Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (7)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MCC (cancer-related)
Small nucleolar RNAs (snoRNAs) are a new type of functional small RNAs involved in the chemical modifications of rRNAs, tRNAs, and small nuclear RNAs. It is reported that they play important roles in tumorigenesis via various regulatory modes. snoRNAs can both participate in the regulation of methylation and pseudouridylation and regulate the expression pattern of their host genes. This research investigated the expression pattern of snoRNAs in eight major cancer types in TCGA via several machine learning algorithms. The expression levels of snoRNAs were first analyzed by a powerful feature selection method, Monte Carlo feature selection (MCFS). A feature list and some informative features were accessed. Then, the incremental feature selection (IFS) was applied to the feature list to extract optimal features/snoRNAs, which can make the support vector machine (SVM) yield best performance. The discriminative snoRNAs included HBII-52-14, HBII-336, SNORD123, HBII-85-29, HBII-420, U3, HBI-43, SNORD116, SNORA73B, SCARNA4, HBII-85-20, etc., on which the SVM can provide a Matthew's correlation coefficient (MCC) of 0.881 for predicting these eight cancer types. On the other hand, the informative features were fed into the Johnson reducer and repeated incremental pruning to produce error reduction (RIPPER) algorithms to generate classification rules, which can clearly show different snoRNAs expression patterns in different cancer types. The analysis results indicated that extracted discriminative snoRNAs can be important for identifying cancer samples in different types and the expression pattern of snoRNAs in different cancer types can be partly uncovered by quantitative recognition rules.
Ugurel S, Spassova I, Wohlfarth J, et al.MHC class-I downregulation in PD-1/PD-L1 inhibitor refractory Merkel cell carcinoma and its potential reversal by histone deacetylase inhibition: a case series.
Cancer Immunol Immunother. 2019; 68(6):983-990 [PubMed
] Related Publications
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer in which PD-1/PD-L1 blockade has shown remarkable response rates. However, a significant proportion of patients shows primary or secondary resistance against PD-1/PD-L1 inhibition, with HLA class-I downregulation and insufficient influx of CD8
CASE PRESENTATIONS: We report four cases of patients with metastatic MCC who did not respond to immunotherapy by PD-1/PD-L1 blockade. Two of the patients received, subsequently, the HDACi panobinostat in combination with PD-1/PD-L1 blockade. Tumor biopsies of the patients were analyzed for cellular and molecular markers of antigen processing and presentation as well as the degree of T-cell infiltration.
RESULTS AND CONCLUSION: Low expression of APM-related genes associated with low HLA class-I surface expression was observed in all MCC patients, progressing on PD-1/PD-L1 blockade. In one evaluable patient, of the two treated with the combination therapy of the HDACi, panobinostat and PD-1/PD-L1 blockade, reintroduction of HLA class-I-related genes, enhanced HLA class-I surface expression, and elevated CD8
Studies on the efficacy of small molecule inhibitors in Merkel cell carcinoma (MCC) have been limited and largely inconclusive. In this study, we investigated the therapeutic potential of a potent BET degrader, BETd-246, in the treatment of MCC. We found that MCC cell lines were significantly more sensitive to BETd-246 than to BET inhibitor treatment. Therapeutic targeting of BET proteins resulted in a loss of "MCC signature" genes but not MYC expression as previously described irrespective of Merkel cell polyomavirus (MCPyV) status. In MCPyV+ MCC cells, BETd-246 alone suppressed downstream targets in the MCPyV-LT Ag axis. We also found enrichment of HOX and cell cycle genes in MCPyV- MCC cell lines that were intrinsically resistant to BETd-246. Our findings uncover a requirement for BET proteins in maintaining MCC lineage identity and point to the potential utility of BET degraders for treating MCC.
Su J, Lai J, Yang R, et al.Capecitabine plus bevacizumab versus capecitabine in maintenance treatment for untreated characterised KRAS exon 2 wild-type metastatic colorectal cancer: a retrospective analysis in Chinese postmenopausal women.
BMC Gastroenterol. 2019; 19(1):17 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Capecitabine plus bevacizumab (CAP-B) maintenance treatment after 6 cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOXB) has demonstrated clinical activity and failure to compromise quality of life in patients with metastatic colorectal cancer (MCC) in a previous phase 3 CAIRO3 study. The objective of this study is to evaluate the efficacy and safety of CAP-B versus CAP in maintenance treatment after 6-cycle CAPOXB induction therapy in Chinese postmenopausal women with untreated characterised KRAS exon 2 wild-type MCC.
METHODS: During 2012-2016, prospectively maintained databases were reviewed to evaluate cohorts with untreated characterised KRAS exon 2 wild-type MCC and stable disease or better after 6-cycle CAPOXB induction treatment. After induction treatment, all patients received either CAP-B or capecitabine (CAP) as maintenance treatment. Median progression-free survival (mPFS) and median overall survival (mOS) were the primary endpoints. Safety was the secondary endpoint.
RESULTS: A total of 263 women with untreated characterised KRAS exon 2 wild-type MCC and stable disease or better after 6-cycle CAPOXB induction treatment were included for the evaluation of efficacy and safety (CAP-B-treated cohort, n = 130 and CAP-treated cohort, n = 133). The mPFS was 11.5 months (95% confidence interval [CI], 5.6-17.4) and 9.2 months (95% CI, 3.6-14.8) for the CAP-B-treated and CAP-treated cohorts, respectively (HR 0.54, 95% CI 0.32~0.85; P = 0.013). The mOS was 16.2 months (95% CI, 11.4-18.7) and 12.4 months (95% CI, 10.6-15.5) for the CAP-B- and CAP-treated cohorts, respectively (HR 0.72, 95% CI 0.51~0.94; P = 0.022). The CAP-B-treated cohort experienced significantly more grade 3 or 4 diarrhoea (P < 0.001) than the CAP-treated cohort.
