0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Correlation of Microsatellite Instability at Multiple Loci With Long-term Survival in Advanced Gastric Carcinoma FREE

Giovanni Corso, MD; Corrado Pedrazzani, MD; Daniele Marrelli, MD; Valeria Pascale; Enrico Pinto, MD; Franco Roviello, MD
[+] Author Affiliations

Author Affiliations: Sezione di Chirurgia Oncologica, Dipartimento di Patologia Umana e Oncologia, Policlinico [[ldquo]]Le Scotte,[[rdquo]] University of Siena, and Istituto Toscano Tumori, Siena, Italy.


Arch Surg. 2009;144(8):722-727. doi:10.1001/archsurg.2009.42.
Text Size: A A A
Published online

Hypothesis  Microsatellite instability (MSI) correlates with clinicopathologic characteristics and long-term prognosis in patients having gastric carcinoma.

Design  Analysis of prospectively collected data and biologic material.

Setting  Tertiary University Hospital, Policlinico “Le Scotte,” Siena, Italy.

Patients  Two hundred fifty patients with gastric carcinoma.

Main Outcome Measures  Five mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21, and NR-27) were analyzed in these patients.

Results  An MSI phenotype was identified in 63 patients (25.2%) and correlated with specific clinicopathologic characteristics. Favorable prognosis was confirmed for patients with an MSI phenotype in univariate (P < .001) and multivariate (P = .05) analyses. Significant differences in clinicopathologic characteristics and long-term prognoses were observed among patients with microsatellite-stable tumors, tumors having instability at 2 to 4 markers, and tumors having instability at all 5 markers (MSI/5). The MSI/5 phenotype was associated with older age (P < .001), female sex (P = .001), antral tumor location (P = .04), intestinal histotype (P = .003), and less infiltration of the serosa (P = .006); lymph node involvement was rare (P < .001) and was limited to few (median, 3) metastatic lymph nodes (P = .001). Long-term survival of patients with the MSI/5 phenotype is favorable and was confirmed in multivariate analysis (relative risk vs patients with stable tumors, 0.32; 95% confidence interval, 0.16-0.63; P = .002).

Conclusions  Compared with stable tumors, MSI tumors have distinct clinicopathologic features and are associated with a better prognosis. Patients with the MSI/5 phenotype have a very good prognosis.

Figures in this Article

Despite a decreasing incidence during the last few decades, gastric carcinoma (GC) remains the fourth most common cancer worldwide and the second leading cause of cancer-related death.1 The overall mortality has decreased during the same period, although the long-term prognosis remains poor, with 5-year survival rates that rarely exceed 40%.2

As with most other tumors, GC develops through the accumulation of genetic and epigenetic alterations affecting oncogenes and tumor suppressor genes. It is widely accepted that microsatellite instability (MSI) and chromosome instability are 2 major genomic instability pathways involved in GC pathogenesis.3 Microsatellite instability has been described as a frequent genetic alteration in colon cancer4 and in several other cancer types.5,6 Although microsatellite alterations have been widely investigated in familial and sporadic colon cancer,7 limited and inconclusive data are available for stomach cancer.

In the present study, we analyzed a large cohort of patients with GC using a panel of 5 quasimonomorphic mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21, and NR-27).8 We assessed clinicopathologic characteristics and long-term prognoses of patients having MSI tumors.

STUDY POPULATION

The study analyzed 250 patients with primary GC and operated on at the Division of Surgical Oncology, Tertiary University Hospital, Policlinico “Le Scotte,” University of Siena, Siena, Italy, between January 1, 1990, and December 31, 2004. All patients underwent resection, including 183 patients with potentially curative (R0) tumors and 35 patients with microscopic (R1) and 32 patients with macroscopic (R2) residual tumors; 20 patients (17 with R1 and R2 residual tumors) had metastatic disease at the time of operation. Clinicopathologic and follow-up data were prospectively collected for the whole cohort. The median follow-up period for surviving patients was 92.1 months (range, 36.3-260.9 months).

