Corrigendum to "Hodgkin Lymphoma Cell Lines Are Characterized by a Specific miRNA Expression Profile." Neoplasia 2009, Feb;11(2):167-176.

[This corrects the article DOI: 10.1593/neo.08980.].

HLA-G protein expression as a potential immune escape mechanism in classical Hodgkin's lymphoma.

Classical Hodgkin's lymphoma (cHL) is characterized by the presence of an abundant reactive infiltrate, lacking effective cytotoxic responses. Especially in Epstein-Barr virus (EBV)-negative cHL, the neoplastic Hodgkin-Reed-Sternberg (HRS) cells have lost protein expression of major histocompatibility complex (MHC) class I, enabling escape from cytotoxic T lymphocyte (CTL) responses. However, downregulation of MHC class I generally induces natural killer (NK) cell activation. The paucity of NK cells in the reactive infiltrate of cHL and the systemic NK cell deficiency observed in cHL patients led us to investigate the expression of human leukocyte antigen (HLA)-G, which is known to inhibit NK-cell- and CTL-mediated cytotoxicity. By immunohistochemistry, HLA-G protein was expressed by HRS cells in 54% (95/175) of cHL cases. This expression was associated with absence of MHC class I on the cell surface of HRS cells (P < 0.001) and EBV-negative status (P < 0.001). Previously, genetic markers located in the proximity of the HLA-A and HLA-G genes had been shown to be associated with susceptibility to EBV-positive cHL. In the present study, these markers associated with MHC class I protein expression but not with presence of HLA-G. Our results suggest that induction of HLA-G protein expression in HRS cells contributes to the modulation of immune responses observed in cHL.

Anti-CD45RB monoclonal antibody prolongs renal allograft survival in cynomolgus monkeys.

Previously, an anti-CD45RB monoclonal antibody (mAb) has been shown to induce murine allograft tolerance. The present study was performed to assess the ability of an anti-human CD45RB mAb to prevent rejection in a monkey MHC-mismatched kidney transplant model. The recipients were allocated into the following treatment groups: (1) isotype control IgG; (2) mouse anti-human CD45RB IgG1 (6G3); (3) human-mouse chimeric anti-CD45RB-IgG1 (C6G3-IgG1); (4) human-mouse chimeric anti-CD45RB-IgG2 (C6G3-IgG2); (5) tacrolimus at a subtherapeutic dose and (6) tacrolimus and C6G3-IgG1 in combination. Monotherapy with anti-CD45RB mAb significantly prolonged renal allograft survival to a median survival of 21 days. Adding a subtherapeutic dose of tacrolimus improved the efficacy of the anti-CD45RB mAb, achieving a median survival of 85 days, whereas a subtherapeutic dose of tacrolimus alone only moderately prolonged survival to 27 days. Treatment with anti-CD45RB mAb resulted in an alteration of the CD45RB(hi) : CD45RB(lo) cell ratio in the peripheral blood. We have, for the first time, demonstrated that an anti-human CD45RB mAb (6G3) can prolong graft survival. Induction with an anti-CD45RB mAb improves the efficacy of tacrolimus in the prevention of rejection. These encouraging results indicate that an anti-CD45RB mAb may be valuable in future clinical transplantation.

Regulation of pri-microRNA BIC transcription and processing in Burkitt lymphoma.

BIC is a primary microRNA (pri-miR-155) that can be processed to mature miR-155. In this study, we show the crucial involvement of protein kinase C (PKC) and nuclear factor-kappaB (NF-kappaB) in the regulation of BIC expression upon B-cell receptor triggering. Surprisingly, Northern blot analysis did not reveal any miR-155 expression upon induction of BIC expression in the Burkitt lymphoma-derived Ramos cell line, whereas other microRNAs were clearly detectable. Ectopic expression of BIC in Ramos and HEK293 cells resulted in miR-155 expression in HEK293, but not in Ramos cells, suggesting a specific block of BIC to miR-155 processing in Ramos. In line with the results obtained with Ramos, lack of miR-155 expression after induction of BIC expression was also observed in other Burkitt lymphoma cell lines, indicating a generic and specific blockade in the processing of BIC in Burkitt lymphoma. In contrast, induction of BIC expression in normal tonsillar B cells resulted in very high levels of miR-155 expression and induction of BIC expression in Hodgkin's lymphoma cell lines. It also resulted in elevated levels of miR-155. Our data provide evidence for two levels of regulation for mature miR-155 expression: one at the transcriptional level involving PKC and NF-kappaB, and one at the processing level. Burkitt lymphoma cells not only express low levels of BIC, but also prevent processing of BIC via an, as yet, unknown mechanism.

