Clinical and biological implication of defective p53 pathway in multiple myeloma (MM)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17516-17516
Author(s):  
W. J. Chng ◽  
T. Price-Troska ◽  
S. Van Wier ◽  
S. Jacobus ◽  
E. Blood ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Electrophoretic Pattern ◽  
P53 Mutation ◽  
Response To Treatment ◽  
Rank Test ◽  
Allelic Loss ◽  
Similar Response ◽  
Newly Diagnosed ◽  
P53 Mutations ◽  
P53 Expression

17516 Background: The p53 tumor suppressor is commonly inactivated by mutations. Even in tumors without mutations, there are defects in the response to p53 activation. In MM, the prognostic significance of p53 mutation is unknown, while there has been no systematic study of p53 function. We seek to address these issues in this study. Methods: p53 mutation was studied by conformation sensitive gel electrophoresis with primers encompassing exons 1 to 10 followed by sequencing of DNA fragments with altered electrophoretic pattern in newly diagnosed MM patients entered into ECOG E9486 trial where patients were randomized to receive variations of melphalan-based conventional chemotherapy (VBMCP). Fisher’s exact tests were used to compare variables between patients. Kaplan-Meier survival curves were compared using the log-rank test. To investigate p53 function, we analyzed the expression of p53, and 3 of its transcriptional targets, APAF1, p21 and MDM2, in a separate cohort of 15 normal plasma cells (PC), 14 MGUS, 13 smoldering myeloma (SMM) and 101 MM (73 new and 28 relapsed) from the Mayo Clinic who had gene expression profiling performed on the Affymetrix U133A chip (Santa Clara, Ca). Results: Two hundred and sixty-eight patients had enough materials for study and were included in the analysis. The prevalence of p53 mutation was 3% (n = 9). Five of the 9 patients (56%, p = 0.001) with mutations also had p53 deletion (studied by fluorescent in-situ hybridization) resulting in bi-allelic loss of p53. Soft tissue plasmacytomas (37% v 7%, p = 0.018), and among the common translocations, t(4;14) and t(14;16) (50% v 18%) were more common in patients with p53 mutations. Despite similar response to treatment, those with p53 mutation had very short OS (16.7 v 41.4 months, p < 0.001). There was induction of p53 expression in MGUS and SMM with concurrent induction of APAF1, p21 and MDM2 whereas loss of this pattern was frequent in MM (45% in new MM and 60% in relapse MM compared to 15% in MGUS/SMM (p = 0.03)). Conclusions: p53 mutations are relatively rare in newly diagnosed MM patients but portend a short survival. However, functional abnormalities of p53 are prevalent and may be important in progression from MGUS/SMM to MM. [Table: see text]

Prognostic Significance of Immunohistochemical Markers in Classical Hodgkin Lymphoma Response to Treatment A Study of 59 Cases.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 972-972 ◽  
Author(s):  
Danielle Canioni ◽  
Benedicte Deau ◽  
Pierre Taupin ◽  
Jacques Bosq ◽  
Vincent Ribrag ◽  
...  
Keyword(s):  
Treatment Response ◽  
Hodgkin Lymphoma ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
Rank Test ◽  
Classical Hodgkin Lymphoma ◽  
High Power Field ◽  
Mixed Cellularity ◽  
P53 Expression ◽  
Immunohistochemical Markers

