Purpose The aims of the TP53 Colorectal Cancer (CRC) International Collaborative Study were to evaluate the possible associations between specific TP53 mutations and tumor site, and to evaluate the prognostic and predictive significance of these mutations in different site, stage, and treatment subgroups. Patients and Methods A total of 3,583 CRC patients from 25 different research groups in 17 countries were recruited to the study. Patients were divided into three groups according to site of the primary tumor. TP53 mutational analyses spanned exons 4 to 8. Results TP53 mutations were found in 34% of the proximal colon tumors and in 45% of the distal colon and rectal tumors. They were associated with lymphatic invasion in proximal tumors. In distal colon tumors, deletions causing loss of amino acids were associated with worse survival. In proximal colon tumors, mutations in exon 5 showed a trend toward statistical significance (P < .05) when overall survival was considered. Dukes' C tumors with wild-type ...

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The TP53 Colorectal Cancer International Collaborative Study on the Prognostic and Predictive Significance of p53 Mutation: Influence of Tumor Site, Type of Mutation, and Adjuvant Treatment

Approximately half of all colorectal cancers show p53 (TP53) gene mutations, with higher frequencies observed in distal colon and rectal tumors and lower frequencies in proximal tumors and those with the microsatellite instability or methylator phenotypes. Alterations to this gene appear to have little or no prognostic value for colorectal cancer patients treated by surgery alone, but are associated with worse survival for patients treated with chemotherapy. There is some evidence that different p53 mutations are associated with different clinical features including prognosis and response to therapy, although further large studies are required to confirm this. Several in vitro, animal and clinical studies have shown that normal p53 is required for the response of colorectal cancers to 5-fluorouracil-based chemotherapy. This should be confirmed by additional retrospective cohort studies and by the incorporation of P53 status in ongoing and future clinical trials. The evaluation of p53 overexpression, using a standardized immunohistochemical (IHC) procedure, could be a clinically useful marker for the identification of colorectal cancer patients likely to benefit from the standard chemotherapy regime currently used for this disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/humu.10175

TP53 Mutation in Colorectal Cancer

Aim
Approximately 20% of patients treated with neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer achieve a pathological complete response (pCR) while the remainder derive the benefit of improved local control and downstaging and a small proportion show a minimal response. The ability to predict which patients will benefit would allow for improved patient stratification directing therapy to those who are likely to achieve a good response, thereby avoiding ineffective treatment in those unlikely to benefit.

Method
A systematic review of the English language literature was conducted to identify pathological factors, imaging modalities and molecular factors that predict pCR following chemoradiotherapy. PubMed, MEDLINE and Cochrane Database searches were conducted with the following keywords and MeSH search terms: ‘rectal neoplasm’, ‘response’, ‘neoadjuvant’, ‘preoperative chemoradiation’, ‘tumor response’. After review of title and abstracts, 85 articles addressing the prediction of pCR were selected.

Results
Clear methods to predict pCR before chemoradiotherapy have not been defined. Clinical and radiological features of the primary cancer have limited ability to predict response. Molecular profiling holds the greatest potential to predict pCR but adoption of this technology will require greater concordance between cohorts for the biomarkers currently under investigation.

Conclusion
At present no robust markers of the prediction of pCR have been identified and the topic remains an area for future research. This review critically evaluates existing literature providing an overview of the methods currently available to predict pCR to nCRT for locally advanced rectal cancer. The review also provides a comprehensive comparison of the accuracy of each modality.

Predicting pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a systematic review.