Preservation of bile ductules mitigates bile duct loss.

The finer branches of the biliary tree (FBBT) contain a regenerative compartment. We hypothesized that preservation of the FBBT together with its microvasculature will lead to recovery of biliary damage and prolonged preservation of bile ductules during the development of chronic liver allograft rejection. The interlobular bile ducts, portal bile ductules and extraportal biliary cells with and without microvessels were studied in sequential biopsies in five patients who fulfilled the Banff criteria of early chronic rejection (CR) (imminence group). Biopsies of CR patients (n = 12) served as controls. Biopsies were double immunostained with CD34 (microvessels) and cytokeratin 7 (biliary structures). Proliferation and proangiogenic activity were assessed with Ki67 and VEGF-A immunostaining. Severe damage of bile ducts in the imminence group did not progress to significant bile duct loss. This was associated with a high proliferative activity in all biliary structures and preservation of the microvascular compartment. VEGF-A expression was increased in all but the reperfusion biopsies. In conclusion, both regenerative activity of the FBBT and an intact microvascular compartment are associated with less damage of the biliary tree and could therefore be prerequisites for biliary regeneration.

The role of microRNAs in normal hematopoiesis and hematopoietic malignancies.

Over the past few years, it has become evident that microRNAs (miRNAs) play an important regulatory role in various biological processes. Much effort has been put into the elucidation of their biogenesis, and this has led to the general concept that a number of key regulators are shared with the processing machinery of small interfering RNAs. Despite the recognition that several miRNAs play crucial roles in normal development and in diseases, little is known about their exact molecular function and the identity of their target genes. In this review, we report on the biological relevance of miRNAs for the differentiation of normal hematopoietic cells and on the contribution of deregulated miRNA expression in their malignant counterparts.

Gene expression analysis of dendritic/Langerhans cells and Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a neoplastic disorder that results in clonal proliferation of cells with a Langerhans cell (LC) phenotype. The pathogenesis of LCH is still poorly understood. In the present study, serial analysis of gene expression (SAGE) was applied to LCs generated from umbilical cord blood CD34+ progenitor cells to identify LC-specific genes and the expression of these genes in LCH was investigated. Besides the expression of several genes known to be highly expressed in LCs and LCH such as CD1a, LYZ, and CD207, high expression of genes not previously reported to be expressed in LCs, such as GSN, MMP12, CCL17, and CCL22, was also identified. Further analysis of these genes by quantitative RT-PCR revealed high expression of FSCN1 and GSN in all 12 LCH cases analysed; of CD207, MMP12, CCL22, and CD1a in the majority of these cases; and CCL17 in three of the 12 cases. Immunohistochemistry confirmed protein expression in the majority of cases. The expression of MMP12 was most abundant in multi-system LCH, which is the LCH type with the worst prognosis. This suggests that expression of MMP12 may play a role in the progression of LCH. These data reveal new insight into the pathology of LCH and provide new starting points for further investigation of this clonal proliferative disorder.

Genetic susceptibility to Hodgkin's lymphoma associated with the human leukocyte antigen region.

Based on the presence of an abundant inflammatory infiltrate, expression of a broad spectrum of cytokines and the professional antigen presenting phenotype of Hodgkin Reed-Sternberg cells it can be anticipated that immunological mechanisms play a major role in the pathogenesis of Hodgkin's lymphoma (HL). Genetic susceptibility to HL probably relates to functionality of the immune system and the large number of associations with the human leukocyte antigen (HLA) region in family and population-based studies supports this relation. In Epstein-Barr virus (EBV) positive HL cases, which usually demonstrate HLA class I expression, HRS cells should be able to present EBV derived antigenic peptides and trigger the immune system. This process depends on the affinity of the HLA binding groove for binding immunogenic peptides and thus on the HLA alleles. It can be anticipated that certain combinations of alleles predispose to or protect from the development of EBV positive HL. In EBV negative HL cases other antigenic peptides, related to malignant transformation, in combination with other HLA alleles may be involved. In addition, differential attraction and activation of inflammatory cells may influence HL subtype. In this article, possible roles of HLA in HL pathogenesis are explored and genetic associations of HLA with HL are reviewed and commented on.