Abstract Classical Hodgkin lymphoma (cHL) belongs to the most curable lymphomas in adults. Some cHL however, are primary refractory to usual treatments including anthracyclins regimen. Currently, only clinical factors are considered as relevant for prognosis. In a previous study of a small cohort of patients, we showed that some immunohistochemical markers could help for predicting the treatment response of cHL. In this study, we extended the markers and increased the number of included patients. We performed a retrospective study on pre-treatment biopsy specimen of 59 patients, 18 with primary refractory cHL and 41 responders to chemotherapy and free of disease for at least 3 years. Most refractory cHL had a nodular sclerosis (NS) histological type, except one which was a mixed cellularity type. Thirty six responders had a NS type, 3 patients had a mixed cellularity type and the 2 others an interfollicular cHL. The semi-quantitative immunohistochemical study used CD20, CD3, CD30, bcl2, p53, Ki67, TiA1 and c-kit antibodies. The results were statistically evaluated using a Fisher ’s exact test or a Wilcoxon sum rank test depending on the variable studied. CD30 and Ki67 stained strongly Hodgkin (Hg) and Reed-Sternberg (RS) cells regarless the response status. In contrast, these cells expressed significantly less frequently CD20 in refractory cHL than in responders (p= 0.032) and were never stained with CD3. P53 and bcl2 had a significantly higher expression on Hg or RS cells in refractory cHL (median = 63% & 51%) compared to responders (median = 40% & 12%) (p=0.004 & p=0.015 respectively). The cytotoxic marker TiA1 stained significant higher number of small lymphocytes in refractory cHL (median=42.5 per high power field (hpf)) compared to responders (median= 21 per hpf) (p= 0.0006). C-kit antibody was negative in Hg or RS cells but stained significant more mastocytes in refractory cHL (median=9 per hpf) comparing to responders (median=3.8 per hpf) (p= 0.001). These results indicate that immunohistochemical markers are useful in cHL and should be used in association with clinical parameters for predict the cHL treatment response. The prognostic significance of CD20 expression in cHL is controversial but in this study seems predictive of a better treatment response and is merely a marker of different gene expression program that may be associated with a more favorable outcome. A high bcl2 and p53 expression in refractory cHL supports the notion that an intact apoptosis cascade is essential for cell killing effect of chemotherapy. The increasing of TiA1 and c-kit positive cells raises the importance of the environmental non-neoplastic cells in cHL and suggests that targeted therapy against mast cells could improve prognosis of refractory cHL.

scholarly journals Evaluation of Prognostic and Predictive Significance of Circulating MicroRNAs in Ovarian Cancer Patients

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Ann Rita Halvorsen ◽  
Gunnar Kristensen ◽  
Andy Embleton ◽  
Cybil Adusei ◽  
Maria Pilar Barretina-Ginesta ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
Rank Test ◽  
Specific Marker ◽  
High Grade ◽  
Standard Chemotherapy ◽  
Validation Set ◽  
Serous Tumors

Ovarian cancer patients are recognized with poor prognosis. This study aimed to identify microRNAs in plasma for predicting response to treatment and outcome. We have investigated microRNAs in plasma from ovarian cancer patients enrolled in a large multicenter study (ICON7), investigating the effect of adding bevacizumab to standard chemotherapy in patients diagnosed with epithelial ovarian cancer. Patients with different histology, grade, and FIGO stages were included (n=207) in this study. Screening of 754 unique microRNAs was performed in the discovery phase (n=91) using TaqMan Low Density Arrays. The results were validated using single assays and RT-qPCR. Low levels of miR-200b, miR-1274A (tRNALys5), and miR-141 were significantly associated with better survival, confirmed with log-rank test in the validation set. The level of miR-1274A (tRNALys5) correlated with outcome was especially pronounced in the high-grade serous tumors. Interestingly, low level of miR-200c was associated with 5-month prolongation of PFS when treated with bevacizumab compared to standard chemotherapy. We found prognostic significance of miR-200b, miR-141, and miR-1274A (tRNALys5) in all histological types, where miR-1274A (tRNALys5) may be a specific marker in high-grade serous tumors. The level of miR-200c may be predictive of effect of treatment with bevacizumab. However, this needs further validation.

Clinical, Laboratory, and Treatment Outcome Characteristics of Chronic Lymphocytic Leukemia (CLL) Patients with p53 Mutations or del(17p) Enrolled on a Prospective Phase III Clinical Trial: Short Progression Free Survival, Irrespective of Fludarabine-Based Treatment Used.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 949-949 ◽  
Author(s):  
David M. Lucas ◽  
Gordon W. Dewald ◽  
Donna S. Neuberg ◽  
John C. Byrd ◽  
Gerard Lozanski ◽  
...  
Keyword(s):  
Cytogenetic Analysis ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
P53 Mutation ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Fish Analysis ◽  
Single Mutation ◽  
P53 Mutations ◽  
Free Survival