CONCLUSIONS: CAP-B maintenance treatment after 6-cycle CAPOX-B in Chinese postmenopausal women with untreated KRAS exon 2 wild-type MCC is poorer tolerated but has a more modest, if any, benefit compared with that of CAP maintenance treatment.
Merkel cell polyomavirus (MCV) contributes to approximately 80% of all Merkel cell carcinomas (MCCs), a highly aggressive neuroendocrine carcinoma of the skin. MCV-positive MCC expresses small T antigen (ST) and a truncated form of large T antigen (LT) and usually contains wild-type p53 (TP53) and RB (RB1). In contrast, virus-negative MCC contains inactivating mutations in TP53 and RB1. While the MCV-truncated LT can bind and inhibit RB, it does not bind p53. We report here that MCV LT binds to RB, leading to increased levels of ARF, an inhibitor of MDM2, and activation of p53. However, coexpression of ST reduced p53 activation. MCV ST recruits the MYC homologue MYCL (L-Myc) to the EP400 chromatin remodeler complex and transactivates specific target genes. We observed that depletion of EP400 in MCV-positive MCC cell lines led to increased p53 target gene expression. We suspected that the MCV ST-MYCL-EP400 complex could functionally inactivate p53, but the underlying mechanism was not known. Integrated ChIP and RNA-sequencing analysis following EP400 depletion identified MDM2 as well as CK1α, an activator of MDM4, as target genes of the ST-MYCL-EP400 complex. In addition, MCV-positive MCC cells expressed high levels of MDM4. Combining MDM2 inhibitors with lenalidomide targeting CK1α or an MDM4 inhibitor caused synergistic activation of p53, leading to an apoptotic response in MCV-positive MCC cells and MCC-derived xenografts in mice. These results support dual targeting of MDM2 and MDM4 in virus-positive MCC and other p53 wild-type tumors.
Wardhani LO, Matsushita M, Kuwamoto S, et al.Expression of Notch 3 and Jagged 1 Is Associated With Merkel Cell Polyomavirus Status and Prognosis in Merkel Cell Carcinoma.
Anticancer Res. 2019; 39(1):319-329 [PubMed
] Related Publications
BACKGROUND/AIM: Merkel cell carcinoma (MCC) is a rare, aggressive, neuroendocrine skin cancer and most MCCs are related to infection with Merkel cell polyomavirus (MCPyV). Notch signaling modulates cell fate in various tissues including the skin during development and homeostasis, and its aberrant activity relates to onset and progression of various malignancies. Therefore, association of NOTCH1/ NOTCH2/NOTCH3/jagged 1 (JAG1) expression with MCPyV status and prognosis in MCC was investigated.
MATERIALS AND METHODS: A total of 19 MCPyV-positive and 19 MCPyV-negative MCC samples from patients were stained immunohistochemically with antibodies against NOTCH1, NOTCH2, NOTCH3, and JAG1 and analyzed.
RESULTS: Expression of NOTCH1 and NOTCH2 was not associated with MCPyV status or prognosis. However, higher JAG1 expression was found in MCPyV-negative than in MCPyV-positive MCC (p<0.001), and NOTCH3 expression was higher in MCPyV-positive MCC (p=0.062). Kaplan-Meier and multivariate analyses showed that patients with MCC with higher NOTCH3 expression had better overall survival than otherwise (p=0.001 and p=0.033, respectively).
CONCLUSION: Expression of NOTCH3, as a tumor suppressor, is an independent predictor of MCC outcome.
Veija T, Kero M, Koljonen V, Böhling TALK and EGFR expression by immunohistochemistry are associated with Merkel cell polyomavirus status in Merkel cell carcinoma.
Histopathology. 2019; 74(6):829-835 [PubMed
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AIMS: Merkel cell carcinoma, a rare cutaneous neuroendocrine tumour of the skin, can be categorised into two groups according to Merkel cell polyomavirus (MCV) presence. MCV-negative tumours are more aggressive and frequently associated with gene mutations. Some of the genes are potential therapeutic targets. We have previously reported EGFR mutations in six of 27 MCC tumours and overexpression of ALK and EZH2 at mRNA level in MCC tumours. In this study, we sought to determine expression of ALK, EGFR and EZH2 in MCC samples and assess their correlation to MCV status and clinical parameters.
METHODS AND RESULTS: Tissue microarrays were utilised and stained with primary antibodies. Staining data were statistically compared to patient sex, tumour location and development of metastasis and MCC-specific death; 112 tumours and their corresponding patient data were included. We found strong expression of ALK in 51% and strong expression of EZH2 in 76% of the tumours. There was evident correlation of ALK expression with MCV-positivity. Expression of EGFR was infrequent, presenting only in seven MCV-negative tumours. None of the proteins associated with development of metastasis or MCC specific death.
CONCLUSIONS: ALK and EZH2 expression are frequent in MCC and ALK expression correlates to MCV positivity. EGFR positive tumours might respond to EGFR inhibiting treatment.