Informed consent was obtained from all patients. The study was approved by the appropriate local ethics committees.

SURGERY

The objective of surgery was complete resection of the tumor, although gastrectomy was performed even in patients with untreatable disease when required for symptom palliation. Gastric resection was performed based on the extent of tumor in the stomach. Distal subtotal gastrectomy was preferred for tumors located in the lower and middle thirds of the stomach provided that the proximal resection margin remained at least 5 cm from the tumor edge; otherwise, total gastrectomy was performed.9 Extended (D2) and superextended (D3) lymphadenectomy (in 157 patients [62.8%]) was performed in most R0 resections and has been routinely used since 1995, except for patients deemed unfit for this procedure.10 None of the patients received preoperative chemotherapy or chemoradiotherapy.

HISTOPATHOLOGIC CLASSIFICATION AND STAGING

Tumor size was calculated by measuring the largest diameter of the neoplasm. The most recent version of the TNM classification by the American Joint Committee on Cancer11 and the International Union Against Cancer was used for histopathologic staging. Level and number of metastatic lymph nodes were also recorded for each patient. Histologic classification followed the criteria by Lauren12; mixed-type tumors were considered together with diffuse (nonintestinal) type. Lymphatic and vascular invasion was assessed for 176 and 184 patients, respectively.

SAMPLES AND DNA EXTRACTION

Frozen samples of normal mucosa and tumor tissue were available for each patient in our biologic material bank. Tumoral mucosa and corresponding normal mucosa of the stomach were flash-frozen in liquid nitrogen. Tumoral and constitutional DNA were extracted after histopathologic confirmation using a commercially available DNA purification kit (Puregene; Gentra Systems, Inc, Minneapolis, Minnesota) and following the manufacturer's instructions.

PENTAPLEX POLYMERASE CHAIN REACTION AND MICROSATELLITE ANALYSIS

Microsatellite analysis was evaluated using 5 quasimonomorphic mononucleotide repeats, namely, BAT-26, BAT-25, NR-24, NR-21, and NR-27.8 The 5′ antisense primer was labeled with a fluorescent dye using FAM for BAT-26 and NR-21, NED for BAT-25 and NR-27, and VIC for NR-24 (ABI PRISM Primer Pairs; Applied Biosystems, Foster City, California).

The 5 mononucleotide repeats were coamplified in one multiplex (pentaplex) polymerase chain reaction (PCR) using the protocol for amplification of microsatellite loci (Multiplex PCR; Qiagen, Studio City, California). The pentaplex PCR was performed on tumoral and matched constitutional DNA of the same patient with GC. The allelic profiles of these 5 mononucleotides were detected on an automated DNA sequencer (ABI PRISM 3100 Genetic Analyzer, Applied Biosystems) according to the manufacturer's protocol (Figure 1).

Place holder to copy figure label and caption
Figure 1.

Typical allelic profiles of microsatellite stability in constitutional DNA samples (A) and microsatellite instability in tumoral samples (B). bp Indicates base pair; N, lymph nodes; and T, tumor size.

Graphic Jump Location
SCORING OF MSI

According to the definition of the National Cancer Institute5 workshop on MSI for cancer detection and familial predisposition, we considered a tumor as having MSI whenever 2 or more markers showed instability on 5 loci. The clinicopathologic characteristics and survival rates associated with tumors having low instability (one locus involved) are similar to those of stable tumors5,13 and were considered together (microsatellite-stable [MSS] phenotype). DNA samples showing an abnormal allelic shift were confirmed by a second PCR and gene scan.

