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Original Article |

Combination of Microsatellite Instability and Lymphocytic Infiltrate as a Prognostic Indicator in Colon Cancer FREE

Eugene Y. Chang, MD; Paul B. Dorsey, MS; Joseph Frankhouse, MD; Randall G. Lee, MD; Deb Walts, MSN; William Johnson, MD; George Anadiotis, DO; Nathalie Johnson, MD
[+] Author Affiliations

Author Affiliations: Oregon Health and Science University, Department of Surgery (Dr Chang), and Legacy Health System (Drs Frankhouse, Lee, W. Johnson, Anadiotis, and N. Johnson, Mr Dorsey, and Ms Walts), Portland.


Arch Surg. 2009;144(6):511-515. doi:10.1001/archsurg.2009.40.
Text Size: A A A
Published online

Background  Microsatellite instability (MSI) is a genetic aberration associated with less aggressive tumor biology. Some tumors with MSI also have lymphocytic infiltrate (LI), which suggests a heightened immune response against the tumor.

Objective  To evaluate the combined prognostic significance of MSI and LI in a colon cancer population.

Design  Colon cancers were prospectively evaluated for MSI by assessing 11 satellite markers and were classified as MSI+ if 2 or more satellite markers displayed instability. Tumors were classified as LI+ if at least 5 lymphocytes were observed per 10 high-power fields.

Setting  Community hospital system.

Patients  Individuals undergoing definitive surgery for colon cancer.

Main Outcome Measures  Overall and disease-free survival were compared according to combined MSI and LI status.

Results  In 150 patients, tumors were classified as follows: 95 were MSI−/LI−, 9 were MSI−/LI+, 30 were MSI+/LI−, and 16 were MSI+/LI+. Median follow-up was 40.6 months. Five-year disease-free survival was 56.7% for patients with MSI−/LI− tumors and 88.9% for those with MSI+/LI+ tumors (P = .01). Patients with MSI+/LI− and MSI−/LI+ tumors had 5-year survival of 75.4% and 75.0%, respectively.

Conclusions  Patients with colon cancer and MSI−/LI− tumors have worse disease-free survival rate regardless of stage at diagnosis. Patients exhibiting both MSI+ and LI+ tumors have more favorable disease-free survival rates. Both MSI and LI show promise as a combined prognostic marker and with further study may prove to be particularly useful in selecting patients with stage II disease for adjunctive therapy.

Figures in this Article

The colon is the third leading cancer tumor site, with an estimated 112 340 cases diagnosed per year in the United States.1 Significant progress has been made in the realm of treatment. New chemotherapeutic regimens are improving response rates. However, we have yet to develop prognostic markers to select patients who would benefit from more aggressive adjunctive therapy. To date, physicians still base that decision on nodal involvement.

Microsatellite instability (MSI) is a phenomenon in colorectal cancer that has attracted attention owing to the prognostic implications associated with it. Almost all cases of colon cancer with hereditary nonpolyposis colorectal cancer2 and approximately 15% of cases of sporadic colon cancer3 demonstrate MSI. Several studies4,5 have demonstrated improved survival rates in patients with colorectal cancer whose tumors demonstrate MSI. The mechanism by which these tumors lead to a more favorable prognosis has been unclear.

A large proportion of tumors with MSI, in sporadic cases and in hereditary nonpolyposis colorectal cancer carriers, are associated with immune host response features. One such feature is a Crohn disease–like peritumoral reaction that consists of lymphoid follicles with germinal centers.6,7 Intratumoral lymphocytic infiltrate (LI), which is often seen in association with a peritumoral stromal lymphocytic inflammatory infiltrate, is another feature often identified.8 CD3 lymphocyte counts in excess of 40 per 1000 epithelial cells occur in 70% of tumors with high-frequency MSI, 33% with low-frequency MSI, and 17.5% of microsatellite-stable tumors.9 CD3 counts in excess of 100 per 1000 epithelial cells are highly sensitive for high-frequency MSI tumors.9 Lymphocytic infiltration is thought to contribute to the improved survival seen in patients with MSI+ tumors, perhaps as a marker of a heightened immune response against the malignancy.10 We sought to evaluate the combined prognostic significance of MSI and LI in a colon cancer population.

