Microsatellite Instability Testing and Its Role in the Management of Colorectal Cancer

Hisato Kawakami, Aziz Zaanan, Frank A Sinicrope

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

TNM stage remains the key determinant of patient prognosis after surgical resection of colorectal cancer (CRC), and informs treatment decisions. However, there is considerable stage-independent variability in clinical outcome that is likely due to molecular heterogeneity. This variability underscores the need for robust prognostic and predictive biomarkers to guide therapeutic decision-making including the use of adjuvant chemotherapy. Although the majority of CRCs develop via a chromosomal instability pathway, approximately 12–15 % have deficient DNA mismatch repair (dMMR) which is characterized in the tumor by microsatellite instability (MSI). Tumors with the dMMR/MSI develop from a germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), i.e., Lynch syndrome, or more commonly from epigenetic inactivation of MLH1 MMR gene. CRCs with dMMR/MSI status have a distinct phenotype that includes predilection for the proximal colon, poor differentiation, and abundant tumor-infiltrating lymphocytes. Consistent data indicate that these tumors have a better stage-adjusted survival compared to proficient MMR or microsatellite stable (MSS) tumors and may respond differently to 5-fluorouracil-based adjuvant chemotherapy. To increase the identification of dMMR/MSI patients in clinical practice that includes those with Lynch syndrome, it is recommended that all resected CRCs to be analyzed for MMR status. Available data indicate that patients with stage II dMMR CRCs have an excellent prognosis and do not benefit from 5-fluorouracil (FU)-based adjuvant chemotherapy which supports their recommended management by surgery alone. In contrast, the benefit of standard adjuvant chemotherapy with the FOLFOX regiment in stage III dMMR CRC patients awaits further study and therefore, all patients should be treated with standard adjuvant FOLFOX.

Original languageEnglish (US)
Article number30
JournalCurrent Treatment Options in Oncology
Volume16
Issue number7
DOIs
StatePublished - Jul 4 2015

Fingerprint

Microsatellite Instability
DNA Mismatch Repair
Colorectal Neoplasms
Adjuvant Chemotherapy
Hereditary Nonpolyposis Colorectal Neoplasms
Fluorouracil
Neoplasms
DNA Repair-Deficiency Disorders
Tumor-Infiltrating Lymphocytes
Chromosomal Instability
Germ-Line Mutation
Epigenomics
Microsatellite Repeats
Genes
Decision Making
Colon
Biomarkers
Phenotype
Survival
Therapeutics

Keywords

  • Adjuvant chemotherapy
  • Colorectal cancer
  • DNA mismatch repair
  • Microsatellite instability

ASJC Scopus subject areas

  • Oncology
  • Pharmacology (medical)

Cite this

Microsatellite Instability Testing and Its Role in the Management of Colorectal Cancer. / Kawakami, Hisato; Zaanan, Aziz; Sinicrope, Frank A.

In: Current Treatment Options in Oncology, Vol. 16, No. 7, 30, 04.07.2015.

Research output: Contribution to journalArticle

@article{6d388fcc97c9480d90fd86920abe6515,
title = "Microsatellite Instability Testing and Its Role in the Management of Colorectal Cancer",
abstract = "TNM stage remains the key determinant of patient prognosis after surgical resection of colorectal cancer (CRC), and informs treatment decisions. However, there is considerable stage-independent variability in clinical outcome that is likely due to molecular heterogeneity. This variability underscores the need for robust prognostic and predictive biomarkers to guide therapeutic decision-making including the use of adjuvant chemotherapy. Although the majority of CRCs develop via a chromosomal instability pathway, approximately 12–15 {\%} have deficient DNA mismatch repair (dMMR) which is characterized in the tumor by microsatellite instability (MSI). Tumors with the dMMR/MSI develop from a germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), i.e., Lynch syndrome, or more commonly from epigenetic inactivation of MLH1 MMR gene. CRCs with dMMR/MSI status have a distinct phenotype that includes predilection for the proximal colon, poor differentiation, and abundant tumor-infiltrating lymphocytes. Consistent data indicate that these tumors have a better stage-adjusted survival compared to proficient MMR or microsatellite stable (MSS) tumors and may respond differently to 5-fluorouracil-based adjuvant chemotherapy. To increase the identification of dMMR/MSI patients in clinical practice that includes those with Lynch syndrome, it is recommended that all resected CRCs to be analyzed for MMR status. Available data indicate that patients with stage II dMMR CRCs have an excellent prognosis and do not benefit from 5-fluorouracil (FU)-based adjuvant chemotherapy which supports their recommended management by surgery alone. In contrast, the benefit of standard adjuvant chemotherapy with the FOLFOX regiment in stage III dMMR CRC patients awaits further study and therefore, all patients should be treated with standard adjuvant FOLFOX.",
keywords = "Adjuvant chemotherapy, Colorectal cancer, DNA mismatch repair, Microsatellite instability",
author = "Hisato Kawakami and Aziz Zaanan and Sinicrope, {Frank A}",
year = "2015",
month = "7",
day = "4",
doi = "10.1007/s11864-015-0348-2",
language = "English (US)",
volume = "16",
journal = "Current Treatment Options in Oncology",
issn = "1527-2729",
publisher = "Springer New York",
number = "7",