We introduce the CDRP (Concatenated Diagnostic-Relapse Prognostic) architecture for multi-task deep learning that incorporates a clinical algorithm, e.g., a risk stratification schema to improve prognostic profiling. We present the first application to survival prediction in High-Risk (HR) Neuroblastoma from transcriptomics data, a task that studies from the MAQC consortium have shown to remain the hardest among multiple diagnostic and prognostic endpoints predictable from the same dataset. To obtain a more accurate risk stratification needed for appropriate treatment strategies, CDRP combines a first component (CDRP-A) synthesizing a diagnostic task and a second component (CDRP-N) dedicated to one or more prognostic tasks. The approach leverages the advent of semi-supervised deep learning structures that can flexibly integrate multimodal data or internally create multiple processing paths. CDRP-A is an autoencoder trained on gene expression on the HR/non-HR risk stratification by the Children's Oncology Group, obtaining a 64-node representation in the bottleneck layer. CDRP-N is a multi-task classifier for two prognostic endpoints, i.e., Event-Free Survival (EFS) and Overall Survival (OS). CDRP-A provides the HR embedding input to the CDRP-N shared layer, from which two branches depart to model EFS and OS, respectively. To control for selection bias, CDRP is trained and evaluated using a Data Analysis Protocol (DAP) developed within the MAQC initiative. CDRP was applied on Illumina RNA-Seq of 498 Neuroblastoma patients (HR: 176) from the SEQC study (12,464 Entrez genes) and on Affymetrix Human Exon Array expression profiles (17,450 genes) of 247 primary diagnostic Neuroblastoma of the TARGET NBL cohort. On the SEQC HR patients, CDRP achieves Matthews Correlation Coefficient (MCC) 0.38 for EFS and MCC = 0.19 for OS in external validation, improving over published SEQC models. We show that a CDRP-N embedding is indeed parametrically associated to increasing severity and the embedding can be used to better stratify patients' survival.
Zhang J, Xiang C, Han Y, et al.Differential diagnosis of pulmonary enteric adenocarcinoma and metastatic colorectal carcinoma with the assistance of next-generation sequencing and immunohistochemistry.
J Cancer Res Clin Oncol. 2019; 145(1):269-279 [PubMed
] Related Publications
PURPOSE: Pulmonary enteric adenocarcinoma (PEAC), defined as tumors with an enteric component exceeding 50% and a histological morphology similar to colorectal cancer (CRC) and metastatic colorectal carcinoma (MCC), is an extremely rare primary lung adenocarcinoma, which was recently recognized by World Health Organization (WHO). Adenocarcinomas with intestinal differentiation have also been described in other anatomic sites, including paranasal sinuses, extrahepatic biliary tree, uterine and cervix, ovary. The morphologic spectrum and immunohistochemical profiles of PEAC overlap with those of colonic adenocarcinomas, the diagnosis of PEAC remains challenging. Currently, colonoscopy has to be performed to confirm the diagnosis, resulting in low compliance due to its invasiveness. Due to the rareness of PEAC, its molecular signature has not been comprehensively examined.
METHODS: In this study, we investigated the molecular signatures associated with PEAC and its histological counterparts, CRC and MCC using capture-based targeted sequencing.
RESULTS: We revealed that 12/13 (92.31%) PEAC patients harbored mutations in well-established driver genes for non-small cell lung cancer and none of them had mutations unique to CRC. Furthermore, 13/15 (86.7%) of MCC harbored mutations that are frequently seen in CRC.
CONCLUSION: Collectively, our study showed that PEAC, exhibiting a similar mutational profile with NSCLC, showed a distinctive signature from CRC and MCC. Furthermore, we derived a classification model, intergrading both IHC markers and genetic signature, to accurately diagnose PEAC.
Johansson B, Sahi H, Koljonen V, Böhling TThe expression of terminal deoxynucleotidyl transferase and paired box gene 5 in Merkel cell carcinomas and its relation to the presence of Merkel cell polyomavirus DNA.
J Cutan Pathol. 2019; 46(1):26-32 [PubMed
] Related Publications
BACKGROUND: Merkel cell carcinoma (MCC) tumor samples frequently express B-lymphoid lineage markers. However, the reasons for expression of specific B-lymphoid lineage markers are still unclear. We studied the expression of TdT and PAX5 (two B-cell lymphoid lineage markers) in a large pool of MCC tissue microarray samples.
METHODS: Immunoexpression and staining intensities of TdT and Pax-5 were statistically correlated with patient, tumor, Merkel cell polyomavirus (MCV), and disease-specific parameters.
RESULTS: In a cohort of 117 MCC patients and their corresponding tumor samples, TdT was expressed in 37 (31.6%) samples and PAX5 in 26 (22.2%). Simultaneous immunostaining for TdT and PAX5 was observed in 13 (11.1%) samples. A statistically significant relationship was observed between MCV virus copy number and positive TdT expression (P = 0.0056). Similarly, a significant relationship was also observed between positive TdT and tumor MCV virus positivity (P = 0.000495).
CONCLUSION: We observed frequent TdT and PAX5 immunoexpression in MCC tumor samples. However, simultaneous immunoexpression of these markers was scarce. TdT expression was statistically significantly associated with MCV positivity. The absence of a statistically significant association between tumor parameters and disease progression markers undermines the systemic use of these markers in clinical practice.
Pan X, Hu X, Zhang YH, et al.Identification of the copy number variant biomarkers for breast cancer subtypes.
Mol Genet Genomics. 2019; 294(1):95-110 [PubMed
] Related Publications
Breast cancer is a common and threatening malignant disease with multiple biological and clinical subtypes. It can be categorized into subtypes of luminal A, luminal B, Her2 positive, and basal-like. Copy number variants (CNVs) have been reported to be a potential and even better biomarker for cancer diagnosis than mRNA biomarkers, because it is considerably more stable and robust than gene expression. Thus, it is meaningful to detect CNVs of different cancers. To identify the CNV biomarker for breast cancer subtypes, we integrated the CNV data of more than 2000 samples from two large breast cancer databases, METABRIC and The Cancer Genome Atlas (TCGA). A Monte Carlo feature selection-based and incremental feature selection-based computational method was proposed and tested to identify the distinctive core CNVs in different breast cancer subtypes. We identified the CNV genes that may contribute to breast cancer tumorigenesis as well as built a set of quantitative distinctive rules for recognition of the breast cancer subtypes. The tenfold cross-validation Matthew's correlation coefficient (MCC) on METABRIC training set and the independent test on TCGA dataset were 0.515 and 0.492, respectively. The CNVs of PGAP3, GRB7, MIR4728, PNMT, STARD3, TCAP and ERBB2 were important for the accurate diagnosis of breast cancer subtypes. The findings reported in this study may further uncover the difference between different breast cancer subtypes and improve the diagnosis accuracy.
Singh NP, Bapi RS, Vinod PKMachine learning models to predict the progression from early to late stages of papillary renal cell carcinoma.
Comput Biol Med. 2018; 100:92-99 [PubMed
] Related Publications
Papillary Renal Cell Carcinoma (PRCC) is a heterogeneous disease with variations in disease progression and clinical outcomes. The advent of next generation sequencing techniques (NGS) has generated data from patients that can be analysed to develop a predictive model. In this study, we have adopted a machine learning approach to identify biomarkers and build classifiers to discriminate between early and late stages of PRCC from gene expression profiles. A machine learning pipeline incorporating different feature selection algorithms and classification models is developed to analyse RNA sequencing dataset (RNASeq). Further, to get a reliable feature set, we extracted features from different partitions of the training dataset and aggregated them into feature sets for classification. We evaluated the performance of different algorithms on the basis of 10-fold cross validation and independent test dataset. 10-fold cross validation was also performed on a microarray dataset of PRCC. A random forest based feature selection (varSelRF) yielded minimum number of features (104) and a best performance with area under Precision Recall curve (PR-AUC) of 0.804, MCC (Matthews Correlation Coefficient) of 0.711 and accuracy of 88% with Shrunken Centroid classifier on a test dataset. We identified 80 genes that are consistently altered between stages by different feature selection algorithms. The extracted features are related to cellular components - centromere, kinetochore and spindle, and biological process mitotic cell cycle. These observations reveal potential mechanisms for an increase in chromosome instability in the late stage of PRCC. Our study demonstrates that the gene expression profiles can be used to classify stages of PRCC.
Neoadjuvant chemoradiotherapy (nCRT) following surgery significantly improves the survival rate of patients with rectal cancer. However, nCRT is associated with significant adverse symptoms and high medical costs. Therefore, it is important to investigate potential biomarkers for the prediction of the response to nCRT in patients with rectal cancer. The present study identified candidate biomarkers for predicting a complete response (CR) to nCRT in patients with rectal cancer and investigated the associated mechanisms. Microarray data (accession no. GSE29298) was downloaded from the Gene Expression Omnibus database. Differentially expressed microRNAs (miRNAs/miR) were screened between the pathological CR (pCR) group and no pCR (incomplete response) group. miRNA target genes were predicted using the miRWalk 2.0 online tool and subjected to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Furthermore, a miRNA co‑regulatory network was constructed and disease‑associated genes were predicted. The results demonstrated that a total of 36 upregulated and 5 downregulated miRNAs were identified between the two groups. Among these differentially expressed miRNAs, miR‑548c‑5p, miR‑548d‑5p and miR‑663a were significantly associated with a CR to nCRT. The co‑regulatory network and pathway analysis indicated that miR‑548c‑5p and miR‑548d‑5p may function together through stem cell pluripotency and ubiquitin‑mediated proteolysis signaling pathways. Furthermore, the prediction of disease‑associated genes demonstrated that miR‑548c‑5p/miR‑548d‑5p and miR‑663a may regulate genes associated with rectal cancer, including mutated in colorectal cancers (MCC) and adenomatous polyposis coli (APC), and colorectal neoplasms, including interleukin‑6 signal transducer (IL6ST), cell cycle checkpoint kinase 2 (CHEK2), marker of proliferation Ki‑67 (MKI67), cadherin 7 (CDH7), calreticulin (CALR) and transforming growth factor β1 (TGFB1). Therefore, miR‑548c‑5p, miR‑548d‑5p and miR‑663a are promising candidate biomarkers for predicting a CR to nCRT. miR‑548c‑5p/miR‑548d‑5p may be associated with a CR by regulating IL6ST, CHEK2, MKI67 and MCC. In addition, it may function through the pluripotency of stem cells and ubiquitin‑mediated proteolysis signaling pathways. miR‑663a may be associated with a CR to nCRT by targeting CDH7, CALR, APC and TGFβ1. Thus, the miRNA biomarkers investigated in the present study may represent novel therapeutic targets for the prediction and eventual improvement of the response to nCRT in patients with rectal cancer.
Garcia-Saenz A, Sánchez de Miguel A, Espinosa A, et al.Evaluating the Association between Artificial Light-at-Night Exposure and Breast and Prostate Cancer Risk in Spain (MCC-Spain Study).
Environ Health Perspect. 2018; 126(4):047011 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Night shift work, exposure to light at night (ALAN) and circadian disruption may increase the risk of hormone-dependent cancers.
OBJECTIVES: We evaluated the association of exposure to ALAN during sleeping time with breast and prostate cancer in a population based multicase-control study (MCC-Spain), among subjects who had never worked at night. We evaluated chronotype, a characteristic that may relate to adaptation to light at night.
METHODS: We enrolled 1,219 breast cancer cases, 1,385 female controls, 623 prostate cancer cases, and 879 male controls from 11 Spanish regions in 2008-2013. Indoor ALAN information was obtained through questionnaires. Outdoor ALAN was analyzed using images from the International Space Station (ISS) available for Barcelona and Madrid for 2012-2013, including data of remotely sensed upward light intensity and blue light spectrum information for each geocoded longest residence of each MCC-Spain subject.
RESULTS: Among Barcelona and Madrid participants with information on both indoor and outdoor ALAN, exposure to outdoor ALAN in the blue light spectrum was associated with breast cancer [adjusted odds ratio (OR) for highest vs. lowest tertile, OR=1.47; 95% CI: 1.00, 2.17] and prostate cancer (OR=2.05; 95% CI: 1.38, 3.03). In contrast, those exposed to the highest versus lowest intensity of outdoor ALAN were more likely to be controls than cases, particularly for prostate cancer. Compared with those who reported sleeping in total darkness, men who slept in "quite illuminated" bedrooms had a higher risk of prostate cancer (OR=2.79; 95% CI: 1.55, 5.04), whereas women had a slightly lower risk of breast cancer (OR=0.77; 95% CI: 0.39, 1.51).