All patients undergoing definitive resection of colorectal cancer tumors in a community hospital system were prospectively identified between January 1, 2001, and December 31, 2003. No restrictions were imposed on patient age, tumor location, or family history of colorectal cancer. Tumors of consenting patients were submitted for evaluation for MSI and LI. For the evaluation of MSI, genomic DNA from the tumor was compared with that from adjacent, histologically normal tissue with respect to a standard panel of 11 markers, including those defined by the 1997 National Cancer Institute guidelines (Clinical Molecular Diagnostic Laboratories, City of Hope Medical Center, Duarte, California).3 Tumors in which none of the loci demonstrated instability were classified as microsatellite stable. Those with a single unstable locus were classified as low-frequency MSI. Tumors with 2 or more unstable loci were classified as high-frequency MSI. Patients with high-frequency MSI are subsequently referred to as MSI+; those with microsatellite stability and low-frequency MSI are referred to as MSI−. Tumors were examined for intratumoral LI using light microscopy and staining with hematoxylin-eosin (Figure 1). The presence of LI (referred to as LI+ herein) was defined as greater than 5 lymphocytes per 10 high-power (×40) fields of the tumor epithelium. Patients were prospectively followed for the development of recurrence and death. Data were collected regarding age, sex, pathological stage of disease, tumor grade, and lymph node involvement. All the procedures were performed under a protocol approved by the institutional review board of the Legacy Health System.

Place holder to copy figure label and caption
Figure 1.

Hematoxylin-eosin–stained section of colonic adenocarcinoma with tumor-infiltrating lymphocytes (arrows).

Graphic Jump Location

Comparisons were made between patients with LI+ and LI− tumors. The unpaired t test was used to compare age. Categorical data, such as sex, tumor grade, pathological stage of disease, and nodal involvement, were compared and P values were generated using the Fisher exact test. Patients were categorized into 4 groups according to MSI and LI status. Time-to-event analyses of disease-free survival (DFS) and overall survival after surgery were performed between the MSI+/LI+ and MSI−/LI− groups. Kaplan-Meier survival estimates were plotted and stratified according to stage of disease, nodal involvement, and tumor grade. When comparing the survival estimates, the log-rank test was used. Multivariate analysis of survival according to MSI status, LI status, T stage, and N stage was performed using a Cox regression analysis. Statistical calculations were performed using a software program (SPSS 13; SPSS Inc, Chicago, Illinois).

One hundred sixty-seven patients were enrolled in the study. Testing for MSI was inconclusive in 6 patients. In 11 patients, there was insufficient tumor mass for analysis. The remaining 150 patients had MSI and LI results and were included for analysis. In 25 patients (16.7%), the tumors demonstrated LI. Of these 25 patients, 9 (36.0%) had MSI+ tumors. Of the 125 patients without LI, 30 (24.0%) had MSI+ tumors. The mean age of patients was 72.5 years for MSI+/LI+ tumors, 71.3 years for MSI+/LI−, 61.3 years for MSI−/LI+, and 69.2 years for MSI−/LI−.

Forty-three patients had stage I disease; 56, stage II; 34, stage III; and 16, stage IV. One patient underwent resection for a local recurrence and was not included in the stage groups. Stage distribution, lymph node involvement, and tumor grade were similar between LI+ and LI− patients.

During follow-up (median, 40.6 months), 49 patients developed recurrence or died (Table 1). Patients with LI+ tumors had 5-year DFS of 84.9% compared with 61.0% in those with LI− tumors (P = .03). The differences were greatest in patients with stage II disease, where 5-year DFS was 100% for patients with LI+ tumors and 61.1% for those with LI− tumors (P = .09).