STATISTICAL ANALYSIS

Analyses were performed using commercially available statistical software (SPSS 14.0 for Windows; SPSS Inc, Chicago, Illinois). Statistical associations between clinicopathologic characteristics and MSI status were assessed by χ2 test for categorical variables and by t test or analysis of variance for continuous variables. Survival curves were estimated using the Kaplan-Meier method and were compared using log-rank test. Multivariate analysis was performed using a Cox proportional hazards regression model by considering the following risk factors: sex, age (older vs the median or younger), tumor location (other vs antrum), Lauren12 histotype (nonintestinal vs intestinal), depth of tumor invasion (pT2, pT3, or pT4 vs pT1), lymph node involvement (pN1, pN2, or pN3 vs pN0), presence of systemic metastasis (M1 vs M0), and R category (R1 or R2 vs R0). Postoperative mortality was assessed, with deaths unrelated to tumor recurrence considered censored observations at the time of death. Because differences in clinicopathologic features and survival rates were observed within the MSI phenotype for tumors with instability at 2 to 4 markers (MSI/<5) vs tumors with instability at all 5 markers (MSI/5), an analysis was performed to separately investigate MSS, MSI/<5, and MSI/5 tumors. P < .05 was considered statically significant.

MSI STATUS AND CLINICOPATHOLOGIC FACTORS

Among 250 patients with GC, MSI was identified in 63 GCs (25.2%). The MSI phenotype was significantly associated with older age (mean [SD], 72.8 [10.7] vs 66.7 [10.6] years; P < .001), and it was more frequent in women (55.6% vs 37.4%, P = .02) with intestinal histotype tumors (81% vs 59.9%, P = .002). The MSI phenotype was rarely associated with systemic metastases (1.6% vs 10.2%, P = .03) or with pT3 or pT4 tumors (38.1% vs 60.4%, P = .002). Compared with the MSS phenotype, pN+ lymph node involvement was less frequent in patients having the MSI phenotype (57.1% vs 75.9%, P < .001), with fewer metastatic lymph nodes (mean [SD], 3.6 [7.1] vs 9.4 [12.1]; P = .001). Conversely, no differences in tumor size (mean [SD], 58.8 [2.9] vs 57.8 [3.2] mm; P = .82) or percentage of R1 or R2 resections (19% vs 29.4%, P = .14) were observed.

The presence of lymphovascular invasion was also evaluated. Both vascular invasion (21.4% vs 53.5%) and lymphatic invasion (33.3% vs 69.3%) were rarely associated with MSI tumors compared with MSS tumors (P < .001).

MSI STATUS AND SURVIVAL

Kaplan-Meier survival estimates according to MSI phenotype are plotted in Figure 2. In patients with M0 and R0 disease, 5-year survival was 46% (median, 48.9 months; 95% confidence interval, 31.0-66.8 months) for patients with MSS tumors and 71% (the median was beyond the observation period) for patients with MSI tumors (P = .002).

Place holder to copy figure label and caption
Figure 2.

Kaplan-Meier survival estimates according to microsatellite instability (MSI) status in 250 patients who underwent gastrectomy. The median (95% confidence interval) survival was 26.7 (20.8-32.5) months for patients with microsatellite-stable (MSS) tumors, and the median was beyond the observation period for patients with MSI tumors (P < .001).

Graphic Jump Location

Multivariate analysis of Cox proportional hazards regression models confirmed MSI as an independent predictor of survival (relative risk vs patients with MSS, 0.62; 95% confidence interval, 0.38-1.00; P = .05). The models controlled for age (P = .74), sex (P = .09), tumor location (P = .70), Lauren12 histotype (P = .10), depth of tumor invasion (P < .001), lymph node involvement (P < .001), presence of systemic metastasis (P = .005), and R category (P < .001).

MSI AT ALL 5 MARKERS

Table 1 shows differences in clinicopathologic characteristics associated with the types of tumors. These include MSS, MSI/<5, and MSI/5 tumors.

Table Graphic Jump LocationTable 1. Clinicopathologic Characteristics of the Study Cohort According to Microsatellite Instability (MSI) Status

The MSI/5 phenotype correlated with older age (P < .001), female sex (P = .001), antral tumor location (P = .04), and intestinal histotype (P = .003). Invasion of the serosa (P = .006) and lymph node metastasis (P < .001) were rarely observed. Among 22 patients having MSI/5 tumors with lymph node involvement, deposits were observed in few (median, 3; range, 1-8) metastatic lymph nodes (P = .001).