Association with HLA class I in Epstein-Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin's lymphoma.

BACKGROUND: Associations of Hodgkin's lymphoma with HLA have been reported for many years. In 20-40% of patients with this disorder, Epstein-Barr virus (EBV) is present in the neoplastic cells. Because presentation of EBV antigenic peptides can elicit vigorous immune responses, we investigated associations of the HLA region with EBV-positive and EBV-negative Hodgkin's lymphoma. METHODS: In a retrospective, population-based study, patients with Hodgkin's lymphoma were reclassified according to the WHO classification, and EBV status was assessed by in-situ hybridisation of EBV-encoded small RNAs. Germline DNA was isolated from 200 patients diagnosed between 1987 and 2000 and from their first-degree relatives. Genotyping was done with 33 microsatellite markers spanning the entire HLA region and two single-nucleotide polymorphisms in the genes for tumour necrosis factor alpha and beta. Classic association analysis and the haplotype sharing statistic were used to compare patients with controls. FINDINGS: Classic association analysis (but not the haplotype sharing statistic) showed an association of consecutive markers D6S265 and D6S510 (p=0.0002 and 0.0003), located in the HLA class I region, with EBV-positive lymphomas. The haplotype sharing statistic (but not classic association analysis) showed a significant difference in mean haplotype sharing between patients and controls surrounding marker D6S273 (p=0.00003), located in HLA class III. INTERPRETATION: Areas within the HLA class I and class III regions are associated with susceptibility to Hodgkin's lymphoma, the association with class I being specific for EBV-positive disease. This finding strongly suggests that antigenic presentation of EBV-derived peptides is involved in the pathogenesis of EBV-involved Hodgkin's lymphoma. RELEVANCE TO PRACTICE: Polymorphisms in the HLA region could explain ethnic variation in the incidence of Hodgkin's lymphoma. The association of EBV-positive Hodgkin's lymphoma with HLA class I suggests that this polymorphism might affect the proper presentation of EBV antigens to cytotoxic T lymphocytes.

High expression of Mcl-1 in ALK positive and negative anaplastic large cell lymphoma.

AIM: To gain more insight into the genes involved in the aetiology and pathogenesis of anaplastic large cell lymphoma (ALCL). METHODS: Serial analysis of gene expression (SAGE) was undertaken on the CD4+ALK+ (anaplastic lymphoma kinase positive) ALCL derived cell line Karpas299 and as comparison on CD4+ T cells. Quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were performed on five ALCL derived cell lines and 32 tissue samples to confirm the SAGE data. RESULTS: High expression of Mcl-1 was seen in the Karpas299 cell line, whereas the two other antiapoptotic Bcl-2 family members, Bcl-2 and Bcl-X(L), were not detected in the SAGE library. Quantitative RT-PCR confirmed the high expression of Mcl-1 mRNA and low expression of Bcl-2 and Bcl-X(L) in Karpas299 and in four other ALCL cell lines. To expand on these initial observations, primary tissue samples were analysed for Mcl-1, Bcl-X(L), and Bcl-2 by immunohistochemistry. All 23 ALK+ and nine ALK- ALCL cases were positive for Mcl-1. Bcl-2 and Bcl-X(L) were expressed infrequently in ALK+ ALCL cases, but were present in a higher proportion of ALK- ALCL cases. CONCLUSION: The consistent high expression of Mcl-1 in ALK+ and ALK- ALCL suggests that Mcl-1 is the main antiapoptotic protein in this disease. The high frequency of Mcl-1, Bcl-2, and Bcl-X(L) positive ALCL cases in the ALK- group compared with the ALK+ group indicates that ALK induced STAT3 activation is not the main regulatory pathway in ALCL.

Mitoxantrone resistance in a small cell lung cancer cell line is associated with ABCA2 upregulation.

The aim of this study was to find factors that could explain the accumulation difference of mitoxantrone in the BCRP1-negative GLC4-MITO cell line compared to GLC4. Comparative genomic hybridisation (CGH) was applied to determine chromosomal differences between GLC4 and GLC4-MITO. Comparative genomic hybridisation analysis revealed gain of 2q, 6p, 9q, 13q, 14q, 15q, 19q and Xp and loss of 1p, 2q, 3p, 3q, 4q, 6q, 8q, 11p, 16p, 17q, 18p, 20p and Xq. In the over-represented chromosomal areas, seven transporter genes were identified: ABCB6, ABCB2 (TAP1), ABCB3 (TAP2), ABCF1 (ABC50), ABCC10 (MRP7), ABCA2 (ABC2) and ABCC4 (MRP4). No RNA or protein upregulation was observed for ABCB6, ABCF1, ABCC10, ABCC4, ABCB2 and ABCB3, but an increased expression was detected for ABCA2 mRNA in GLC4-MITO. ABCA2 is known to be involved in resistance to estramustine. In the MTT assay, GLC4-MITO was two-fold resistant to estramustine compared to GLC4. Coincubation with estramustine and mitoxantrone increased mitoxantrone accumulation in GLC4-MITO, while this was not affected in GLC4. This suggests that estramustine is able to block mitoxantrone efflux in GLC4-MITO cells. These data reveal that cellular reduction of mitoxantrone in a mitoxantrone-resistant cell line is associated with overexpression of ABCA2.

Expression of Bcl-2 family members and presence of Epstein-Barr virus in the regulation of cell growth and death in classical Hodgkin's lymphoma.

AIMS: To examine the expression of the Bcl-2 family of proteins (Bcl-2, Bcl-x, Bcl-xL and Bax) in classical Hodgkin's lymphoma (cHL) and to correlate the expression of these proteins with proliferation, apoptosis and the presence of Epstein-Barr virus (EBV). METHODS AND RESULTS: Expression of the Bcl-2 family of proteins was detected by immunohistochemistry, proliferation was determined by Ki67 labelling and apoptosis by TUNEL in-situ hybridization. EBV was detected by Epstein-Barr virus early RNA (EBER) in-situ hybridization. Expression of Bcl-2, Bcl-x, Bcl-xL and Bax was detected in the Hodgkin/Reed-Sternberg (H/RS) cells in 43.7% (27/62), 87.5% (56/64), 67.2% (41/61) and 74.6% (47/63) of the cHL cases, respectively. EBER was detected in 53% (35/66) of the cases, whereas Ki67 was observed in 86.7% (52/60) of the cases. Apoptotic H/RS cells were observed infrequently, and only 43.2% (11/26) of the cases showed an apoptotic index of > or = 10% in the H/RS cells. A statistically significant inverse relationship was observed between the expression of Bcl-2 and the presence of EBV (P = 0.003). Bcl-xL showed an inverse correlation with apoptosis in the H/RS cells (P = 0.004). CONCLUSIONS: The higher Bcl-xL expression (67.2%) compared with Bcl-2 expression (43.5%) observed in cHL as well as the statistically significant inverse relationship between Bcl-xL and apoptosis suggests that Bcl-xL plays an important role in the survival of H/RS cells. Expression of Bax may be neutralized by other anti-apoptotic members of the family such as Bcl-2 and/or Bcl-xL.

The immunophenotypic patterns of follicle centre and mantle zone in Castleman's disease.

BACKGROUND: Castleman's disease is an uncommon disease and the histopathogenesis is poorly understood. This study aims to investigate their clinicopathological and immunophenotypic profile. MATERIALS AND METHODS: Castleman's disease was reconfirmed in biopsy tissue from 10 patients in a period of 17 years. Immunohistochemical staining was performed on the archival materials, with antibodies to lymphoid antigens and oncogene products, Bcl-6 and Bcl-2. Six reactive hyperplastic lymph nodes and three tonsils were used for comparative study of the phenotypic expression. RESULT: There were three cases of plasma-cell and seven of hyaline-vascular variant. The ages of patients ranged from eight to 60 years (median 30 years). The three patients with plasma-cell variant were older, all females. Two of the plasma-cell variant had multicentric lesions associated with systemic disease. All patients with hyaline-vascular variant had localised disease. Atrophic follicle centres were present in all the diagnostic tissue of both subtypes, with loss of Bcl-6 follicular centre B-cells and presence of relatively few CD57 T-cells. These follicle centres stained strongly with anti-CD21. In the mantle zone, CD5 expression was observed in only two cases and Bcl-2 expression similar to reactive follicles was present in six. CONCLUSION: Loss of Bcl-6 B-cells in the atrophic follicle centres, characteristic CD21 network patterns, low rate of CD5 and Bcl-2 expression in the mantle-zone lymphocytes are present in both variants of Castleman's disease, differ distinctly from reactive follicles. The phenotypic similarity in these two variants suggests possibility of closely related pathogeneses.

Chemokines, cytokines and their receptors in Hodgkin's lymphoma cell lines and tissues.

BACKGROUND: Hodgkin's lymphoma (HL) is characterized by a minority of neoplastic cells, the so-called Reed-Sternberg (RS) cells, and an admixture of reactive cells including lymphocytes, plasma cells, eosinophils and histiocytes. Cytokines produced in HL, either by RS or infiltrating cells, might explain the presence and maintenance of an impaired immune response. Chemokines (cytokines with chemoattractant properties) produced by RS cells play a major role in leukocyte trafficking. These molecules with specific receptor affinities contribute, for example by attracting TH2-like T cells, to the maintenance of a favorable environment for survival of RS cells. RESULTS AND DISCUSSION: Cross-talk between RS cells and reactive elements involves several cytokine/chemokines that process proliferative [interleukin (IL)-13 and IL-17], immunosuppressive (IL-10 and transforming growth factor-beta) and background formation (IL-5, TARC, MDC, IP-10, RANTES, Mig and others) messages. These autocrine and paracrine interactions lead to an environment where RS cells are able to proliferate, escape from apoptosis and survive host anti-tumor defense. CONCLUSIONS: The proper modulation of these complex pathways may allow the development of new strategies in HL therapy.

TP53 gene mutations in Hodgkin lymphoma are infrequent and not associated with absence of Epstein-Barr virus.

Reed-Sternberg (RS) cells, the neoplastic cells of Hodgkin lymphoma (HL) have clonal immunoglobulin gene rearrangements. The presence of somatic mutations suggests a germinal center origin, whereas the presence of crippling mutations suggests rescue of RS precursors from apoptosis by a transforming event. Epstein-Barr virus (EBV), which can be detected in 30-50% of HL cases, probably plays a role in this transforming event. The frequent presence of p53 protein expression in RS cells also suggests a role of the TP53 gene in this escape from apoptosis. Although mutations of the TP53 gene occur infrequently in RS cells, it has been suggested that in EBV-negative cases this gene mutation may be fundamental for the inhibition of apoptosis. In this study, we tested the hypothesis that there is an inverse correlation between the presence of TP53 gene mutations and the presence of EBV. In 21 of 67 cases EBV encoded small RNA (EBER)1-2 mRNAs were detected. Immunostaining for p53 protein revealed positivity in all 67 cases with variable percentages of positive cells and staining intensity. Screening for mutations in exons 5, 6, 7 and 8 of the TP53 gene in single RS cells obtained by laser microdissection from 26 HL specimens and 4 HL-derived cell lines revealed mutations in 2 of 15 EBV-positive cases and in 1 of 11 EBV-negative cases. Our results confirm the presence of infrequent (11.5%) TP53 gene mutations in HL and suggest that mutations of the TP53 gene are not correlated to the absence of EBV.

Expression of anti-OV6 antibody and anti-N-CAM antibody along the biliary line of normal and diseased human livers.

Following hepatic injury, proliferation of anastomosing ductules can be observed. The origin of this ductular reaction is not completely clear, although there is considerable evidence for proliferation of a putative hepatic progenitor cell, reported to be located in the canals of Hering (CoH) and showing morphologic similarities with rat oval cells. In this study, we analyzed the immunophenotype of solitary oval cell-like cells (SOC), intralobular groups of cuboidal cells that might represent lining cells of CoH, bile ductular cells (BDC), bile duct epithelial cells (BEC), and hepatocytes. We used the antibodies OV6, CK19, and CD56 (NCAM) in a double-staining method in a series of 111 liver specimens. The series consisted of a variety of liver diseases, primary liver tumors, and normal livers. In normal livers, SOC, CoH, BDC, and BEC were uniformly and predominantly CK19+, OV6+, and CD56-. In diseased livers SOC and BDC were CK19+, OV6+, and also CD56+. Occasionally, BEC was CD56+ in damaged bile ducts in diseased liver, e.g., PSC. CoH lining cells were not present in cirrhotic nodules and were indistinguishable from BDC in the fibrous septa. The consistent and uniform staining patterns of SOC, CoH, and BDC support the concept that these cells share the same biliary lineage and might represent one biliary structure. The expression of CD56 on these cells in diseased livers indicates that CD56 is a useful marker for a reparative or regenerative state of the biliary liver-cell constituents but not to discriminate a putative hepatic stem cell.