Table Graphic Jump LocationTable 1. Patients Who Developed Disease Recurrence or Died, According to Microsatellite Instability (MSI) and Lymphocytic Infiltrate (LI) Status

When patients were grouped according to MSI and LI status, those with MSI−/LI− tumors had 5-year DFS of 56.7% compared with 88.9% for those with MSI+/LI+ (P = .01). Five-year DFS for patients with MSI−/LI+ and MSI+/LI− tumors was 75.0% and 75.4%, respectively (Figure 2).

Place holder to copy figure label and caption
Figure 2.

Kaplan-Meier estimates of disease-free survival for patients grouped into 4 categories according to the presence of microsatellite instability (MSI) and lymphocytic infiltration (LI). LI+ indicates LI present; LI−, LI absent; MSI+, high-frequency MSI; and MSI−, microsatellite stable or low-frequency MSI.

Graphic Jump Location

Similar patterns of survival were seen when patients were stratified by tumor grade (Table 2). Of patients with moderately differentiated tumors, those with MSI−/LI− tumors had 5-year DFS of 59.3% compared with 100% for those with MSI+/LI+ tumors (P = .03). Of patients with poorly differentiated tumors, those with MSI−/LI− tumors had 5-year DFS of 44.4% compared with 66.7% for those with MSI+/LI+ tumors (P = .20).

Table Graphic Jump LocationTable 2. Five-Year Disease-Free Survival of Patients According to Microsatellite Instability (MSI) Status and the Presence of Lymphocytic Infiltrate (LI), Stratified by Tumor Grade and Stage of Disease

Of patients with node-negative disease, those with MSI−/LI− tumors had 5-year DFS of 65.3% compared with 100% for those with MSI+/LI+ (P = .04). In patients with nodal involvement, those with MSI−/LI− tumors had 5-year DFS of 42.9% compared with 66.7% for those with MSI+/LI+ (P = .18).

Multivariate analyses of MSI, LI, T stage, and N stage were performed using Cox regression (Table 3). High-frequency MSI was associated with a hazard ratio of 0.433 (P = .04). The presence of LI was associated with a hazard ratio of 0.425 (P = .16). T3 (or greater) and N1 (or greater) staging were associated with hazard ratios of 3.171 (P = .006) and 1.567 (P = .13), respectively.

Table Graphic Jump LocationTable 3. Hazard Ratios for Disease Recurrence or Death According to Multivariate Analysis by Cox Regression

In terms of overall survival, patients with LI+ tumors had 5-year overall survival of 83.6% compared with 59.0% in those with LI− tumors (P = .12). Patients with MSI+ tumors had 5-year overall survival of 74.4% compared with 57.3% in those with MSI− tumors (P = .08). Patients with MSI+/LI+ tumors had 5-year overall survival of 88.9% compared with 55.3% in those with MSI−/LI− tumors (P = .06).

The results of this study confirm that tumors with MSI and LI have a more favorable prognosis. When patients are grouped by MSI and LI, the group with MSI+ and LI+ tumors demonstrated the most favorable survival rate, whereas the survival rates of those with neither MSI+ nor LI+ tumors were the least favorable. This pattern of DFS was seen regardless of tumor grade (Table 2).

Multivariate analysis of MSI and LI status in conjunction with known prognostic indicators confirmed that increased depth of tumor invasion and nodal involvement are associated with worse DFS, as expected. Moreover, this analysis suggests that MSI and LI status are independently associated with improved DFS. The analysis of LI status did not reach statistical significance, but this may be due to an insufficient number of patients to detect the association because nodal status (an accepted staging criterion) also did not reach statistical significance in this analysis. However, we submit that combining MSI and LI status to the currently accepted tumor depth of invasion and nodal status gives a more accurate prediction of outcome.

In stage II disease, LI+ tumors are associated with improved DFS even in patients with MSI− tumors. Similarly, patients with MSI+/LI− tumors also had an intermediate survival rate, which suggests that MSI status and LI status play a role in determining the behavior of the tumor, perhaps through separate mechanisms. Elucidation of these mechanisms may yield strategies toward the development of new approaches to disease treatment.

The mechanism by which MSI is associated with longer survival is not well understood. Some researchers1113 have attributed the less aggressive biological mechanism of MSI+ tumors to a lower prevalence of mutations in the K-ras gene or a loss of heterozygosity in the DCC or p53 genes, each of which have been associated with a worse prognosis. Another postulated mechanism is that MSI is often associated with LI, which suggests a heightened immune response to MSI+ tumors. The presence of intratumoral lymphocytes may represent part of a more complex host immune response to the tumor.

One theorized mechanism is that MSI may be associated with the production of immunogenic peptides.14 High-frequency MSI tumors have been found to have a significantly higher percentage of cells undergoing apoptosis. Dolcetti et al10 showed that most CD8+ lymphocytes infiltrating MSI+ tumors are cytotoxic effectors characterized by a high degree of activation, with polarization of cytotoxic granules in close proximity to apoptotic bodies or cells with DNA fragmentation. This suggests that these lymphocytes may be involved in targeted cell-mediated killing of neoplastic cells.

The finding that LI alone correlated with 5-year DFS suggests a heightened immune response to these tumors, but the exact mechanism remains unknown. One possibility is that LI represents an inflammatory reaction to tumors that are particularly immunogenic. Further studies will hopefully clarify what kinds of genes or protein expressions enhance an immune response. Another possible mechanism is that the immune system of certain individuals enables them to mount a heightened immune response to a tumor. If the latter proves to be true, it may suggest a potential role for immunomodulatory drugs in the treatment of LI− tumors.

When patients were stratified by stage, we found that the more favorable DFS associated with LI was seen predominantly in patients with stage II disease. Clinically, this is an exciting finding. Currently, patients with stage II disease do not usually receive adjunctive therapy. Larger studies should be performed to bear out the association of MSI−/LI− tumors with worse outcome in stage II disease. This subgroup of patients may stand to gain the most benefit from adjuvant chemotherapy.

This study was performed on hematoxylin-eosin–stained samples using a specific cutoff value for identifying tumors with LI+, performed by an expert pathologist. Although this technique is subject to interobserver variation,8 it seems to be effective in identifying the population of patients with improved prognosis at Legacy Health System. This technique is, therefore, a feasible alternative to formal quantitation of intratumoral T-cell infiltrates, performed with anti-CD3 pan–T-cell antibody. Although the latter technique may provide more objective results, it requires additional expense and processing time.

Testing for MSI, which is a relatively complex DNA assay, is fairly expensive and can be difficult for most laboratories to perform. It has been proposed that the presence of LI could be used as a screening tool to identify tumors that should undergo MSI testing.15 In this study, however, 25 of 30 patients without LI had MSI+ tumors. Thus, this approach would miss approximately 65% of MSI+ cases. Other histopathologic features, such as a medullary-type pattern, LI, and poor differentiation, also are not sensitive markers for MSI+ tumors.8

Molecular profiling of tumors is currently the standard for several malignancies (including breast cancer, gastrointestinal stromal tumors, and lymphoma). To be successful, markers should be easily reproducible and widely available. Microsatellite instability and lymphocytic infiltration bear the potential to be included in the standard molecular profile of colorectal cancer. Although microRNA profiling has recently been described,16 it is far more difficult to perform and would not be readily available to most community laboratories. Recently, immunohistochemical staining for mismatch repair proteins has been used to complement MSI testing for the detection of mismatch repair mutations. Immunohistochemical analysis may be performed at a lower cost than formal MSI testing. Its accuracy depends on the quality of nuclear staining and the availability of an experienced pathologist. Immunohistochemical analysis will accurately detect the absence of mismatch repair proteins in mutations that truncate the protein or reduce its expression and will miss approximately 6% of mutations that involve more subtle alterations in the protein, such as those resulting from missense mutations. However, it can be readily added to the armamentarium of most pathology departments.

Given that the LI and MSI status of a tumor seems to affect cancer recurrence, these tests should, at a minimum, be more widely used and reported. The presence of lymphocytic infiltration should be routinely included in pathologic reports of colorectal cancer. These variables should be considered in the design of clinical studies evaluating the effect of chemotherapy in patients with colorectal malignancies. This may be of particular importance when studying adjuvant therapy in the early-stage population.

Correspondence: Nathalie Johnson, MD, Legacy Health System, Surgical Associates, 1130 NW 22nd St, Ste 500, Portland, OR 97210 (njohnson@lhs.org).

Accepted for Publication: June 2, 2008.

Author Contributions:Study concept and design: Dorsey, Frankhouse, Lee, W. Johnson, Anadiotis, and N. Johnson. Acquisition of data: Chang, Dorsey, Frankhouse, Lee, Walts, W. Johnson, Anadiotis, and N. Johnson. Analysis and interpretation of data: Chang, Dorsey, Frankhouse, Lee, W. Johnson, and N. Johnson. Drafting of the manuscript: Chang, Lee, Walts, W. Johnson, and N. Johnson. Critical revision of the manuscript for important intellectual content: Chang, Dorsey, Frankhouse, Lee, W. Johnson, Anadiotis, and N. Johnson. Statistical analysis: Chang. Obtained funding: Dorsey, Lee, W. Johnson, and N. Johnson. Administrative, technical, and material support: Chang, Dorsey, Lee, W. Johnson, Anadiotis, and N. Johnson. Study supervision: Frankhouse, Lee, W. Johnson, Anadiotis, and N. Johnson.

Financial Disclosure: None reported.

Funding/Support: Direct funding for this project was provided by Colon Cancer MSI research grant 2222 from the Legacy Health Foundation.

Role of the Sponsor: Legacy Health Foundation was not involved in the collection, management, analysis, or interpretation of the data or in the preparation, review, or approval of the manuscript.

Previous Presentation: This study was presented at the Annual Meeting of the Pacific Coast Surgical Association; February 16, 2008; Coronado, California.

 Cancer Facts & Figures 2007.  Atlanta, GA American Cancer Society2007;
Peltomäki  P The genetics of hereditary non-polyposis colorectal cancer and non-polypotic colon cancer. Adv Exp Med Biol 1999;47095- 98
PubMed
Boland  CRThibodeau  SNHamilton  SR  et al.  A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58 (22) 5248- 5257
PubMed
Chang  EYDorsey  PBJohnson  N  et al.  A prospective analysis of microsatellite instability as a molecular marker in colorectal cancer. Am J Surg 2006;191 (5) 646- 651
PubMed Link to Article
Galon  JCostes  ASanchez-Cabo  F  et al.  Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313 (5795) 1960- 1964
PubMed Link to Article
Kim  HJen  JVogelstein  BHamilton  SR Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994;145 (1) 148- 156
PubMed
Risio  MReato  Gdi Celle  PFFizzotti  MRossini  FPFoa  R Microsatellite instability is associated with the histological features of the tumor in nonfamilial colorectal cancer. Cancer Res 1996;56 (23) 5470- 5474
PubMed
Alexander  JWatanabe  TWu  TTRashid  ALi  SHamilton  SR Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 2001;158 (2) 527- 535
PubMed Link to Article
Jass  JR Pathology of hereditary nonpolyposis colorectal cancer. Ann N Y Acad Sci 2000;91062- 73
PubMed Link to Article
Dolcetti  RViel  ADoglioni  C  et al.  High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol 1999;154 (6) 1805- 1813
PubMed Link to Article
Forster  SSattler  HPHack  M  et al.  Microsatellite instability in sporadic carcinomas of the proximal colon: association with diploid DNA content, negative protein expression of p53, and distinct histomorphologic features. Surgery 1998;123 (1) 13- 18
PubMed Link to Article
Fujiwara  TStolker  JMWatanabe  T  et al.  Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences. Am J Pathol 1998;153 (4) 1063- 1078
PubMed Link to Article
Jass  JRBiden  KGCummings  MC  et al.  Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways. J Clin Pathol 1999;52 (6) 455- 460
PubMed Link to Article
Linnebacher  MGebert  JRudy  W  et al.  Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens. Int J Cancer 2001;93 (1) 6- 11
PubMed Link to Article
Lynch  HTKaul  K Microsatellite instability, clinical implications, and new methodologies. J Natl Cancer Inst 2000;92 (7) 511- 512
PubMed Link to Article
Schetter  AJLeung  SYSohn  JJ  et al.  MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 2008;299 (4) 425- 436
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Hematoxylin-eosin–stained section of colonic adenocarcinoma with tumor-infiltrating lymphocytes (arrows).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Kaplan-Meier estimates of disease-free survival for patients grouped into 4 categories according to the presence of microsatellite instability (MSI) and lymphocytic infiltration (LI). LI+ indicates LI present; LI−, LI absent; MSI+, high-frequency MSI; and MSI−, microsatellite stable or low-frequency MSI.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Patients Who Developed Disease Recurrence or Died, According to Microsatellite Instability (MSI) and Lymphocytic Infiltrate (LI) Status
Table Graphic Jump LocationTable 2. Five-Year Disease-Free Survival of Patients According to Microsatellite Instability (MSI) Status and the Presence of Lymphocytic Infiltrate (LI), Stratified by Tumor Grade and Stage of Disease
Table Graphic Jump LocationTable 3. Hazard Ratios for Disease Recurrence or Death According to Multivariate Analysis by Cox Regression

References

 Cancer Facts & Figures 2007.  Atlanta, GA American Cancer Society2007;
Peltomäki  P The genetics of hereditary non-polyposis colorectal cancer and non-polypotic colon cancer. Adv Exp Med Biol 1999;47095- 98
PubMed
Boland  CRThibodeau  SNHamilton  SR  et al.  A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58 (22) 5248- 5257
PubMed
Chang  EYDorsey  PBJohnson  N  et al.  A prospective analysis of microsatellite instability as a molecular marker in colorectal cancer. Am J Surg 2006;191 (5) 646- 651
PubMed Link to Article
Galon  JCostes  ASanchez-Cabo  F  et al.  Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313 (5795) 1960- 1964
PubMed Link to Article
Kim  HJen  JVogelstein  BHamilton  SR Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994;145 (1) 148- 156
PubMed
Risio  MReato  Gdi Celle  PFFizzotti  MRossini  FPFoa  R Microsatellite instability is associated with the histological features of the tumor in nonfamilial colorectal cancer. Cancer Res 1996;56 (23) 5470- 5474
PubMed
Alexander  JWatanabe  TWu  TTRashid  ALi  SHamilton  SR Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 2001;158 (2) 527- 535
PubMed Link to Article
Jass  JR Pathology of hereditary nonpolyposis colorectal cancer. Ann N Y Acad Sci 2000;91062- 73
PubMed Link to Article
Dolcetti  RViel  ADoglioni  C  et al.  High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol 1999;154 (6) 1805- 1813
PubMed Link to Article
Forster  SSattler  HPHack  M  et al.  Microsatellite instability in sporadic carcinomas of the proximal colon: association with diploid DNA content, negative protein expression of p53, and distinct histomorphologic features. Surgery 1998;123 (1) 13- 18
PubMed Link to Article
Fujiwara  TStolker  JMWatanabe  T  et al.  Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences. Am J Pathol 1998;153 (4) 1063- 1078
PubMed Link to Article
Jass  JRBiden  KGCummings  MC  et al.  Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways. J Clin Pathol 1999;52 (6) 455- 460
PubMed Link to Article
Linnebacher  MGebert  JRudy  W  et al.  Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens. Int J Cancer 2001;93 (1) 6- 11
PubMed Link to Article
Lynch  HTKaul  K Microsatellite instability, clinical implications, and new methodologies. J Natl Cancer Inst 2000;92 (7) 511- 512
PubMed Link to Article
Schetter  AJLeung  SYSohn  JJ  et al.  MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 2008;299 (4) 425- 436
PubMed Link to Article

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