Lymphovascular MSI invasion was rare compared with that in MSS tumors (P < .001). Vascular invasion was observed in 33.3% of MSI/<5 tumors and in 14.8% of MSI/5 tumors (P = .24). Lymphatic invasion was equally frequent (33.3%) in MSI/<5 and MSI/5 tumors.

Figure 3 shows Kaplan-Meier curves for patients with MSS, MSI/<5, and MSI/5 tumors (P < .001). Survival rates for patients with M0 disease who underwent potentially curative (R0) resections are shown in Figure 4 (P = .004). Limiting the analysis to patients who underwent noncurative (R1 or R2) resections, the median (95% confidence interval) survival was 9.0 months (5.6-12.4 months) for 55 patients with MSS tumors, 5.2 months (2.1-8.3 months) for 7 patients with MSI/<5 tumors, and 58.4 months (0.0-132.5 months) for 5 patients with MSI/5 tumors (P < .009).

Place holder to copy figure label and caption
Figure 3.

Kaplan-Meier survival estimates according to microsatellite instability (MSI) in 250 patients who underwent gastrectomy. The median (95% confidence interval) survival was 26.7 (20.8-32.5) months for patients with microsatellite-stable (MSS) tumors and 18.5 (0.0-50.1) months for patients with MSI tumors having instability at 2 to 4 markers (MSI/<5), and the median was beyond the observation period for patients with MSI tumors having instability at all 5 markers (MSI/5) (P < . 001).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Kaplan-Meier survival estimates according to the number of microsatellite instability (MSI) markers in 180 patients with M0 disease who underwent potentially curative (R0) gastrectomy. The median (95% confidence interval) survival was 48.9 (31.0-86.8) months for patients with microsatellite-stable (MSS) tumors, and the median was beyond the observation period for patients with MSI tumors having instability at 2 to 4 markers (MSI/<5) or with MSI tumors having instability at all 5 markers (MSI/5) (P = . 004).

Graphic Jump Location

Table 2 summarizes results of the multivariate analyses using Cox proportional hazards regression models controlling for other risk factors. The MSI/5 phenotype was confirmed to be an independent predictor of long-term survival (relative risk vs patients with the MSS phenotype, 0.32; 95% confidence interval, 0.16-0.63; P = .002).

Table Graphic Jump LocationTable 2. Relative Risks of Death From Gastric Carcinoma as a Function of Microsatellite Instability (MSI)a

Microsatellite instability is defined as the presence of replication errors resulting in insertions or deletions of bases within nucleotide repeats, known as microsatellite regions. Although a consensus panel for determination of MSI phenotype has been proposed and accepted for colorectal cancer,5 several markers with differing results have been used for determination of MSI in GC.1419 Based on evaluation using several markers, the MSI phenotype generally characterizes 15% to 25% of patients with GC tumors, more frequently in older women.3,18 Most MSI tumors are of intestinal histotype located in the distal part of the stomach, with limited lymph node involvement. Our data regarding MSI phenotype are consistent with other findings reported to date.3,18

Several observations of unexpectedly good prognoses in patients with advanced tumors and instability at all 5 markers led us to look at this subset of patients. The case of a 31-year-old woman who had undergone palliative subtotal gastrectomy with macroscopic residual (R2) tumor 63 months previously for a nonintestinal pT4N2 tumor is still alive. The favorable survival in patients with the MSI/5 phenotype was also evident among patients who underwent palliative resection (median survival, 58.4 months; 95% confidence interval, 0.0-132.5 months).

Older age, female sex, antral tumor location, intestinal histotype, less invasion of the serosa, and involvement of fewer lymph nodes significantly correlated with MSI/5 phenotype. The number of involved lymph nodes was particularly low in patients having tumors with instability at all 5 markers. Among 22 patients with MSI/5 pN+ disease, 21 had fewer than 6 positive lymph nodes, while the 31-year-old patient already mentioned had 8 positive lymph nodes.