CONCLUSION: Both prostate and breast cancer were associated with high estimated exposure to outdoor ALAN in the blue-enriched light spectrum. https://doi.org/10.1289/EHP1837.
Berry D, Mahadevan M, Wick MRDetection of synchronous primary lung adenocarcinomas with genomic sequencing.
Ann Diagn Pathol. 2018; 34:42-44 [PubMed
] Related Publications
In the setting of synchronous pulmonary carcinomas, distinguishing between a monoclonal process with intrapulmonary metastasis and two independent tumors has significant therapeutic and prognostic implications. We describe two cases in which molecular profiling was used to characterize synchronous, primary pulmonary tumors and guide clinical management. In both cases, the patients underwent surgical resection without adjuvant chemotherapy or radiation and remain free of disease.
Dierssen-Sotos T, Palazuelos-Calderón C, Jiménez-Moleón JJ, et al.Reproductive risk factors in breast cancer and genetic hormonal pathways: a gene-environment interaction in the MCC-Spain project.
BMC Cancer. 2018; 18(1):280 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Reproductive factors are well known risk factors for breast cancer; however, little is known about how genetic variants in hormonal pathways interact with that relationship.
METHODS: One thousand one hundred thirty nine cases of breast cancer in women and 1322 frequency-matched controls were compared. Genetic variants in hormonal pathways (identified in the Kyoto Encyclopedia of Genes and Genomes) were screened according to their relationship with breast cancer using the Cochran-Armitage statistic. Information on reproductive factors was obtained using a face-to-face questionnaire. The interaction among the selected genetic variants and reproductive factors was tested with logistic regression.
RESULTS: Concerning C allele in rs2229712, compared to nulliparity in non-carriers the ORs for 1-2 and > 2 deliveries were 0.48 (0.28-0.81) and 0.34 (0.19-0.59), and in C carriers they were 0.92 (0.42-1.98) and 0.71 (0.31-1.61). Similar results were found in women carrying the C allele in rs1269851. Carriers of Allele T in rs35652107 and allele C in rs6018027 had the delivery number effect more pronounced.
CONCLUSIONS: The number of deliveries had a dose-response protective effect on breast cancer; women carrying C allele in rs2229712 did not benefit from this protective effect.
García-Pérez J, Lope V, Pérez-Gómez B, et al.Risk of breast cancer and residential proximity to industrial installations: New findings from a multicase-control study (MCC-Spain).
Environ Pollut. 2018; 237:559-568 [PubMed
] Related Publications
Breast cancer is the most frequent tumor in women worldwide, although well-established risk factors account for 53%-55% of cases. Therefore, other risk factors, including environmental exposures, may explain the remaining variation. Our objective was to assess the relationship between risk of breast cancer and residential proximity to industries, according to categories of industrial groups and specific pollutants released, in the context of a population-based multicase-control study of incident cancer carried out in Spain (MCC-Spain). Using the current residence of cases and controls, this study was restricted to small administrative divisions, including both breast cancer cases (452) and controls (1511) in the 10 geographical areas recruiting breast cancer cases. Distances were calculated from the respective woman's residences to the 116 industries located in the study area. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (between 1 km and 3 km) to industrial plants, adjusting for matching variables and other confounders. Excess risk (OR; 95%CI) of breast cancer was found near industries overall (1.30; 1.00-1.69 at 3 km), particularly organic chemical industry (2.12; 1.20-3.76 at 2.5 km), food/beverage sector (1.87; 1.26-2.78 at 3 km), ceramic (4.71; 1.62-13.66 at 1.5 km), surface treatment with organic solvents (2.00; 1.23-3.24 at 3 km), and surface treatment of plastic and metals (1.51; 1.06-2.14 at 3 km). By pollutants, the excess risk (OR; 95%CI) was detected near industries releasing pesticides (2.09; 1.14-3.82 at 2 km), and dichloromethane (2.09; 1.28-3.40 at 3 km). Our results suggest a possible increased risk of breast cancer in women living near specific industrial plants and support the need for more detailed exposure assessment of certain agents released by these plants.
Around 5% of colorectal cancers are due to mutations within DNA mismatch repair genes, resulting in Lynch syndrome (LS). These mutations have a high penetrance with early onset of colorectal cancer at a mean age of 45 years. The mainstay of surgical management is either a segmental or extensive colectomy. Currently there is no unified agreement as to which management strategy is superior due to limited conclusive empirical evidence available. A systematic review and meta- analysis to evaluate the risk of metachronous colorectal cancer (MCC) and mortality in LS following segmental and extensive colectomy. A systematic review of the PubMed database was conducted. Studies were included/ excluded based on pre-specified criteria. To assess the risk of MCC and mortality attributed to segmental or extensive colectomies, relative risks (RR) were calculated and corresponding 95% confidence intervals (CI). Publication bias was investigated using funnel plots. Data about mortality, as well as patient ascertainment [Amsterdam criteria (AC), germline mutation (GM)] were also extracted. Statistical analysis was conducted using the R program (version 3.2.3). The literature search identified 85 studies. After further analysis ten studies were eligible for inclusion in data synthesis. Pooled data identified 1389 patients followed up for a mean of 100.7 months with a mean age of onset of 45.5 years of age. A total 1119 patients underwent segmental colectomies with an absolute risk of MCC in this group of 22.4% at the end of follow-up. The 270 patients who had extensive colectomies had a MCC absolute risk of 4.7% (0% in those with a panproctocolecomy). Segmental colectomy was significantly associated with an increased relative risk of MCC (RR = 5.12; 95% CI 2.88-9.11; Fig. 1), although no significant association with mortality was identified (RR = 1.65; 95% CI 0.90-3.02). There was no statistically significant difference in the risk of MCC between AC and GM cohorts (p = 0.5, Chi-squared test). In LS, segmental colectomy results in a significant increased risk of developing MCC. Despite the choice of segmental or extensive colectomies having no statistically significant impact on mortality, the choice of initial surgical management can impact a patient's requirement for further surgery. An extensive colectomy can result in decreased need for further surgery; reduced hospital stays and associated costs. The significant difference in the risk of MCC, following segmental or extensive colectomies should be discussed with patients when deciding appropriate management. An individualised approach should be utilised, taking into account the patient's age, co-morbidities and genotype. In order to determine likely germline-specific effects, or a difference in survival, larger and more comprehensive studies are required.