Abstract Deletions or mutations of the tumor suppressor p53 have been associated with more aggressive disease in many types of cancer including CLL, and are more commonly found in relapsed or refractory patients. We studied symptomatic patients (pts) enrolled on ECOG 2997, a randomized phase III trial of fludarabine monotherapy (F) versus fludarabine plus cyclophosphamide (CF) for previously untreated CLL. A total of 235 pretreatment samples were analyzed for p53 mutations in exons 5–9 using denaturing gradient gel electrophoresis (DGGE), followed by confirmation of mutations using automated sequencing. Cytogenetic analysis was also performed on 243 patient samples by Fluorescence In Situ Hybridization (FISH) using a probe to detect deletions in 17p13.1, the chromosomal location of the p53 gene. In the analysis by DGGE, a total of 25 pts (10.6%) were found to have p53 mutations. In 22 cases there was a single mutation, and in three cases there were two mutations. Mutations in exon 6 were the most common, and in each of the cases with two mutations, one of these was in exon 6. Results by exon are as follows: Exon 5 (1 pt, 0.4%), Exon 6 (15 pts, 6.4%), Exon 7 (5 pts, 2.1%), Exon 8 (3 pts, 1.3%), Exon 9 (4 pts, 1.7%). The interphase cytogenetic analysis included 24 of the 25 pts with a p53 mutation by DGGE. Of the 19 (7.8%) pts with del(17p13.1) as the leading cytogenetic anomaly, seven were cases that also had mutations in p53 by DGGE. The remaining 17 pts with mutations in p53 by DGGE had as leading cytogenetic anomaly: del(11q) (2 pts); trisomy 12 (3 pts), normal cytogenetics (2 pts), and del(13q) (10 pts). Results from both the DGGE and FISH analyses were combined to identify a group of 37 pts with either del(17p) or p53 mutation. This constituted 16% of the 230 pts in which either FISH or p53 mutational analysis was performed. Immunocytochemistry staining for p53 was performed on all pts, and no correlation was found between over-expression of p53 protein with mutation and/or deletion of this gene. The pts were then assessed by treatment arm for response and progression-free survival (PFS), relative to patients without p53 abnormality either by DGGE or FISH analysis. In the FC group: 13 pts had either a p53 mutation or del(17p), nine (69%) of whom achieved a CR or a PR, versus 56/74 (76%) of those with normal p53 (p=0.73). In the F group: 15 pts had either a p53 mutation or del(17p), of whom four (27%) achieved a CR or a PR, versus 38/70 (54%) of those with normal p53 (p=0.09). Pts with a detectable abnormality in p53 had a significantly reduced PFS, regardless of whether they received fludarabine alone (p=0.02) or fludarabine plus cyclophosphamide (p=0.005). This study suggests that routine immunocytochemistry staining should not be substituted for p53 mutational studies. While some short responses were observed in patients with p53 mutation and/or deletion receiving fludarabine and/or fludarabine cyclophosphamide, the time to progression was significantly shorter, emphasizing the prognostic significance of p53 abnormalities for this disease.

Melphalan-Prednisone-Thalidomide (MP-T) Demonstrates a Significant Survival Advantage in Elderly Patients ≥75 Years with Multiple Myeloma Compared with Melphalan-Prednisone (MP) in a Randomized, Double-Blind, Placebo-Controlled Trial, IFM 01/01.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 75-75 ◽  
Author(s):  
Cyrille Hulin ◽  
Thierry Facon ◽  
Philippe Rodon ◽  
Brigitte Pegourie ◽  
Lotfi Benboubker ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Partial Response ◽  
Elderly Patients ◽  
Controlled Trial ◽  
Response To Treatment ◽  
Rank Test ◽  
Newly Diagnosed ◽  
Very Elderly ◽  
Double Blind ◽  
Vte Prophylaxis