Significantly lower rates of lymphovascular invasion were consistently observed for MSI/5 and MSI/<5 tumors compared with MSS tumors. These data should correlate with less tumor aggression, lower disease stage, and older age in patients with MSI/5 tumors. Some of these characteristics have been reported in MSI tumors,13 but they seem to be particularly evident in MSI/5 tumors.

The MSI/5 phenotype delineates a subset of tumors with a similar growth pattern but with less propensity to invade serosal layers and spread systemically or via lymph nodes. Considering the locoregional growth of this class of tumors, one could argue for an aggressive surgical approach even in very advanced cases.

Survival analysis confirms high survival rates for patients with MSI/5 tumors (Figures 3 and 4). Survival of patients with the MSI/5 phenotype was significantly better than that of patients with the MSI/<5 phenotype, and this difference was confirmed in multivariate analysis. These novel findings identify a particular subset of MSI tumors with less biologic aggression and with a favorable prognosis. Other findings similarly correlate tumor characteristics and differentiation with tumor invasion and genetic changes.20

In conclusion, our data confirm previous evidence that tumors with MSI demonstrate distinct clinicopathologic features and better prognosis compared with patients having stable tumors. A subset of tumors was observed with instability at 5 quasimonomorphic mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21, and NR-27) . These tumors have a low predilection to spread systemically or to involve lymph nodes, and they are associated with favorable long-term prognosis even in patients with advanced disease. Further studies among more patients are necessary to confirm our results and to render them reproducible and useful in clinical practice.

Correspondence: Corrado Pedrazzani, MD, Sezione di Chirurgia Oncologica, Dipartimento di Patologia Umana e Oncologia, Policlinico “Le Scotte,” University of Siena, 53100 Siena, Italy (pedrazzani@unisi.it).

Accepted for Publication: May 28, 2008.

Author Contributions: All authors take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Corso, Pedrazzani, Pinto, and Roviello. Acquisition of data: Marrelli. Analysis and interpretation of data: Corso, Pedrazzani, Marrelli, and Pascale. Drafting of the manuscript: Corso, Pedrazzani, Marrelli, and Pascale. Critical revision of the manuscript for important intellectual content: Pedrazzani, Pinto, and Roviello. Statistical analysis: Pedrazzani and Marrelli. Obtained funding: Pinto and Roviello. Administrative, technical, and material support: Corso, Marrelli, and Pascale. Study supervision: Roviello.

Financial Disclosure: None reported.

Funding/Support: This study was supported by grant 2005064071_004PRIN (Progetti di Ricerca di Interesse Nazionale) 2005, “Fattori genetici ed eredofamiliari nel carcinoma gastrico,” from Ministero Universitá e Ricerca.

Additional Contributions: Lorenzo Garosi provided valuable help in data collection, material storage, and technical support.