TARC, a CC chemokine, is frequently expressed in classic Hodgkin's lymphoma but not in NLP Hodgkin's lymphoma, T-cell-rich B-cell lymphoma, and most cases of anaplastic large cell lymphoma.

Thymus and activation-regulated chemokine (TARC) has been identified as a lymphocyte-directed CC chemokine that attracts activated T-helper type 2 (Th2) cells in humans. Recent studies showed that the T cells surrounding Reed-Sternberg cells in Hodgkin's lymphomas (HL) are Th2 type. Anaplastic large cell lymphomas (ALCL), T-cell-rich B-cell lymphoma (TCRBCL) can mimic HL in some instances. This study aimed to establish the pattern of TARC expression in these diseases. Immunohistochemical stain using a polyclonal goat anti-human antibody to TARC was performed on 119 cases of confirmed HL; 99 were classical type (43 mixed cellularity, 43 nodular sclerosis, 5 lymphocyte depleted, 4 lymphocyte rich, 4 unclassifiable) and 20 lymphocyte predominant HL. Additional 27 ALCL (9 T-, 18 null-cell phenotype), 16 T-cell and 8 B-cell non-Hodgkin's lymphoma (NHL) were studied. A total of 85.8% of the classical HL, one case of ALCL, and one case of large cell B-cell lymphoma with anaplastic morphology showed positive TARC expression in the tumor cells. The expression was paranuclear and/or diffuse in the cell cytoplasm. The tumor cells in all cases of lymphocyte predominant HL, TCRBCL, null ALCL, and T-NHL did not express TARC. The high frequency of TARC expression in the Reed-Sternberg cells of classical HL may explain the characteristic T-cell infiltrate in this disease. The absence in other types that may be morphologically similar indicates that staining for TARC may aid in differential diagnosis.

Prognostic significance of K-ras and TP53 mutations in the role of adjuvant chemotherapy on survival in patients with Dukes C colon cancer.

PURPOSE: Mutations in K-ras and TP53 genes are common in colorectal cancer. They affect biologic behavior and might influence chemotherapy susceptibility in these tumors. We investigated whether the survival of patients with Dukes C colon cancer treated with adjuvant chemotherapy is influenced by K-ras and TP53 mutations. METHODS: Mutation screening of the hot spots of the K-ras gene and of the evolutionarily conserved regions of the TP53 gene was performed by denaturing gradient gel electrophoresis technique in formalin-fixed paraffin-embedded specimens of 55 consecutive patients with Dukes C colon cancer treated with adjuvant 5-fluorouracil-based chemotherapy. The median follow-up was 47 (range, 32-66) months. RESULTS: Alterations in the mutation hot spots of K-ras were found at codon 12 (n = 11) and 13 (n = 4) in 15 of the 55 carcinomas (27 percent). No mutation was found at codon 61. Mutations of a probably causative nature in the evolutionarily conserved regions (exons 5-8) of the TP53 gene were found in 24 tumors (44 percent). K-ras and TP53 mutations were found equally in the group with recurrent disease (7/26 (26 percent) and 12/27 (44 percent), respectively) and in the group without recurrences (8/28 (24 percent) and 12/28 (43 percent), respectively). Cancer-specific survival did not differ significantly between patients with K-ras or TP53 or both mutated and nonmutated tumors, respectively (log-rank test: K-ras, P = 0.72 and TP53, P = 0.77; K-ras and TP53, P = 0.8). Also, potentially aggressive K-ras codon 12 and 13 mutations had the same survival as tumors without these mutations (log-rank test; P = 0.73). CONCLUSIONS: Patients with K-ras or TP53 or both mutated Dukes C colon tumors have the same survival as nonmutated tumors when treated with adjuvant chemotherapy. These data suggest that mutations in K-ras or TP53 alone are not prognostic indicators in patients with Dukes C colon cancer receiving adjuvant 5-Fluorouracil-based therapy.