Abstract Background: The MP-T combination has become the standard treatment for newly diagnosed MM patients (pts) aged 65 to 75 years (Facon et al; Lancet 2007 [Epub ahead of print]). However, no specific therapeutic recommendation exists for pts ≥75 years regarding the benefit of adding thalidomide to MP. Patients older than 75 years have frequently been excluded from large clinical trials, although they represent more than 20% of MM pts. Methods: The IFM 01-01 trial was initiated in 4/2002. Pts ≥75 years with untreated MM were randomized to receive MP-placebo (M [0.2mg/kg/d] + P [2 mg/kg/d day1–4]) x 12 courses every 6-weeks + placebo) or MP-T (MP + daily thalidomide [100mg/d]). No anti-VTE prophylaxis was given. The primary end-point was overall survival (OS). Secondary end points were progression-free survival (PFS), response to treatment, and toxicity. Trial enrollment was prospectively planned for 258 patients. Two interim analyses were performed after inclusion of 150 and 200 patients. The IFM board decided to stop enrollment after the second interim analysis. Results: In all, 232 pts were randomized and 3 failed to meet inclusion criteria. In all, 229 pts were analyzed (113 MP-T; 116 MP-placebo) with a median age of 78.5 years (36% ≥80years). No differences between the 2 groups for baseline characteristics were observed except for gender (p=0.03). Data were analysed on an intent-to-treat basis. The median follow-up time was 24 months. The median OS time (se) was 45.3 (1.6) months with MP-T vs 27.7 (2.1) months with MP-placebo, the benefit was significant (p=0.03 log-rank test). The median PFS time (se) was 24.1 (2) months with MP-T vs 19 (1.4) months with MP-placebo (p=0.001). Rates of at least partial response, very good partial response and complete response were 62%, 22% and 7% with MP-T vs 31%, 7% and 1% with MP-placebo, respectively (p<0.001). In the MP-T arm, 42% of pts stopped treatment due to toxicity vs 11% in the MP-placebo arm. The major reasons in the MP-T arm were peripheral neuropathy (12/48), neutropenia (7/48), and DVT (7/48). Some toxicities (Grade 2–4) were significantly increased with MP-T: peripheral neuropathy (20% vs 5%), neutropenia (23% vs 9%) depression (7% vs 2%). There were no significative differences in DVT rates for MP-T (6%) vs MP-placebo (4%) or somnolence (6% vs 3%, respectively). After relapse in the MP-placebo arm, 77% of patients received Thalidomide. Survival time after progression was similar in the 2 groups, 9.8 months after MP-placebo and 9.3 months after MP-T. Conclusion: These results confirm the superiority of MP-T over MP for prolonging OS in elderly patients with newly diagnosed MM. The toxicity was acceptable in this very elderly population ≥ 75 years. A new era of progress is opened for these very elderly patients.

scholarly journals The Multi-biomarker Disease Activity test for assessing response to treatment strategies using methotrexate with or without prednisone in the CAMERA-II Trial

2020 ◽  
Author(s):  
Maud Jurgens ◽  
Mary Safy-Khan ◽  
Maria de Hair ◽  
Johannes Bijlsma ◽  
Paco Welsing ◽  
...  
Keyword(s):  
Disease Activity ◽  
Treatment Response ◽  
Treatment Strategies ◽  
Response To Treatment ◽  
Rank Test ◽  
Treat To Target ◽  
Similar Response ◽  
Gradual Improvement ◽  
Signed Rank Test ◽  
Response Profiles

Abstract ObjectivesThe CAMERA-II trial compared two tight-control, treat-to-target strategies, initiating methotrexate with prednisone (MTX+pred) or MTX with placebo (MTX+plac), in early RA-patients. The multi-biomarker disease activity (MBDA) blood test objectively measures RA disease activity with a score of 1−100. In CAMERA-II, response profiles of the MBDA score, its individual biomarkers and DAS28 were assessed.MethodsWe evaluated 92 patients from CAMERA-II of whom clinical data and serum for MBDA testing at baseline and ≥1 timepoint from months 1, 2, 3, 4, 5, 6, 9 or 12 were available. Changes (∆) from baseline for DAS28 and MBDA score and comparisons of ∆DAS28 and ∆MBDA score over time within the MTX+pred versus the MTX+plac strategy, were tested for significance with t-tests. Changes in biomarker concentration from baseline to months 1−5 were tested with Wilcoxon signed rank test and tested for difference between treatment arms by Mann-Whitney U test. ResultsMBDA and DAS28 showed similar response profiles, with gradual improvement over the first 6 months in the MTX+plac group, and in the MTX+pred group faster improvement during month 1, followed by gradual improvement. The 12 MBDA biomarkers could be grouped into 4 categories of response profiles, with significant responses for 4 biomarkers during the MTX+plac strategy and 9 biomarkers during the MTX+pred strategy.ConclusionsMBDA tracked treatment response in CAMERA-II similarly to DAS28. More individual MBDA biomarkers tracked treatment response of MTX+pred than of MTX+plac. Four response profiles could be observed.

scholarly journals p53 Abnormalities in B-Cell Prolymphocytic Leukemia

Blood ◽  
1997 ◽  
Vol 89 (6) ◽  
pp. 2015-2023 ◽  
Author(s):  
Daniela Lens ◽  
Pierre J.J.C. De Schouwer ◽  
Rifat A. Hamoudi ◽  
Munah Abdul-Rauf ◽  
Nahla Farahat ◽  
...  
Keyword(s):  
B Cell ◽  
Hematologic Malignancies ◽  
P53 Mutation ◽  
Lymphocytic Leukemia ◽  
Cathepsin G ◽  
P53 Mutations ◽  
B Cell Malignancies ◽  
Prolymphocytic Leukemia ◽  
P53 Expression ◽  
Pathologic Features

Abstract B-cell prolymphocytic leukemia (B-PLL) is an aggressive disorder of mature B cells with distinct clinical and pathologic features. To determine the incidence of abnormalities of p53, we analyzed 19 cases of B-PLL by DNA blot to assess loss of heterozygosity (LOH) at 17p13.3, by immunocytochemistry to assess p53 expression, and by direct DNA sequencing of polymerase chain reaction-amplified exons 5 to 9 of the p53 gene. LOH was detected in 10 of 19 (53%) cases, p53 expression was detected in 8 of 17 (47%), and p53 mutations were detected in 10 of 19 (53%) cases. The pattern of mutations was distinct from that observed in other B-cell malignancies. Six cases exhibited missense mutations; 4 were transversions and 2 were transitions. The G:C → A:T transition at cathepsin G dinucleotides commonly reported in p53 mutations in chronic lymphocytic leukemia (CLL) and other hematologic malignancies was observed in only 1 case of B-PLL. Three cases exhibited deletions (ranging from 3 to 35 bp in length) and one case exhibited a 2-bp insertion. In 1 case, a 27-bp deletion resulted in the expression of a p53 protein lacking 9 amino acids from the DNA binding region. All samples with p53 mutation showed loss of germline p53 sequences. However, 3 of 10 showed no LOH by Southern blot, indicating a localized deletion around the p53 locus at 17p13.1. Five of the 10 cases with p53 mutation exhibited detectable p53 expression, including 4 cases with p53 missense mutation and 1 case with deletion. Two of 7 cases with no detectable mutation of p53 nevertheless overexpressed p53. Therefore, there was no correlation between protein expression and p53 mutation in B-PLL. Our data indicate that the overall abnormalities of p53 occurred in 14 of 19 (75%) cases of B-PLL. The frequency of p53 mutation (53%) in B-PLL is the highest reported in B-cell malignancies and may be responsible for the frequent resistance to therapy of this disease. In addition, the pattern of p53 mutation was different from that observed in CLL and other hematologic malignancies and may indicate that a distinct pathogenic mechanism operates in B-PLL.

scholarly journals Efficient Generation of P53 Biallelic Mutations in Diannan Miniature Pigs Using RNA-Guided Base Editing

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1417
Author(s):  
Honghui Li ◽  
Wenmin Cheng ◽  
Bowei Chen ◽  
Shaoxia Pu ◽  
Ninglin Fan ◽  
...  
Keyword(s):  
Disease Model ◽  
P53 Gene ◽  
P53 Mutation ◽  
P53 Mutations ◽  
P53 Expression ◽  
Base Editing ◽  
System A ◽  
Reconstructed Embryos ◽  
Monoallelic Mutation ◽  
Biallelic Mutations

