Lack of p53 Nuclear Immunostaining Is Not Indicative of Absence of TP53 Gene Mutations in Colorectal Adenocarcinomas

Colomer, Anna; Erill, Nadina; Verdú, Montse; Román, Ruth; Vidal, August; Cordon‐Cardo, Carlos; Puig, Xavier

doi:10.1097/00129039-200306000-00007

Cited by 16 publications

(14 citation statements)

References 40 publications

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“…We defined the p53 system as functional by the association of low expression of p53 and high expression of the MDM2 cofactor, and p21 WAF1/CIP1 , although p21 WAF1/CIP1 can also accumulate in a p53-independent pathway related to cell cycle arrest due to senescence, terminal differentiation, and apoptosis (56). We also found complete loss of p53 and MDM2 immunostaining in 29 cases indicating an underlying p53 mutation as previously suggested (57), that were considered as nonfunctioning. p53 expression has been used as a tool to indicate cancers that might or might not be sensitive to 5-FU -based chemotherapy (49).…”

Section: Thymidylate Synthase and Microsatellite Instabilitysupporting

confidence: 70%

High Thymidylate Synthase Expression in Colorectal Cancer with Microsatellite Instability: Implications for Chemotherapeutic Strategies

Ricciardiello

Ceccarelli

Angiolini

et al. 2005

Clinical Cancer Research

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Colon cancers displaying microsatellite instability (MSI) are clinically less aggressive. Based on in vitro studies and recent clinical data, cancers displaying MSI do not respond to 5-fluorouracil (5-FU). The reasons why MSI tumors are clinically less aggressive and do not respond to 5-FUb ased therapies have not been fully elucidated. Purpose: We investigated biomolecular markers in an attempt to explain the different clinical behavior and chemotherapeutic responses of MSI and non-MSI colon cancers. Experimental Design: One hundred ninety-two sporadic colon cancers were tested for MSI with five mononucleotide markers and methylation of the hMLH1promoter. Slides were stained for thymidylate synthase (TS), p53, MDM2, p21, h-catenin, vascular endothelial growth factor, hMLH1, hMSH2, and hMSH6.Tumors were regarded as having wild-type, functional p53 (Fp53) if reduced expression of p53 and positive MDM2 and p21 WAF1/CIP1 expressions were found. Results: Of the cases, 12.5% were MSI-H (at least two markers mutated). Of MSI-H cases, 83.3% were characterized by a complete loss of at least one of the mismatch repair proteins, in particular loss of hMLH1by promoter hypermethylation. MSI-H colon cancers showed higher expression of TS compared with MSS (no mutated markers)/MSI-L (one mutated marker) colon cancers (66.6% for MSI-H versus 14.8 % MSS/MSI-L; P < 0.0001); 20.8% of MSI-H cases showed high expression of the vascular endothelial growth factor, compared with 45.8% MSS/ MSI-L colon cancers (P = 0.0005); 45.8% MSI-H cases had Fp53 compared 11.9% MSS/MSI-L cases (P < 0.0001).Conclusions: About 12% of colon cancers display MSI mostly due to lack of hMLH1 resulting from promoter hypermethylation. These tumors have high expression of TS and retain fully functional p53 system. Thus, these data suggest why sporadic hMLH1-defective colon cancers often do not respond to 5-FU.

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Section: Thymidylate Synthase and Microsatellite Instabilitysupporting

confidence: 70%

High Thymidylate Synthase Expression in Colorectal Cancer with Microsatellite Instability: Implications for Chemotherapeutic Strategies

Ricciardiello

Ceccarelli

Angiolini

et al. 2005

Clinical Cancer Research

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“…Immunohistochemical evaluation was conducted double-blind by scoring the estimated percentage of tumor cells showing nuclear staining. Consistent with previous reports, [33][34][35] certain intratumoral heterogeneity was observed in the distribution of both p53-and Ki67-stained neoplastic cells. In these cases, the score was produced by estimating the percentage of positive cells in microscopic fields displaying the most intense immunoreactive tumor cells.…”

