Taiwan, particularly among males and smokers.

Arcaini L, Morello L, Tucci A, et al.
Autologous stem cell transplantation with in vivo purged progenitor cells shows long-term efficacy in relapsed/refractory follicular lymphoma.
Am J Hematol. 2015; 90(3):230-4 [PubMed] Related Publications
High-dose chemotherapy with autologous stem cell transplantation (ASCT) has been shown effective in the control of relapsed/refractory follicular lymphoma. We evaluate the long-term outcome of patients with relapsed or refractory follicular lymphoma treated with ASCT with in vivo purged progenitors cells. We report the long-term results of a prospective multicenter phase 2 trial on 124 relapsed/refractory follicular lymphoma patients treated with a program of anthracycline-based debulking chemotherapy, immunochemotherapy, mobilization of in vivo purged PBSC followed by ASCT. Median age was 52 years; 14% of patients had grade 3A histology. Debulking chemotherapy produced CR in 16% and PR in 71%, while 13% of patients progressed. After rituximab, cyclophosphamide, vincristine, prednisone (R-COP), CR was obtained in 60% and PR in 35%; 118 patients successfully mobilized PBSC and 117 proceeded to ASCT. The harvest in all the 32 molecularly informative patients was bcl-2 negative. TRM was 0%. The 5-year PFS was 54% and the 5-year OS was 83%. After a median f-up of 6.7 years (range 1.5-13.6), 54% are still in CR. These data show that prolonged PFS is achievable in relapsed/refractory patients with high dose autologous transplantation of in vivo purged progenitor cells.

Wayua C, Low PS
Evaluation of a nonpeptidic ligand for imaging of cholecystokinin 2 receptor-expressing cancers.
J Nucl Med. 2015; 56(1):113-9 [PubMed] Related Publications
UNLABELLED: Tumor-specific targeting ligands were recently exploited to deliver both imaging and therapeutic agents selectively to cancer tissues in vivo. Because the cholecystokinin 2 receptor (CCK2R) is overexpressed in various human cancers (e.g., lung, medullary thyroid, pancreatic, colon, and gastrointestinal stromal tumors) but displays limited expression in normal tissues, natural ligands of CCK2R were recently explored for use in the imaging of CCK2R-expressing cancers. Unfortunately, the results from these studies revealed not only that the peptidic CCK2R ligands were unstable in vivo but also that the ligands that mediated good uptake by tumor tissues also promoted a high level of retention of the radioimaging agent in the kidneys, probably because of capture of the conjugates by peptide-scavenging receptors. In an effort to reduce the normal organ retention of CCK2R-targeted drugs, we synthesized a nonpeptidic ligand of CCK2R and examined its specificity for CCK2R both in vitro and in vivo.
METHODS: Nonpeptidic agonists and antagonists of CCK2R described in the literature were evaluated for their affinities and specificities for CCK2R. Z-360, a benzodiazepine-derived CCK2R antagonist with subnanomolar affinity, was selected for complexation to (99m)Tc via multiple spacers. After synthesis and purification, 4 complexes with different physicochemical properties were evaluated for binding to CCK2R-transfected HEK 293 cells. The best conjugate, termed CRL-3-(99m)Tc, was injected into mice bearing CCK2R tumor xenografts and examined by γ scintigraphy and SPECT/CT. The uptake of the conjugate in various organs was also quantified by tissue resection and γ counting.
RESULTS: CRL-3-(99m)Tc was shown to bind with low nanomolar affinity to CCK2R in vitro and was localized to tumor tissues in athymic nu/nu mice implanted with CCK2R-expressing tumors. At 4 h after injection, tumor uptake was measured at 12.0 ± 2.0 percentage injected dose per gram of tissue.
CONCLUSION: Because the uptake of CRL-3-(99m)Tc by nonmalignant tissues was negligible and retention in the kidneys was only transient, we suggest that CRL-3-(99m)Tc may be a useful radioimaging agent for the detection, sizing, and monitoring of CCK2R-expressing tumors.