Background. Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an anti-oxidant and it can act as an anti-inflammatory agent. The aim of this study was to elucidate mechanisms and effect of curcumin in colon cancer cells using gene expression profiling. Methods. Gene expression changes in response to curcumin exposure were studied in two human colon cancer cell lines, using cDNA microarrays with four thousand human genes. HT29 cells were exposed to two different concentrations of curcumin and gene expression changes were followed in time (3, 6, 12, 24 and 48 hours). Gene expression changes after short-term exposure (3 or 6 hours) to curcumin were also studied in a second cell type, Caco-2 cells. Results. Gene expression changes (>1.5-fold) were found at all time points. HT29 cells were more sensitive to curcumin than Caco-2 cells. Early response genes were involved in cell cycle, signal transduction, DNA repair, gene transcription, cell adhesion and xenobiotic metabolism. In HT29 cells curcumin modulated a number of cell cycle genes of which several have a role in transition through the G2/M phase. This corresponded to a cell cycle arrest in the G2/M phase as was observed by flow cytometry. Functional groups with a similar expression profile included genes involved in phase-II metabolism that were induced by curcumin after 12 and 24 hours. Expression of some cytochrome P450 genes was downregulated by curcumin in HT29 and Caco-2 cells. In addition, curcumin affected expression of metallothionein genes, tubulin genes, p53 and other genes involved in colon carcinogenesis. Conclusions. This study has extended knowledge on pathways or processes already reported to be affected by curcumin (cell cycle arrest, phase-II genes). Moreover, potential new leads to genes and pathways that could play a role in colon cancer prevention by curcumin were identified. © 2004 van Erk et al; licensee BioMed Central Ltd.

Time- and dose-dependent effects of curcumin on gene expression in human colon cancer cells

Background:

In terms of genetics, colorectal cancer is one of the best understood of all malignant diseases Genetic influences on prognosis may have far-reaching implications, especially for the design of surgical and chemoradiotherapeutic regimens However, their significance in determining prognosis remains unclear This study aimed to review the literature on the specific role of key genes in determining the survival of patients with colorectal cancer



Methods:

A Medline search was carried out to identify all original scientific papers relating colorectal cancer genetics to patient survival, up to December 2002 Cochrane and Embase databases were also searched Identified articles were retrieved and searched carefully for additional information This review includes K-ras, p53, DCC, NM23 and DNA mismatch repair genes



Results and conclusion:

Conflicting evidence exists as to the prognostic significance of genes commonly implicated in the pathogenesis of colorectal carcinoma Possible causes for such discrepancy include differences in study methods and laboratory techniques, variable duration of follow-up, statistical differences in study power, and heterogeneity in study populations Future studies should adopt standardized protocols to define clinically relevant genetic observations Copyright © 2004 British Journal of Surgery Society Ltd Published by John Wiley & Sons, Ltd

Systematic review of genetic influences on the prognosis of colorectal cancer.

Objectives: To investigate the relationship between the histopathologic effects of preoperative chemoradiotherapy in rectal cancer and the proteins, proliferating cell nuclear antig

Preoperatively irradiated rectal carcinoma: analysis of the histopathologic response and predictive value of proliferating cell nuclear antigen immunostaining.

Objetivo. Analizar el valor pronostico que posee la proteina p53 en cada estadio tumoral, como indicador de riesgo de recidiva. Pacientes y metodo. Estudio prospectivo de una cohorte de 288 pacientes intervenidos por adenocarcinoma colorrectal. Cuarenta y dos pacientes (14,6%) se encontraban en estadio I de la clasificacion TNM (tumor-nodo-metastasis); 144 (50%), en estadio II, y 102 (35,4%), en estadio III. Se analizaron, en muestras tumorales fijadas en formol y parafinadas, variables histopatologicas y se determinaron mediante inmunohistoquimica las proteinas p53 (anticuerpo DO7) y PCNA (proliferative cell nuclear antigen) (anticuerpo PC10). Se analizaron los resultados de p53 en cada una de las categorias de las variables clinicas e histopatologicas. Se calculo la supervivencia sin recidiva mediante el metodo de Kaplan-Meier. Se analizo el valor de cada variable como indicador predictivo de aparicion de recidiva tumoral mediante analisis de regresion de Cox. Se calcularon las hazard ratio y los intervalos de confianza (IC) del 95%, como indicadores del riesgo relativo. El analisis se aplico en toda la cohorte de pacientes y, posteriormente, fue repetido en cada estadio tumoral TNM por separado. Resultados. Los tumores con sobreexpresion de proteina p53 desarrollaron con mayor frecuencia recidiva tumoral y presentaron menor supervivencia sin recurrencia a los 5 anos de seguimiento. Sin embargo, unicamente en los tumores en estadio III la asociacion entre expresion de p53 y evolucion postoperatoria alcanzo significacion estadistica. En este subgrupo de pacientes, la supervivencia sin recidiva a los 60 meses de seguimiento fue del 60% en los tumores con p53 negativo y del 26% en aquellos con p53 positivo (p = 0,010). En el analisis multivariante, p53 se mostro como un factor pronostico independiente asociado a un riesgo elevado de recidiva en tumores en estadio III (hazard ratio = 2,76; IC del 95%, 1,29-5,9; p = 0,009). La sobreexpresion de p53 aporto valor pronostico como indicador de riesgo elevado de recidiva en forma de metastasis (hazard ratio = 2,23; IC del 95%, 1,04-4,75) y no como factor pronostico de recidiva locorregional. No se observo relacion entre el estado de la proteina p53 y el efecto de la quimioterapia adyuvante postoperatoria. Conclusion. La proteina p53 no posee el mismo valor como factor pronostico en todos los estadios tumorales. Esta proteina unicamente posee valor predictivo indicativo de riesgo elevado de recidiva en el subgrupo de pacientes con tumores en estadio III.