Merkel cell polyomavirus (MCPyV) is the first polyomavirus to be associated with human cancer. Mechanistic studies attempting to fully elucidate MCPyV's oncogenic mechanisms have been hampered by the lack of animal models for MCPyV infection. In this study, we examined the ability of MCPyV-GFP pseudovirus (containing a green fluorescent protein [GFP] reporter construct), MCPyV recombinant virions, and several MCPyV chimeric viruses to infect dermal fibroblasts isolated from various model animals, including mouse (
Castelló A, Fernández de Larrea N, Martín V, et al.High adherence to the Western, Prudent, and Mediterranean dietary patterns and risk of gastric adenocarcinoma: MCC-Spain study.
Gastric Cancer. 2018; 21(3):372-382 [PubMed
] Related Publications
BACKGROUND: The influence of dietary habits on the development of gastric adenocarcinoma is not clear. The objective of the present study was to explore the association of three previously identified dietary patterns with gastric adenocarcinoma by sex, age, cancer site, and morphology.
METHODS: MCC-Spain is a multicase-control study that included 295 incident cases of gastric adenocarcinoma and 3040 controls. The association of the Western, Prudent, and Mediterranean dietary patterns-derived in another Spanish case-control study-with gastric adenocarcinoma was assessed using multivariable logistic regression models with random province-specific intercepts and considering a possible interaction with sex and age. Risk according to tumor site (cardia, non-cardia) and morphology (intestinal/diffuse) was evaluated using multinomial regression models.
RESULTS: A high adherence to the Western pattern increased gastric adenocarcinoma risk [odds ratio
CONCLUSION: Decreasing the consumption of fatty and sugary products and of red and processed meat in favor of an increase in the intake of fruits, vegetables, legumes, olive oil, nuts, and fish might prevent gastric adenocarcinoma.
Cell motility and migration is a complex, multistep, and multicomponent process intrinsic to progression and metastasis. Motility is dependent on the activities of integrin receptors and Rho family GTPases, resulting in the remodeling of the actin cytoskeleton and formation of various motile actin-based protrusions. Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high likelihood of recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is associated with the majority of MCC cases, and MCPyV-induced tumorigenesis largely depends on the expression of the small tumor antigen (ST). Since the discovery of MCPyV, a number of mechanisms have been suggested to account for replication and tumorigenesis, but to date, little is known about potential links between MCPyV T antigen expression and the metastatic nature of MCC. Previously, we described the action of MCPyV ST on the microtubule network and how it impacts cell motility and migration. Here, we demonstrate that MCPyV ST affects the actin cytoskeleton to promote the formation of filopodia through a mechanism involving the catalytic subunit of protein phosphatase 4 (PP4C). We also show that MCPyV ST-induced cell motility is dependent upon the activities of the Rho family GTPases Cdc42 and RhoA. In addition, our results indicate that the MCPyV ST-PP4C interaction results in the dephosphorylation of β
Alonso-Molero J, González-Donquiles C, Palazuelos C, et al.The RS4939827 polymorphism in the SMAD7 GENE and its association with Mediterranean diet in colorectal carcinogenesis.
BMC Med Genet. 2017; 18(1):122 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: The objective of our investigation is to study the relationship between the rs4939827 SNP in the SMAD7 gene, Mediterranean diet pattern and the risk of colorectal cancer.
METHODS: We examined 1087 cases of colorectal cancer and 2409 population controls with available DNA samples from the MCC-Spain study, 2008-2012. Descriptive statistical analyses, and multivariate logistic mixed models were performed. The potential synergistic effect of rs4939827 and the Mediterranean diet pattern was evaluated with logistic regression in different strata of of adherence to the Mediterranean diet and the genotype.
RESULTS: High adherence to Mediterrenean diet was statistically significantly associated with colorectal cancer risk. A decreased risk for CRC cancer was observed for the CC compared to the TT genotype (OR = 0.65 and 95% CI = 0.51-0.81) of the rs4939827 SNP Also, we could show an association between the Mediterranean diet pattern (protective factor) and rs4939827. Although the decreased risk for the CC genotype was slightly more pronounced in subjects with high adherence to Mediterrenean diet, there was no statistically significant synergistic effect between genotype CC and adherence to the Mediterranean dietary pattern factors.
CONCLUSION: The SMAD7 gene and specifically the allele C could be protective for colorectal cancer. An independent protective association was also observed between high adherence Mediterranean diet pattern and CRC risk. Findings form this study indicate that high adherence to Mediterranean diet pattern has a protective role for CRC cancer probably involving the Tumor Growth Factor- β pathway in this cancer.
Carter MD, Gaston D, Huang WY, et al.Genetic profiles of different subsets of Merkel cell carcinoma show links between combined and pure MCPyV-negative tumors.