The base editing 3 (BE3) system, a single-base gene editing technology developed using CRISPR/Cas9n, has a broad range of applications for human disease model construction and gene therapy, as it is highly efficient, accurate, and non-destructive. P53 mutations are present in more than 50% of human malignancies. Due to the similarities between humans and pigs at the molecular level, pig models carrying P53 mutations can be used to research the mechanism of tumorigenesis and improve tumor diagnosis and treatment. According to pathogenic mutations of the human P53 gene at W146* and Q100*, sgRNAs were designed to target exon 4 and exon 5 of the porcine P53 gene. The target editing efficiencies of the two sgRNAs were 61.9% and 50.0%, respectively. The editing efficiency of the BE3 system was highest (about 60%) when C (or G) was at the 5th base. Puromycin screening revealed that 75.0% (21/28) and 68.7% (22/32) of cell colonies contained a P53 mutation at sgRNA-Exon5 and sgRNA-Exon4, respectively. The reconstructed embryos from sgRNA-Exon5-5# were transferred into six recipient gilts, all of which aborted. The reconstructed embryos from sgRNA-Exon4-7# were transferred into 6 recipient gilts, 3 of which became pregnant, resulting in 14 live and 3 dead piglets. Sequencing analyses of the target site confirmed 1 P53 monoallelic mutation and 16 biallelic mutations. The qPCR analysis showed that the P53 mRNA expression level was significantly decreased in different tissues of the P53 mutant piglets (p < 0.05). Additionally, confocal microscopy and western blot analysis revealed an absence of P53 expression in the P53 mutant fibroblasts, livers, and lung tissues. In conclusion, a porcine cancer model with a P53 point mutation can be obtained via the BE3 system and somatic cell nuclear transfer (SCNT).

Prognostic impact of allelic losses in 1p32–36 (HYTM1), 4p15.2 (D4S2397), 5q22.2 (D5S346), 8p22 (D8S254), 18q12.3 (D18S474), and microsatellite instability for colorectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4132-4132
Author(s):  
R. Melcher ◽  
T. Kudlich ◽  
H. Luehrs ◽  
T. Katzenberger ◽  
B. Illert ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Normal Mucosa ◽  
Stage I ◽  
Rank Test ◽  
Allelic Loss ◽  
Prognostic Impact ◽  
Tumour Stage

4132 Background: The aim of this prospective study was to analyse the prognostic impact of allelic losses in the chromosomal regions 1p32–36 (HYTM1), 4p14–16 (D4S2397), 5q22 (D5S346), 8p21–22 (D8S254), 18q12.3 (D18S474) and microsatellite instability (MSI) in colorectal cancer (CRC). The microsatellite markers HYTM1, D4S2397, D8S254, and D18S474 were previously shown to have prognostic relevance in retrospective studies. The National Cancer Institute (NCI) microsatellite panel (BAT25, BAT26, D2S123, D5S346 and D17S250) was used for MSI-Analysis. Methods: Between July 1999 and February 2004, the data from a total of 165 patients, preoperatively diagnosed with colorectal cancer, and operated on in the Department of Surgery, University of Wuerzburg were collected. Inclusion criteria were: (a) electively operated primary adenocarcinomas; (b) obtainment of fresh paired normal mucosa-tumor samples; (c) no postoperative death (survival < 1 month); and (d) availability of follow-up data. Allelic loss (LOH) was determined by comparing the PCR-patterns of tumor DNA with corresponding normal tissue (signal reduction of at least 50%). MSI-L (low microsatellite instability) was defined as one marker out of five NCI-markers, MSI-H (high microsatellite instability) as more than two markers to display microsatellite instability. MSI-H tumours were excluded for further LOH-analysis. The endpoint of the study was tumour specific death. Kaplan-Meier survival curves were compared using the log-rank test. Results: We found expected frequencies in age, gender, tumour stage, and tumour grading. Tumour stage, grading, and an allelic loss of D18S474 was confirmed to be of prognostic significance for UICC I-IV, I-III, and II cancer in univariate analysis. Tumour stage and LOH D18S474 were also independent prognostic variables in stage I-IV and I-III. There was no significant prognostic impact of a loss of the markers HYTM1, D4S2397, D5S346, D8S254, MSI-L and MSI-H in either UICC stage I-IV, I-III, and II colorectal cancer patients. Conclusions: A loss of D18S474 defines a high-risk subgroup of patients with stage I-IV, I-III and stage II colorectal cancers. No significant financial relationships to disclose.

Prognostic significance of high-risk human papilloma virus (HPV), p16, and p53 status in women with vulvar squamous cell carcinoma (VSCC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5105-5105
Author(s):  
Ghassan Allo ◽  
Mei Ling Yap ◽  
Julie Cuartero ◽  
Helen Mackay ◽  
Michael Milosevic ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Disease Recurrence ◽  
Hpv Infection ◽  
Rank Test ◽  
P53 Expression ◽  
Hpv Status ◽  
P53 Status ◽  
Cell Cycle Deregulation

5105 Background: The incidence of VSCC is increasing. Studies suggest the presence of two histologically and molecularly distinct subsets of VSCC; one contingent on and another independent of HPV infection. However, it is uncertain if HPV status has prognostic significance. HPV oncoproteins can result in degradation of the tumor suppressor p53, cell cycle deregulation and abnormal expression of cyclin dependant kinase inhibitor p16. The aim of this study was to investigate HPV infection, p16 and p53 in relation to clinical parameters in women with VSCC. Methods: Sequential cases of VSCC from patients (pts) treated at Princess Margaret Hospital (PMH) from 2000 to 2008 were reviewed. HPV infection was evaluated by Roche Linear array. A tissue microarray was constructed. p16 and p53 immunohistochemistry was performed. Clinical data was abstracted from medical records and PMH Cancer Database. Survival analysis was performed using Kaplan-Meier curves and log rank test. Results: We identified124 pts with VSCC. HPV was detected in 43/123 (35%) pts (median age 71 ± 16 yrs). HPV16 was the most common serotype (38/43; 88.4%). p16 was expressed in 30/115 (26%) pts and p53 in 59/117 (50.4%) pts. Median age of pts was not different in relation to HPV, p16 and p53 status. Expression of p16 (p<0.0001) and loss of p53 (p=0.007) were associated with HPV infection. Pts with HPV positive tumors were less likely to recur (recurrence rate at 5 years (RR) 12.5% vs 50.3%, p=0.009). HPV positive VSCC were not associated with better 5 yr disease free survival (DFS), 58% vs 31%; p=0.15, or overall survival (OS), 61% vs 61% ; p=0.94. p16 positive tumors had a lower RR at 5 yrs, 23.8% vs 59%, p=0.006 and better 5yr DFS (61% vs 27% ; p=0.009) but not significant for OS (65% vs 59%; p=0.94). Among pts with HPV positive VSCC, OS and DFS were not different between p16 positive and negative VSCC. In the 46 pts treated with radiotherapy, HPV and p16 positive tumors were associated with a lower RR (p=0.004 and 0.005). p53 expression was not prognostic in any pt group. Conclusions: Women with HPV-positiveVSCC have a lower risk of disease recurrence. p16-expressing VSCC are associated with reduced disease recurrence and improved DFS.

p53 and K-ras Gene Mutations Correlate With Tumor Aggressiveness But Are Not of Routine Prognostic Value in Colorectal Cancer

1999 ◽  
Vol 17 (5) ◽  
pp. 1375-1375 ◽  
Author(s):  
Silvia Tortola ◽  
Eugenio Marcuello ◽  
Isabel González ◽  
Germán Reyes ◽  
Rosa Arribas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
P53 Gene ◽  
Radical Resection ◽  
Genetic Alterations ◽  
Rank Test ◽  
P53 Mutations ◽  
Ras Gene ◽  
Ras Mutations

PURPOSE: p53 gene and K-ras mutations are among the most common genetic alterations present in colorectal cancer. The prognostic utility of such mutations remains controversial. The purpose of this study was to prospectively evaluate the prognostic significance of p53 and K-ras gene mutations in colorectal cancer. PATIENTS AND METHODS: One hundred forty patients were analyzed. Tumors belonging to the microsatellite mutator phenotype were excluded (n = 8). Mutations at the K-ras and p53 genes were detected and characterized by restriction fragment length polymorphism, single-strand conformation polymorphism, and sequencing, as appropriate. RESULTS: p53 mutations were detected in 66 (50%) and K-ras mutations were detected in 54 (41%) of the 132 patients. In 26 cases (20%), ras and p53 mutations coexisted; in 38 cases (29%), neither mutation was found. Multivariate analysis of the whole population analyzed (n = 132) showed that survival was strongly correlated with the presence of p53 mutations alone or in combination with K-ras mutations (P = .002; log-rank test). When only patients undergoing a radical resection were considered (R0; n = 101), p53 mutations were no longer of prognostic significance. CONCLUSION: p53 mutations alone or in combination with K-ras mutations are correlated with a worse outcome. However, the routine use of these mutations as prognostic markers in the clinical setting is not recommended.

Sign in / Sign up

Export Citation Format

Share Document