Variación del valor pronóstico de la proteína p53 en relación con el estadio tumoral en pacientes con adenocarcinoma colorrectal

Poster: "ECR 2015 / C-2172 / Pancreatic tumors: review and keys for differential diagnosis " by: " J. Silva 1, P. L. Arenas Garcia1, P. Ramos1, M. Gamo2, C. Sainz Azara1, C. Carcamo Flores1, M. Huelves Garcia1, C. Castillo Torres1, M. A. Cruz Diaz1; 1Alcala de Henares/ES, 2Meco/ES"

Pancreatic tumors: review and keys for differential diagnosis

Background The prevalence of genetic alterations is different in primary carcinomas from the proximal colon when compared with carcinomas from the distal colorectum. The objective of this work was to explore the existence of possible differences in the informative weight of the risk of tumor recurrence provided by p53 immunostaining depending on the localization of the neoplasm. Patients and methods Nuclear immunohistochemical expression of p53 protein was determined in formalin-fixed paraffin-embedded archival tumor tissue samples from 190 primary colorectal adenocarcinomas. The relative prognostic importance on the risk of recurrence of each variable was assessed in a Cox's proportional hazard regression analysis. Multiplicative interaction terms between p53 and tumor site were included in the multivariate models in order to test their joint effect on survival. Results One hundred and one patients (53.1%) manifested nuclear accumulation of the protein. P53 overexpression was more frequent in distal than in proximal tumors (58.5% ve s 41.7%) (p = 0.03). Disease-free survival was lower in p53-positive cases (75% versus 38%) (p = 0.006), but significance of the association varied according to the localization of the tumor (p = 0.004 in proximal carcinomas and p = 0.049 in distal carcinomas). Multivariate analysis identified p53 positivity and distal tumor localization as the factors significantly associated with a high risk of recurrence Interaction between p53 expression and localization was present. P53 exhibited different prognostic value in distal and proximal colon. While adjusted hazard ratio for positive p53 was 1.99 in distal cancers, it was 8.04 for proximal tumors. Conclusion The prognostic with value of tumor recurrence associated overexpression of p53 protein is influenced by the location of the tumor. The negative predictive weight is significantly higher in proximal than in distal cancers.

Influence of tumor localization on the prognostic value of P53 protein in colorectal adenocarcinomas

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Preoperatively irradiated rectal carcinoma: analysis of the histopathologic response and predictive value of proliferating cell nuclear antigen immunostaining.

Variación del valor pronóstico de la proteína p53 en relación con el estadio tumoral en pacientes con adenocarcinoma colorrectal

Pancreatic tumors: review and keys for differential diagnosis

Influence of tumor localization on the prognostic value of P53 protein in colorectal adenocarcinomas