Hum Pathol. 2018; 71:117-125 [PubMed
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Tumorigenesis in Merkel cell carcinoma (MCC) is driven by (1) clonal integration of the Merkel cell polyomavirus (MCPyV) in neoplastic cells and/or (2) genetic damage by ultraviolet (UV) light. A higher mutational burden, a UV-mutational signature, and many mutations in the TP53 and RB1 genes characterize the virus-negative subset. MCPyV-negative MCCs include combined (often squamous and neuroendocrine) and pure (neuroendocrine) tumors. Because a combined morphology could elude detection microscopically, we sought a genetic link between combined and pure virus-negative tumors. From a global cohort of 46 cases, 9 pure MCPyV-positive, 9 pure MCPyV-negative, and 10 combined MCPyV-negative MCCs were studied by genome-wide microarray in search of copy number aberrations. The entire cohort (n=46) was evaluated by next-generation sequencing for mutations in selected tumor suppressor genes and oncogenes. More copy number aberrations and a greater fraction of the genome were changed in combined and pure MCPyV-negative tumors relative to MCPyV-positive cases (P<.01 for all comparisons). No difference in these parameters was found between the 2 MCPyV-negative groups. Copy number loss of RB1 or an inactivating RB1 mutation (either or both) was common in combined (8/10, 80%) and pure (7/9, 78%) MCPyV-negative tumors but not MCPyV-positive cases (1/9, 11%). A similar trend was seen for TP53 (combined [2/10, 20%] and pure virus-negative tumors [5/9, 56%] showed gene copy number loss or mutations contrasted with pure virus-positive cases [0/9, 0%]). The shared genetic profiles of combined and pure MCPyV-negative tumors link these subsets and separate them from MCPyV-positive tumors.
Benthani FA, Herrmann D, Tran PN, et al.'MCC' protein interacts with E-cadherin and β-catenin strengthening cell-cell adhesion of HCT116 colon cancer cells.
Oncogene. 2018; 37(5):663-672 [PubMed
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E-cadherin and β-catenin are key proteins that are essential in the formation of the epithelial cell layer in the colon but their regulatory pathways that are disrupted in cancer metastasis are not completely understood. Mutated in colorectal cancer (MCC) is a tumour suppressor gene that is silenced by promoter methylation in colorectal cancer and particularly in patients with increased lymph node metastasis. Here, we show that MCC methylation is found in 45% of colon and 24% of rectal cancers and is associated with proximal colon, poorly differentiated, circumferential and mucinous tumours as well as increasing T stage and larger tumour size. Knockdown of MCC in HCT116 colon cancer cells caused a reduction in E-cadherin protein level, which is a hallmark of epithelial-mesenchymal transition in cancer, and consequently diminished the E-cadherin/β-catenin complex. MCC knockdown disrupted cell-cell adhesive strength and integrity in the dispase and transepithelial electrical resistance assays, enhanced hepatocyte growth factor-induced cell scatter and increased tumour cell invasiveness in an organotypic assay. The Src/Abl inhibitor dasatinib, a candidate anti-invasive drug, abrogated the invasive properties induced by MCC deficiency. Mechanistically, we establish that MCC interacts with the E-cadherin/β-catenin complex. These data provide a significant advance in the current understanding of cell-cell adhesion in colon cancer cells.
Merkel cell carcinoma (MCC) frequently contains integrated copies of Merkel cell polyomavirus DNA that express a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). While LT binds RB and inactivates its tumor suppressor function, it is less clear how ST contributes to MCC tumorigenesis. Here we show that ST binds specifically to the MYC homolog MYCL (L-MYC) and recruits it to the 15-component EP400 histone acetyltransferase and chromatin remodeling complex. We performed a large-scale immunoprecipitation for ST and identified co-precipitating proteins by mass spectrometry. In addition to protein phosphatase 2A (PP2A) subunits, we identified MYCL and its heterodimeric partner MAX plus the EP400 complex. Immunoprecipitation for MAX and EP400 complex components confirmed their association with ST. We determined that the ST-MYCL-EP400 complex binds together to specific gene promoters and activates their expression by integrating chromatin immunoprecipitation with sequencing (ChIP-seq) and RNA-seq. MYCL and EP400 were required for maintenance of cell viability and cooperated with ST to promote gene expression in MCC cell lines. A genome-wide CRISPR-Cas9 screen confirmed the requirement for MYCL and EP400 in MCPyV-positive MCC cell lines. We demonstrate that ST can activate gene expression in a EP400 and MYCL dependent manner and this activity contributes to cellular transformation and generation of induced pluripotent stem cells.
Fernández de Larrea-Baz N, Pérez-Gómez B, Michel A, et al.Helicobacter pylori serological biomarkers of gastric cancer risk in the MCC-Spain case-control Study.
Cancer Epidemiol. 2017; 50(Pt A):76-84 [PubMed
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BACKGROUND: Helicobacter pylori infection is one of the main risk factors for non-cardia gastric cancer. However, only a minority of infected persons develop the disease. This study aims at identifying H. pylori related serological biomarkers of risk for gastric cancer.
METHODS: Incident gastric cancer cases and population controls (age, sex and region frequency-matched) from the MCC-Spain multicase-control Study were included. Seroreactivities against 16H. pylori proteins were determined using multiplex serology. Infection was defined as seropositivity against≥4 proteins. Relation of serological results to non-cardia and cardia gastric cancer was assessed using multivariable mixed logistic regression and principal components analysis.
RESULTS: Seroprevalence was 88% among 2071 controls, 95% among 202 non-cardia gastric cancer cases (OR=1.9 (95% CI: 1.0-3.6)) and 85% among 62 cardia cancer cases (OR=0.5 (95% CI: 0.3-1.1)). In infected subjects, seropositivity for UreA, HP231, NapA and Cagδ was associated with lower non-cardia gastric cancer risk, while seropositivity for CagA and VacA was associated with higher risk. Seropositivity for CagA and seronegativity for Cagδ maintained the association after additional adjustment by serostatus of significant proteins. We identified two antibody reactivity patterns: the "virulent-pattern", related to a threefold higher risk of non-cardia gastric cancer and the "non-virulent pattern", related to a 60% decreased risk (4th vs. first quartile).
CONCLUSIONS: In our population, people seropositive for H. pylori were characterized by two patterns of antibody reactivity against H. pylori proteins: 1) Combined high seroreactivity against several proteins, associated with a lower non-cardia gastric cancer risk, and 2) High seroreactivity against CagA and VacA, associated with an increased risk.
Importance: Merkel cell carcinoma (MCC) is a malignant neuroendocrine skin tumor frequently associated with the Merkel cell polyomavirus. Immune checkpoint therapy showed remarkable results, although not all patients are responsive to this therapy. Anti-tropomyosin receptor kinase A (TrkA)-targeted treatment has shown promising results in several tumor entities.
Objective: To determine TrkA expression in MCC as a rationale for potential targeted therapy.
Design, Setting, and Participants: This case series study investigated the MCC specimens of 55 patients treated at the Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany, from January 1, 2005, through December 31, 2015. Thirty-nine of the 55 samples were suitable for further histopathologic examination. Expression of TrkA was explored by immunohistochemical analysis.
Exposure: Diagnosis of MCC was confirmed by staining positive for cytokeratin 20 (CK20) and synaptophysin.
Main Outcomes and Measures: Expression of TrkA on the tumor cells.
Results: Specimens of 39 patients (21 women and 18 men; mean [SD] age, 75.0 [7.8] years) underwent immunohistochemical investigation. Thirty-eight of 38 specimens expressed CK20 and synaptophysin on the MCC tumor cells (100% expression). Merkel cell polyomavirus was detected in 32 of 38 specimens (84%). Tropomyosin receptor kinase A was found in all 36 evaluable specimens on the tumor cells; 34 (94%) showed a weak and 2 (6%) showed a strong cytoplasmic expression. In addition, strongly positive perinuclear dots were observed in 30 of 36 specimens (83%).
Conclusions and Relevance: Tropomyosin receptor kinase A was expressed on MCC tumor cells in 100% of evaluable specimens. This result may lead to the exploration of new targeted treatment options in MCC, especially for patients who do not respond to anti-programmed cell death protein 1 treatment.
BACKGROUND: The aim of this study was to determine the prevalence of MCPyV in Merkel cell carcinoma (MCC) primaries versus lymph node metastasis and to evaluate possible prognostic factors.
METHODS: Samples of MCC primaries and lymph node metastases were stained immunohistochemically for the MCPyV large T-antigen and expression was compared to patients´ clinical outcome.
RESULTS: 41 MCC patients were included. 33 (61%) out of 54 specimens were MCPyV-positive in the immunohistochemistry. 15 (47%) out of 32 primary tumors were positive compared to 18 (82%) out of 22 lymph node metastases. Eleven patients with positive polyomavirus expression died from the carcinoma compared to 4 patients without virus expression. Cox regression analysis showed worse disease-free survival in patients with MCPyV compared to virus-negative lymph nodes (p = 0.002).
CONCLUSIONS: To our knowledge this is the first study to describe a negative prognostic effect of the MCPyV expression in lymph node metastasis in MCC patients.
Harms KL, Chubb H, Zhao L, et al.Increased expression of EZH2 in Merkel cell carcinoma is associated with disease progression and poorer prognosis.
Hum Pathol. 2017; 67:78-84 [PubMed
] Related Publications
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that affects tumorigenesis by epigenetic gene silencing. Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that has a high risk of disease progression with nodal and distant metastases. Here, we evaluated EZH2 expression by immunohistochemistry in a cohort of 85 MCC tumors (29 primary tumors, 41 lymph node metastases, 13 in-transit metastases, and 2 distant metastases) with clinical follow-up. We show strong/moderate EZH2 expression in 54% of tumors. Importantly, weak expression of EZH2 in the primary tumor, but not nodal metastases, correlated with improved prognosis compared to moderate/strong EZH2 expression (5-year MCC-specific survival of 68% versus 22%, respectively, P=.024). In addition, EZH2 was expressed at higher levels in nodal metastases compared to primary tumors (P=.005). Our data demonstrate that EZH2 has prognostic value and may play an oncogenic role in MCC.
BACKGROUND: Evidence for a protective role of physical activity against development of stomach cancer is yet inconclusive. We studied the association of domain-specific physical activity and the risk of gastric adenocarcinoma (GAC), by site and histology, in the MCC-Spain case-control study.
METHODS: 428 histologically confirmed GAC cases (67% men) including the gastro-esophageal region and 3225 controls were included. Cases were recruited in hospitals from 10 different Spanish regions, whereas population controls were randomly selected within the respective hospitals' catchment areas. A physical activity (PA) questionnaire was used to gather information on household and recreational activities, allowing estimation of PA volume (in metabolic equivalents (MET)-min/week). Participants also reported the intensity of working PA and daily sitting time. Questionnaire data on diet, lifestyles and clinical variables including Helicobacter pylori serology were available. Adjusted odds ratios (OR) of GAC were estimated for domains of physical activity, stratifying by sex, site (cardia vs. non-cardia), and Lauren classification (intestinal vs. diffuse).
RESULTS: Household physical activity (HPA) showed a strong inverse association with GAC, observed for both cardia and non-cardia tumours. Risk of overall gastric cancer was 50% lower risk among participants in the highest HPA category (OR = 0.50, 95%CI: 0.38, 0.66). Recreational physical activity (RPA) was also associated with lower overall GAC risk (OR = 0.68, 95% CI: 0.52, 0.88), particularly at moderate levels of intensity such as walking (OR = 0.61, 95% CI: 0.46, 0.79). The protective effect of RPA was strongest for non-cardia tumours. Sedentary time was not related to GAC risk (p-trend = 0.392), but the potential protective effect of RPA was restricted to non-sedentary participants.
CONCLUSIONS: Both household and recreational physical activities were independently related to lower GAC risk in the MCC-Spain study.