Section: Immunohistochemical Analysissupporting

confidence: 92%

A Novel Logistic Model Based on Clinicopathological Features Predicts Microsatellite Instability in Colorectal Carcinomas

Colomer¹,

Erill²,

Vidal³

et al. 2005

Diagnostic Molecular Pathology

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High-frequency microsatellite instability has been reported to be associated with good prognosis in colorectal adenocarcinoma. However, methods to assess microsatellite instability (MIN) are based on genetic assays and are not ideally suited to most histopathology laboratories. The aim of the present study was to develop a model for prediction of MIN status in colorectal cancer based on phenotypic characteristics. Clinicopathological features of a cohort of 204 patients with primary colon cancer were retrospectively reviewed following predetermined criteria. Genetic assessment of MIN status was performed on DNA extracted from sections of formalin-fixed, paraffin-embedded specimens by testing a panel of 11 microsatellite markers. Logistic regression analysis generated a mathematical tool capable of identifying colorectal tumors displaying MIN status with a sensitivity of 77.8% and a specificity of 96.8%. Features associated with instability included the proximal location of the lesions, occurrence of solid and/or mucinous differentiation, absence of cribriform structures, presence of peritumoral Crohn-like reaction, expansive growth pattern, high Ki67 proliferative index, and p53-negative phenotype. This approach predicts microsatellite instability in colorectal carcinoma with an overall assigned accuracy of 95.1% and a negative predictive value of 97.8%. Implementation of this tool to routine histopathological studies could improve the management of patients with colorectal cancer, especially those presenting with stage II and III of the disease. It will also assist in identifying a subset of patients likely to benefit from adjuvant chemotherapy.

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“…Tumors were screened by single-stranded conformation polymorphism analysis for the presence of somatic p53 mutations, as previously described [46], [47]. p53 exons 5−8 were amplified by polymerase chain reaction (PCR) from microdissected, paraffin-embedded tumor tissue, as described [48].…”

Section: Methodsmentioning

confidence: 99%

Household Income Is Associated with the p53 Mutation Frequency in Human Breast Tumors

et al. 2013

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BackgroundA study from Scotland reported that the p53 mutation frequency in breast tumors is associated with socio-economic deprivation.MethodsWe analyzed the association of the tumor p53 mutational status with tumor characteristics, education, and self-reported annual household income (HI) among 173 breast cancer patients from the greater Baltimore area, United States.Resultsp53 mutational frequency was significantly associated with HI. Patients with < $15,000 HI had the highest p53 mutation frequency (21%), followed by the income group between $15,000 and $60,000 (18%), while those above $60,000 HI had the fewest mutations (5%). When dichotomized at $60,000, 26 out of 135 patients in the low income category had acquired a p53 mutation, while only 2 out of 38 with a high income carried a mutation (P < 0.05). In the adjusted logistic regression analysis with 3 income categories (trend test), the association between HI and p53 mutational status was independent of tumor characteristics, age, race/ethnicity, tobacco smoking and body mass. Further analyses revealed that HI may impact the p53 mutational frequency preferentially in patients who develop an estrogen receptor (ER)-negative disease. Within this group, 42% of the low income patients (< $15,000 HI) carried a mutation, followed by the middle income group (21%), while those above $60,000 HI did not carry mutations (P trend < 0.05).Conclusions:HI is associated with the p53 mutational frequency in patients who develop an ER-negative disease. Furthermore, high income patients may acquire fewer p53 mutations than other patients, suggesting that lifetime exposures associated with socio-economic status may impact breast cancer biology.

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Lack of p53 Nuclear Immunostaining Is Not Indicative of Absence of TP53 Gene Mutations in Colorectal Adenocarcinomas

Cited by 16 publications

References 40 publications

High Thymidylate Synthase Expression in Colorectal Cancer with Microsatellite Instability: Implications for Chemotherapeutic Strategies

High Thymidylate Synthase Expression in Colorectal Cancer with Microsatellite Instability: Implications for Chemotherapeutic Strategies

A Novel Logistic Model Based on Clinicopathological Features Predicts Microsatellite Instability in Colorectal Carcinomas

Household Income Is Associated with the p53 Mutation Frequency in Human Breast Tumors

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