Song Q, Zhang Z, Liu Y, et al.
The tag SNP rs10746463 in decay-accelerating factor is associated with the susceptibility to gastric cancer.
Mol Immunol. 2015; 63(2):473-8 [PubMed] Related Publications
BACKGROUND: Complement activation involved in the innate immunity and adaptive immunity and further contributed to the development of tumor growth. This study aimed to investigate the association of genetic variants in complement 3 (C3) and decay-accelerating factor (DAF) genes with the risk of gastric cancer.
METHODS: This case-control study included 500 gastric cancer patients and 500 cancer-free controls. Based on the Chinese population data from HapMap database, we used Haploview 4.2 program to select candidate tag SNPs. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression to evaluate the association of each genetic variant with the risk of gastric cancer.
RESULTS: Among 12 tag SNPs of C3, no correlation was observed between C3 genetic variants and risk of gastric cancer. For tag SNPS of DAF, logistic regression analysis revealed that the carriers with DAF rs10746463 AA genotype had a significantly increased risk for developing gastric cancer (OR = 1.46, 95% CI = 1.01–2.10) when compared with GG genotype, but those carrying with rs10746463 AG genotype didn't (OR = 1.31, 95% CI = 0.98-1.75). When stratified by smoking status, we found that the risk of gastric cancer was associated with rs10746463 GA or AA genotype carriers among smoker with OR (95% CI) of 1.64 (1.06-2.54), but not among non-smoker (OR = 1.37, 95% CI = 0.97-1.94).
CONCLUSION: DAF rs10746463 polymorphism effects on the risk of developing gastric cancer in Chinese population.

Pratheeshkumar P, Son YO, Divya SP, et al.
Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways.
Toxicol Appl Pharmacol. 2014; 281(2):230-41 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis.

Jorns JM, Thomas DG, Healy PN, et al.
Estrogen receptor expression is high but is of lower intensity in tubular carcinoma than in well-differentiated invasive ductal carcinoma.
Arch Pathol Lab Med. 2014; 138(11):1507-13 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
CONTEXT: Tubular carcinoma (TC) is a rare, luminal A subtype of breast carcinoma with excellent prognosis, for which adjuvant chemotherapy is usually contraindicated.
OBJECTIVE: To examine the levels of estrogen receptor (ER) and progesterone receptor expression in cases of TC and well-differentiated invasive ductal carcinoma as compared to normal breast glands and to determine if any significant differences could be detected via molecular testing.
DESIGN: We examined ER and progesterone receptor via immunohistochemistry in tubular (N = 27), mixed ductal/tubular (N = 16), and well-differentiated ductal (N = 27) carcinomas with comparison to surrounding normal breast tissue. We additionally performed molecular subtyping of 10 TCs and 10 ductal carcinomas via the PAM50 assay.
RESULTS: Although ER expression was high for all groups, TC had statistically significantly lower ER staining percentage (ER%) (P = .003) and difference in ER expression between tumor and accompanying normal tissue (P = .02) than well-differentiated ductal carcinomas, with mixed ductal/tubular carcinomas falling between these 2 groups. Mean ER% was 79%, 87%, and 94%, and mean tumor-normal ER% differences were 13.6%, 25.9%, and 32.6% in tubular, mixed, and ductal carcinomas, respectively. Most tumors that had molecular subtyping were luminal A (9 of 10 tubular and 8 of 10 ductal), and no significant differences in specific gene expression between the 2 groups were identified.
CONCLUSIONS: Tubular carcinoma exhibited decreased intensity in ER expression, closer to that of normal breast parenchyma, likely as a consequence of a high degree of differentiation. Lower ER% expression by TC may represent a potential pitfall when performing commercially available breast carcinoma prognostic assays that rely heavily on ER-related gene expression.