}

TY - JOUR

T1 - Microsatellite Instability Testing and Its Role in the Management of Colorectal Cancer

AU - Kawakami, Hisato

AU - Zaanan, Aziz

AU - Sinicrope, Frank A

PY - 2015/7/4

Y1 - 2015/7/4

N2 - TNM stage remains the key determinant of patient prognosis after surgical resection of colorectal cancer (CRC), and informs treatment decisions. However, there is considerable stage-independent variability in clinical outcome that is likely due to molecular heterogeneity. This variability underscores the need for robust prognostic and predictive biomarkers to guide therapeutic decision-making including the use of adjuvant chemotherapy. Although the majority of CRCs develop via a chromosomal instability pathway, approximately 12–15 % have deficient DNA mismatch repair (dMMR) which is characterized in the tumor by microsatellite instability (MSI). Tumors with the dMMR/MSI develop from a germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), i.e., Lynch syndrome, or more commonly from epigenetic inactivation of MLH1 MMR gene. CRCs with dMMR/MSI status have a distinct phenotype that includes predilection for the proximal colon, poor differentiation, and abundant tumor-infiltrating lymphocytes. Consistent data indicate that these tumors have a better stage-adjusted survival compared to proficient MMR or microsatellite stable (MSS) tumors and may respond differently to 5-fluorouracil-based adjuvant chemotherapy. To increase the identification of dMMR/MSI patients in clinical practice that includes those with Lynch syndrome, it is recommended that all resected CRCs to be analyzed for MMR status. Available data indicate that patients with stage II dMMR CRCs have an excellent prognosis and do not benefit from 5-fluorouracil (FU)-based adjuvant chemotherapy which supports their recommended management by surgery alone. In contrast, the benefit of standard adjuvant chemotherapy with the FOLFOX regiment in stage III dMMR CRC patients awaits further study and therefore, all patients should be treated with standard adjuvant FOLFOX.

AB - TNM stage remains the key determinant of patient prognosis after surgical resection of colorectal cancer (CRC), and informs treatment decisions. However, there is considerable stage-independent variability in clinical outcome that is likely due to molecular heterogeneity. This variability underscores the need for robust prognostic and predictive biomarkers to guide therapeutic decision-making including the use of adjuvant chemotherapy. Although the majority of CRCs develop via a chromosomal instability pathway, approximately 12–15 % have deficient DNA mismatch repair (dMMR) which is characterized in the tumor by microsatellite instability (MSI). Tumors with the dMMR/MSI develop from a germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), i.e., Lynch syndrome, or more commonly from epigenetic inactivation of MLH1 MMR gene. CRCs with dMMR/MSI status have a distinct phenotype that includes predilection for the proximal colon, poor differentiation, and abundant tumor-infiltrating lymphocytes. Consistent data indicate that these tumors have a better stage-adjusted survival compared to proficient MMR or microsatellite stable (MSS) tumors and may respond differently to 5-fluorouracil-based adjuvant chemotherapy. To increase the identification of dMMR/MSI patients in clinical practice that includes those with Lynch syndrome, it is recommended that all resected CRCs to be analyzed for MMR status. Available data indicate that patients with stage II dMMR CRCs have an excellent prognosis and do not benefit from 5-fluorouracil (FU)-based adjuvant chemotherapy which supports their recommended management by surgery alone. In contrast, the benefit of standard adjuvant chemotherapy with the FOLFOX regiment in stage III dMMR CRC patients awaits further study and therefore, all patients should be treated with standard adjuvant FOLFOX.

KW - Adjuvant chemotherapy

KW - Colorectal cancer

KW - DNA mismatch repair

KW - Microsatellite instability

UR - http://www.scopus.com/inward/record.url?scp=84930646253&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930646253&partnerID=8YFLogxK

U2 - 10.1007/s11864-015-0348-2

DO - 10.1007/s11864-015-0348-2

M3 - Article

VL - 16

JO - Current Treatment Options in Oncology

JF - Current Treatment Options in Oncology

SN - 1527-2729

IS - 7

M1 - 30

ER -