Parkin  DMBray  FFerlay  JPisani  P Global cancer statistics, 2002. CA Cancer J Clin 2005;55 (2) 74- 108
PubMed Link to Article
Chau  INorman  ARCunningham  DWaters  JSOates  JRoss  PJ Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer: pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 2004;22 (12) 2395- 2403
PubMed Link to Article
Ottini  LFalchetti  MLupi  R  et al.  Patterns of genomic instability in gastric cancer: clinical implications and perspectives. Ann Oncol 2006;17 ((suppl 7)) vii97- vii102
PubMed Link to Article
Popat  SHubner  RHoulston  RS Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005;23 (3) 609- 618
PubMed Link to Article
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
Zighelboim  IGoodfellow  PJGao  F  et al.  Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type. J Clin Oncol 2007;25 (15) 2042- 2048
PubMed Link to Article
Konishi  MKikuchi-Yanoshita  RTanaka  K  et al.  Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 1996;111 (2) 307- 317
PubMed Link to Article
Suraweera  NDuval  AReperant  M  et al.  Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology 2002;123 (6) 1804- 1811
PubMed Link to Article
Marrelli  DDe Stefano  Ade Manzoni  GMorgagni  PDi Leo  ARoviello  F Prediction of recurrence after radical surgery for gastric cancer: a scoring system obtained from a prospective multicenter study. Ann Surg 2005;241 (2) 247- 255
PubMed Link to Article
Marrelli  DPedrazzani  CNeri  A  et al.  Complications after extended (D2) and superextended (D3) lymphadenectomy for gastric cancer: analysis of potential risk factors. Ann Surg Oncol 2007;14 (1) 25- 33
PubMed Link to Article
American Joint Committee on Cancer, AJCC Cancer Staging Atlas.  New York, NY Springer Science + Business Media, Inc2006;
Lauren  P The two histological main types of gastric carcinoma: diffuse and so-called intestinal carcinoma: an attempt at histo-clinical classification. Acta Pathol Microbiol Scand 1965;6431- 49
PubMed
dos Santos  NRSeruca  RConstância  MSeixas  MSobrinho-Simões  M Microsatellite instability at multiple loci in gastric carcinoma: clinicopathologic implications and prognosis. Gastroenterology 1996;110 (1) 38- 44
PubMed Link to Article
Grundei  TVogelsang  HOtt  K  et al.  Loss of heterozygosity and microsatellite instability as predictive markers for neoadjuvant treatment in gastric carcinoma. Clin Cancer Res 2000;6 (12) 4782- 4788
PubMed
Oliveira  CSeruca  RSeixas  MSobrinho-Simões  M The clinicopathological features of gastric carcinomas with microsatellite instability may be mediated by mutations of different “target genes”: a study of the TGFβ RII, IGFII R, and BAX genes. Am J Pathol 1998;153 (4) 1211- 1219
PubMed Link to Article
Peltomäki  PLothe  RAAaltonen  LA  et al.  Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 1993;53 (24) 5853- 5855
PubMed
Ottini  LPalli  DFalchetti  M  et al.  Microsatellite instability in gastric cancer is associated with tumor location and family history in a high-risk population from Tuscany. Cancer Res 1997;57 (20) 4523- 4529
PubMed
Beghelli  Sde Manzoni  GBarbi  S  et al.  Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery 2006;139 (3) 347- 356
PubMed Link to Article
Theuer  CPCampbell  BSPeel  DJ  et al.  Microsatellite instability in Japanese vs European American patients with gastric cancer. Arch Surg 2002;137 (8) 960- 965, discussion 965-966
PubMed Link to Article
Yamazaki  KTajima  YMakino  R  et al.  Tumor differentiation phenotype in gastric differentiated-type tumors and its relation to tumor invasion and genetic alteration. World J Gastroenterol 2006;12 (24) 3803- 3809
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Typical allelic profiles of microsatellite stability in constitutional DNA samples (A) and microsatellite instability in tumoral samples (B). bp Indicates base pair; N, lymph nodes; and T, tumor size.

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

Kaplan-Meier survival estimates according to microsatellite instability (MSI) status in 250 patients who underwent gastrectomy. The median (95% confidence interval) survival was 26.7 (20.8-32.5) months for patients with microsatellite-stable (MSS) tumors, and the median was beyond the observation period for patients with MSI tumors (P < .001).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Kaplan-Meier survival estimates according to microsatellite instability (MSI) in 250 patients who underwent gastrectomy. The median (95% confidence interval) survival was 26.7 (20.8-32.5) months for patients with microsatellite-stable (MSS) tumors and 18.5 (0.0-50.1) months for patients with MSI tumors having instability at 2 to 4 markers (MSI/<5), and the median was beyond the observation period for patients with MSI tumors having instability at all 5 markers (MSI/5) (P < . 001).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Kaplan-Meier survival estimates according to the number of microsatellite instability (MSI) markers in 180 patients with M0 disease who underwent potentially curative (R0) gastrectomy. The median (95% confidence interval) survival was 48.9 (31.0-86.8) months for patients with microsatellite-stable (MSS) tumors, and the median was beyond the observation period for patients with MSI tumors having instability at 2 to 4 markers (MSI/<5) or with MSI tumors having instability at all 5 markers (MSI/5) (P = . 004).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Clinicopathologic Characteristics of the Study Cohort According to Microsatellite Instability (MSI) Status
Table Graphic Jump LocationTable 2. Relative Risks of Death From Gastric Carcinoma as a Function of Microsatellite Instability (MSI)a