Vallabhajosula S, Nikolopoulou A, Babich JW, et al.
99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen: pharmacokinetics and biodistribution studies in healthy subjects and patients with metastatic prostate cancer.
J Nucl Med. 2014; 55(11):1791-8 [PubMed] Related Publications
UNLABELLED: Prostate-specific membrane antigen (PSMA) is a well-established target for developing radiopharmaceuticals for imaging and therapy of prostate cancer (PCa). We have recently reported that novel (99m)Tc-labeled small-molecule PSMA inhibitors bind with high affinity to PSMA-positive tumor cells in vitro and localize in PCa xenografts. This study reports the first, to our knowledge, human data in men with metastatic PCa and in healthy male subjects.
METHODS: Under an exploratory investigational new drug, using a cross-over design, we compared the pharmacokinetics, biodistribution, and tumor uptake of (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405 in 6 healthy men and 6 men with radiographic evidence of metastatic PCa. Whole-body images were obtained at 10 min and 1, 2, 4, and 24 h. SPECT was performed between 3 and 4 h after injection.
RESULTS: Both agents cleared the blood rapidly, with MIP-1404 demonstrating significantly lower urinary activity (7%) than MIP-1405 (26%). Both agents showed persistent uptake in the salivary, lacrimal, and parotid glands. Uptake in the liver and kidney was acceptable for imaging at 1-2 h. In men with PCa, both agents rapidly localized in bone and lymph node lesions as early as 1 h. SPECT demonstrated excellent lesion contrast. Good correlation was seen with bone scanning; however, more lesions were demonstrated with (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405. The high-contrast images exhibited tumor-to-background ratios from 3:1 to 9:1 at 4 and 20 h.
CONCLUSION: Compared with the standard-of-care bone scanning, (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405 identified most bone metastatic lesions and rapidly detected soft-tissue PCa lesions including subcentimeter lymph nodes. Because (99m)Tc-MIP-1404 has minimal activity in the bladder, further work is planned to correlate imaging findings with histopathology in patients with high-risk metastatic PCa.

Shadrina AS, Boyarskikh UA, Oskina NA, et al.
TERT polymorphisms rs2853669 and rs7726159 influence on prostate cancer risk in Russian population.
Tumour Biol. 2015; 36(2):841-7 [PubMed] Related Publications
Telomere length and telomerase activity have been hypothesized to play a role in cancer development. The aim of our study was to investigate the association of allelic variants of three functional polymorphisms rs2853669, rs2736100, and rs7726159 in the telomerase reverse transcriptase (TERT) gene with the risk of the breast cancer and prostate cancer in Russian population. Six hundred sixty women with breast cancer, 372 men with prostate cancer, and corresponding control groups of 523 women and 363 men were included in the present case-control study. We observed an association of allele rs2853669 C with increased risk of prostate cancer (co-dominant model TC vs. TT OR = 1.65, P = 0.002; additive model OR = 1.42, P = 0.005; dominant model: OR = 1.64, P = 0.001) and allele rs7726159 A with reduced risk of this malignancy (сo-dominant model: AA vs. CC OR = 0.42, P = 0.002; additive model: OR = 0.69, P = 0.002; dominant model: OR = 0.67, P = 0.01; recessive model: OR = 0.48, P = 0.005). None of the studied polymorphisms showed an association with the risk of breast cancer. Our results provide evidence that the TERT gene variability modulate prostate cancer predisposition in ethnical Russians.

Ma M, Jin GJ, Yun K, et al.
Correlation of IL-1F genetic polymorphisms with the risk of colorectal cancer among Chinese populations.
Tumour Biol. 2015; 36(2):807-14 [PubMed] Related Publications
Inflammatory/immune cells have the power of infiltrating almost all human solid tumors and influencing all stages of carcinogenesis because of their stimulation of various cytokine subsets. This study aims to determine the correlation of single nucleotide polymorphisms in the IL-17F gene and the risk of colorectal cancer (CRC). One thousand patients diagnosed with CRC and a control group of 354 healthy controls were involved. Peripheral blood samples were collected. The PCR-RFLP method was used to detect the 7383A>G (rs2397084) and 7488T>C (rs763780) in the IL-17F gene. Statistical analyses were conducted with version 12.0 STATA statistical software. We found that the allele model suggested that patients carrying C allele were 1.67 times more likely to develop CRC than healthy controls (odds ratio (OR) = 1.67, 95% confidence interval (CI) = 1.22-2.27, P = 0.001). Similarly, the homozygous and dominant models also revealed that the minor IL-17F 7488C allele conferred an increased CRC risk compared to the major T allele among our study participants (CC vs. TT: OR = 4.15, 95% CI = 1.26-13.36, P = 0.011; TC+CC vs. TT: OR = 1.46, 95% CI = 1.04-2.05, P = 0.027). However, all genetic models indicated that the IL-17F 7383A>G (rs2397084) polymorphism was not associated with CRC risk (all P > 0.05). The results of this study indicate that the 7488T>C (rs763780) in the IL-17F gene may be correlated with increased risk of CRC.

Barlogie B, Mitchell A, van Rhee F, et al.
Curing myeloma at last: defining criteria and providing the evidence.
Blood. 2014; 124(20):3043-51 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Does the dogma that multiple myeloma is incurable still hold?. The genomic chaos and resulting resistance to apoptosis of myeloma, long considered an obstacle to cure, formed the basis of Total Therapy (TT) program. The TT approach uses all myeloma-active drugs upfront to target drug-resistant subclones during initial treatment to prevent later relapse. Long-term follow-up of 1202 patients (TT1: n = 231, median follow-up: 21 years; TT2: 668, median follow-up: 12 years; TT3a: n = 303, median follow-up: 9 years) permitted investigation of whether progression-free survival (PFS) and complete response (CR) duration were consistent with curability, ie observation of plateaus in Kaplan-Meier plots for PFS and CR duration. In the subset of 627 patients with plasma cell gene expression profiling data, cure plateaus were apparent at 5 years in the 14% with high-risk myeloma compared with 10 years in the remainder with low-risk disease. A parametric model based on PFS and CR duration supported an increase in curability: 10-year PFS and CR estimates increased from 8.8%/17.9% in TT1 to 15.5%/28.2% in TT2's control arm to 25.1%/35.6% in TT2's thalidomide arm and to 32.9%/48.8% in TT3a. Toward developing novel therapies, we recommend a concerted focus on patients with high-risk myeloma whose outcome has not been advanced.

Lam HM, Ouyang B, Chen J, et al.
Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer.
Endocr Relat Cancer. 2014; 21(6):903-14 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Castration-resistant prostate cancer (CRPC) is an advanced-stage prostate cancer (PC) associated with high mortality. We reported that G-1, a selective agonist of G protein-coupled receptor 30 (GPR30), inhibited PC cell growth by inducing G2 cell cycle arrest and arrested PC-3 xenograft growth. However, the therapeutic actions of G-1 and their relationships with androgen in vivo are unclear. Using the LNCaP xenograft to model PC growth during the androgen-sensitive (AS) versus the castration-resistant (CR) phase, we found that G-1 inhibited growth of CR but not AS tumors with no observable toxicity to the host. Substantial necrosis (approximately 65%) accompanied by marked intratumoral infiltration of neutrophils was observed only in CR tumors. Global transcriptome profiling of human genes identified 99 differentially expressed genes with 'interplay between innate and adaptive immune responses' as the top pathway. Quantitative PCR confirmed upregulation of neutrophil-related chemokines and inflammation-mediated cytokines only in the G-1-treated CR tumors. Expression of murine neutrophil-related cytokines also was elevated in these tumors. GPR30 (GPER1) expression was significantly higher in CR tumors than in AS tumors. In cell-based experiments, androgen repressed GPR30 expression, a response reversible by anti-androgen or siRNA-induced androgen receptor silencing. Finally, in clinical specimens, 80% of CRPC metastases (n=123) expressed a high level of GPR30, whereas only 54% of the primary PCs (n=232) showed high GPR30 expression. Together, these results provide the first evidence, to our knowledge, that GPR30 is an androgen-repressed target and G-1 mediates the anti-tumor effect via neutrophil-infiltration-associated necrosis in CRPC. Additional studies are warranted to firmly establish GPR30 as a therapeutic target in CRPC.

Schlenk RF, Kayser S, Bullinger L, et al.
Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation.
Blood. 2014; 124(23):3441-9 [PubMed] Related Publications
The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITDs), as well as concurrent gene mutations, with regard to postremission therapy in 323 patients with FLT3-ITD-positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (P = .004) and IS in the tyrosine kinase domain 1 (TKD1, P = .06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (n = 121) or autologous hematopoietic stem cell transplantation (HSCT, n = 17), an allelic ratio ≥ 0.51 was associated with an unfavorable relapse-free (RFS, P = .0008) and overall survival (OS, P = .004); after allogeneic HSCT (n = 93), outcome was significantly improved in patients with a high allelic ratio (RFS, P = .02; OS, P = .03), whereas no benefit was seen in patients with a low allelic ratio (RFS, P = .38; OS, P = .64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AMLHD93 and AMLHD98A, previously published; AML SG 07-04, ClinicalTrials.gov identifier #NCT00151242.

Zhang L, Qiu F, Lu X, et al.
A functional polymorphism in the 3'-UTR of PXR interacts with smoking to increase lung cancer risk in southern and eastern Chinese smoker.
Int J Mol Sci. 2014; 15(10):17457-68 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Pregnane X receptor (PXR) is an important member of the nuclear receptor superfamily that copes with various endobiotic and xenobiotic stimuli, such as carcinogens by regulating an array of environmental response genes. Low PXR expression has been shown to promote tumor initiation and metastasis. The aim of the current study was to investigate whether the single nucleotide polymorphisms (SNPs) of PXR could alter lung cancer susceptibility in Chinese by affecting the function or expression of PXR. We genotyped three putatively functional SNPs of PXR (i.e., rs3814055C>T, rs3732360C>T, and rs3814058C>T) and analyzed their associations with lung cancer risk in a two-stage case-control study with a total of 1559 lung cancer cases and 1679 controls in the southern and eastern Chinese population. We found that in comparison to the rs3814058CC common genotype, the rs3814058T variants (TC/TT) which is located in the 3'-untranslated region (3'-UTR) of PXR conferred a consistently increased risk of lung cancer in both the southern Chinese (odd ratios (OR)=1.24, 95% confidence interval (CI)=1.03-1.49) and the eastern Chinese (OR=1.33, 95% CI=1.02-1.75). The variants also significantly interacted with smoking on increasing cancer risk (p=0.023). Moreover, lung cancer tissues with the rs3814058T variants showed significantly lower PXR expression than those with rs3814058CC genotype in the smokers (p=0.041). These results suggested that the rs3814058C>T polymorphism of PXR interacts with smoking on increasing lung cancer risk in Chinese smokers, which might be a functional genetic biomarker for lung cancer.

Garufi A, D'Orazi G
High glucose dephosphorylates serine 46 and inhibits p53 apoptotic activity.
J Exp Clin Cancer Res. 2014; 33:79 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: In response to diverse genotoxic stimuli p53 is activated as transcription factor to exert its tumor-suppressor function. P53 activation requires protein stabilization, nuclear localization and posttranslational modifications in key residues that may influence p53 selection of target genes. Among them, serine 46 (Ser46) phosphorylation is considered specific for apoptotic activation. Hyperglicaemia, the high blood glucose condition, may negatively affect tumor response to therapies through several mechanisms, conferring resistance to drug-induced cell death. However, whether high glucose might modify p53Ser46 phosphorylation has never been addressed.
METHODS AND RESULTS: Here, we performed biochemical and molecular analyses in different cancer cell lines treated with chemotherapy in the presence or absence of high glucose condition. Analyses of p53 posttranslational modifications showed that drug-induced p53Ser46 phosphorylation was reduced by high glucose. Such reduction depended by high glucose-induced calyculin A-sensitive phosphatase(s), able to specifically target p53Ser46 phosphorylation. The specific effect on Ser46 phosphorylation was addressed by analysing Ser15 phosphorylation that instead was not modified by high glucose. In agreement, a constitutively phosphorylated Ser46D p53 mutant was resistant to high glucose. As a consequence of phosphoSer46 impairment, high glucose reduced the tumor cell response to drugs, correlating with reduced p53 apoptotic transactivation. The drug-induced apoptotic cell death, reduced by high glucose, was finally restored by the phosphatase inhibitor calyculin A.
CONCLUSIONS: These data indicate that high glucose specifically inhibited Ser46 phosphorylation thus reducing p53 apoptotic activity. These results uncover a new mechanism of p53 inactivation providing an interesting novel molecular link between metabolic diseases such as diabetes or obesity and tumor progression and resistance to therapies.

Gao L, Thakur A, Liang Y, et al.
Polymorphisms in the TERT gene are associated with lung cancer risk in the Chinese Han population.
Eur J Cancer Prev. 2014; 23(6):497-501 [PubMed] Related Publications
Lung cancer has the highest mortality rate among cancers; however, its nosogenesis is still unclear. Genome-wide association studies have shown that the telomerase reverse transcriptase (TERT) gene, located in the chromosome 5p15.33 region, is one of the genes associated with the risk of lung cancer. In this case-control study, we genotyped 11 tag single-nucleotide polymorphisms of the TERT gene to evaluate their association with lung cancer risk in the Han Chinese population. Two tag single-nucleotide polymorphisms were found to be associated with lung cancer risk on using the χ2-test: rs4246742 [odds ratio (OR)=0.77, 95% confidence interval (CI) 0.60-0.98; P=0.03] and rs2853672 (OR=1.26, 95% CI 1.01-1.57; P=0.045). By using SNPStats software we also found rs2242652 (OR=1.47, 95% CI 1.02-2.13; P=0.04) in the dominant model and rs2736098 (OR=1.38, 95% CI 1.06-1.80; P=0.017), rs2853672 (OR=1.41, 95% CI 1.11-1.80; P=0.0048), and rs4246742 (OR=0.75, 95% CI 0.58-0.97; P=0.029) in the log-additive model. 'T/C-T/T' of rs10069690 conferred an increased risk for male sex in the dominant model (OR=1.80, 95% CI, 1.05-3.08; P=0.03) and 'TC' increased risk for male sex in the overdominant model (OR=1.85, 95% CI, 1.08-3.17; P=0.031). Our findings, combined with previous studies, suggest that polymorphisms in the TERT gene contribute to the risk for lung cancer in the Chinese Han population.

Yin J, Liu H, Liu Z, et al.
Genetic variants in fanconi anemia pathway genes BRCA2 and FANCA predict melanoma survival.
J Invest Dermatol. 2015; 135(2):542-50 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Cutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi anemia (FA) pathway involved in DNA crosslink repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2,339 common single-nucleotide polymorphisms (SNPs) in 14 autosomal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 (AG vs. GG: adjusted hazard ratio (adjHR)=1.85, 95% confidence interval (CI)=1.16-2.95, P=0.010), rs206118 (CC vs. TT+TC: adjHR=2.44, 95% CI=1.27-4.67, P=0.007), rs3752447 (CC vs. TT+TC: adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage, and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.

Lin Z, Chen L, Song M, et al.
Association between a polymorphism in miR-34b/c and susceptibility to cancer--a meta-analysis.
Asian Pac J Cancer Prev. 2014; 15(17):7251-5 [PubMed] Related Publications
MicroRNAs (miRNAs) act as tumor suppressors or promoters in neoplasia by regulating relative gene expression. The association between a single nucleotide polymorphism (SNP) rs4938723 in miR-34b/c and susceptibility to cancers was inconsistent in previous studies. In this study, we conducted a literature search of PubMed, Web of Science and Embase to identify all relevant studies in this meta-analysis with 6,036 cases and 6,204 controls. We found that the miR-34b/c rs4938723 polymorphism was significantly associated with increased risk of cancers in the heterozygous model (TC versus TT, OR=1.09, 95% CI=1.01-1.18, P=0.02). Subgroup analysis also revealed increased risk for Asian ethnicity in the heterozygous model (TC versus TT, OR=1.12, 95% CI=1.02-1.22, P=0.02), but decreased risk of colorectal cancer in homozygote model (CC versus TT, OR=0.66, 95% CI=0.47-0.92, P=0.02) and in the recessive model (CC versus TC+TT, OR=0.67, 95% CI=0.48-0.93, P=0.02) by cancer type. The current meta-analysis indicated that the miR-34b/c rs4938723 polymorphism may decrease susceptibility to colorectal cancer. Well-designed studies with larger sample size are required to further validate the results.

Cito L, Indovina P, Forte IM, et al.
pRb2/p130 localizes to the cytoplasm in diffuse gastric cancer.
J Cell Physiol. 2015; 230(4):802-5 [PubMed] Related Publications
pRb2/p130 is a key tumor suppressor, whose oncosuppressive activity has mainly been attributed to its ability to negatively regulate cell cycle by interacting with the E2F4 and E2F5 transcription factors. Indeed, pRb2/p130 has been found altered in various cancer types in which it functions as a valuable prognostic marker. Here, we analyzed pRb2/p130 expression in gastric cancer tissue samples of diffuse histotype, in comparison with their normal counterparts. We found a cytoplasmic localization of pRb2/p130 in cancer tissue samples, whereas, in normal counterparts, we observed the expected nuclear localization. pRb2/p130 cytoplasmic delocalization can lead to cell cycle deregulation, but considering the emerging involvement of pRb2/p130 in other key cellular processes, it could contribute to gastric tumorigenesis also through other mechanisms. Our data support the necessity of further investigations to verify the possibility of using pRb2/p130 as a biomarker or potential therapeutic target for diffuse gastric cancer.

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