References

Parkin  DMBray  FFerlay  JPisani  P Global cancer statistics, 2002. CA Cancer J Clin 2005;55 (2) 74- 108
PubMed Link to Article
Chau  INorman  ARCunningham  DWaters  JSOates  JRoss  PJ Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer: pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 2004;22 (12) 2395- 2403
PubMed Link to Article
Ottini  LFalchetti  MLupi  R  et al.  Patterns of genomic instability in gastric cancer: clinical implications and perspectives. Ann Oncol 2006;17 ((suppl 7)) vii97- vii102
PubMed Link to Article
Popat  SHubner  RHoulston  RS Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005;23 (3) 609- 618
PubMed Link to Article
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
Zighelboim  IGoodfellow  PJGao  F  et al.  Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type. J Clin Oncol 2007;25 (15) 2042- 2048
PubMed Link to Article
Konishi  MKikuchi-Yanoshita  RTanaka  K  et al.  Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 1996;111 (2) 307- 317
PubMed Link to Article
Suraweera  NDuval  AReperant  M  et al.  Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology 2002;123 (6) 1804- 1811
PubMed Link to Article
Marrelli  DDe Stefano  Ade Manzoni  GMorgagni  PDi Leo  ARoviello  F Prediction of recurrence after radical surgery for gastric cancer: a scoring system obtained from a prospective multicenter study. Ann Surg 2005;241 (2) 247- 255
PubMed Link to Article
Marrelli  DPedrazzani  CNeri  A  et al.  Complications after extended (D2) and superextended (D3) lymphadenectomy for gastric cancer: analysis of potential risk factors. Ann Surg Oncol 2007;14 (1) 25- 33
PubMed Link to Article
American Joint Committee on Cancer, AJCC Cancer Staging Atlas.  New York, NY Springer Science + Business Media, Inc2006;
Lauren  P The two histological main types of gastric carcinoma: diffuse and so-called intestinal carcinoma: an attempt at histo-clinical classification. Acta Pathol Microbiol Scand 1965;6431- 49
PubMed
dos Santos  NRSeruca  RConstância  MSeixas  MSobrinho-Simões  M Microsatellite instability at multiple loci in gastric carcinoma: clinicopathologic implications and prognosis. Gastroenterology 1996;110 (1) 38- 44
PubMed Link to Article
Grundei  TVogelsang  HOtt  K  et al.  Loss of heterozygosity and microsatellite instability as predictive markers for neoadjuvant treatment in gastric carcinoma. Clin Cancer Res 2000;6 (12) 4782- 4788
PubMed
Oliveira  CSeruca  RSeixas  MSobrinho-Simões  M The clinicopathological features of gastric carcinomas with microsatellite instability may be mediated by mutations of different “target genes”: a study of the TGFβ RII, IGFII R, and BAX genes. Am J Pathol 1998;153 (4) 1211- 1219
PubMed Link to Article
Peltomäki  PLothe  RAAaltonen  LA  et al.  Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 1993;53 (24) 5853- 5855
PubMed
Ottini  LPalli  DFalchetti  M  et al.  Microsatellite instability in gastric cancer is associated with tumor location and family history in a high-risk population from Tuscany. Cancer Res 1997;57 (20) 4523- 4529
PubMed
Beghelli  Sde Manzoni  GBarbi  S  et al.  Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery 2006;139 (3) 347- 356
PubMed Link to Article
Theuer  CPCampbell  BSPeel  DJ  et al.  Microsatellite instability in Japanese vs European American patients with gastric cancer. Arch Surg 2002;137 (8) 960- 965, discussion 965-966
PubMed Link to Article
Yamazaki  KTajima  YMakino  R  et al.  Tumor differentiation phenotype in gastric differentiated-type tumors and its relation to tumor invasion and genetic alteration. World J Gastroenterol 2006;12 (24) 3803- 3809
PubMed

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 30

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles