Microsatellite Alterations with Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis

Minoru Koi, Melissa Garcia, Chan Choi, Hyeong Rok Kim, Junichi Koike, Hiromichi Hemmi, Takeshi Nagasaka, Yoshinaga Okugawa, Yuji Toiyama, Takahito Kitajima, Hiroki Imaoka, Masato Kusunoki, Yin Hsiu Chen, Bhramar Mukherjee, C. Richard Boland, John M. Carethers

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background & Aims Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers (CRCs) are poorly understood. Patients with stage II or III primary CRC with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability (E/L) are more likely to have disease recurrence after treatment. Hypoxia and/or inflammation not only promote metastasis, but also induce elevated microsatellite alterations at selected tetranucleotide repeats by causing deficiency of MSH3 in the cancer cell nucleus. We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival. Methods We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan. Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity (LOH) as possible consequences of MSH3 deficiency. Highly altered loci were examined for association with E/L in liver metastases. We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L. Results LOH at several loci at chromosome 9p24.2 (9p24.2-LOH) was associated with E/L in liver metastases (odds ratio = 10.5; 95% confidence interval: 2.69-40.80; P =.0007). We found no significant difference in the frequency of E/L, 9p24.2-LOH, mutations in KRAS or BRAF, or the combination of E/L and 9p24.2-LOH, between primary colorectal tumors and their matched metastases. Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival after CRC recurrence (hazard ratio = 0.25; 95% CI: 0.12-0.50; P =.0001), compared with patients without with E/L and 9p24.2-LOH. E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC (hazard ratio = 0.06; 95% CI: 0.01-0.57; P =.01). Conclusions E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors.

Original languageEnglish
Pages (from-to)944-955
Number of pages12
JournalGastroenterology
Volume150
Issue number4
DOIs
Publication statusPublished - Apr 1 2016

Fingerprint

Loss of Heterozygosity
Microsatellite Repeats
Colorectal Neoplasms
Neoplasm Metastasis
Liver
Recurrence
Survival
Microsatellite Instability
Frameshift Mutation
Korea
Cell Nucleus
Japan
Chromosomes
Biomarkers
Odds Ratio
Confidence Intervals
Inflammation
Mutation

Keywords

  • Colon Cancer
  • Microsatellite Instability
  • Progression
  • Recurrence

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Koi, M., Garcia, M., Choi, C., Kim, H. R., Koike, J., Hemmi, H., ... Carethers, J. M. (2016). Microsatellite Alterations with Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis. Gastroenterology, 150(4), 944-955. https://doi.org/10.1053/j.gastro.2015.12.032

Microsatellite Alterations with Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis. / Koi, Minoru; Garcia, Melissa; Choi, Chan; Kim, Hyeong Rok; Koike, Junichi; Hemmi, Hiromichi; Nagasaka, Takeshi; Okugawa, Yoshinaga; Toiyama, Yuji; Kitajima, Takahito; Imaoka, Hiroki; Kusunoki, Masato; Chen, Yin Hsiu; Mukherjee, Bhramar; Boland, C. Richard; Carethers, John M.

In: Gastroenterology, Vol. 150, No. 4, 01.04.2016, p. 944-955.

Research output: Contribution to journalArticle

Koi, M, Garcia, M, Choi, C, Kim, HR, Koike, J, Hemmi, H, Nagasaka, T, Okugawa, Y, Toiyama, Y, Kitajima, T, Imaoka, H, Kusunoki, M, Chen, YH, Mukherjee, B, Boland, CR & Carethers, JM 2016, 'Microsatellite Alterations with Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis', Gastroenterology, vol. 150, no. 4, pp. 944-955. https://doi.org/10.1053/j.gastro.2015.12.032
Koi, Minoru ; Garcia, Melissa ; Choi, Chan ; Kim, Hyeong Rok ; Koike, Junichi ; Hemmi, Hiromichi ; Nagasaka, Takeshi ; Okugawa, Yoshinaga ; Toiyama, Yuji ; Kitajima, Takahito ; Imaoka, Hiroki ; Kusunoki, Masato ; Chen, Yin Hsiu ; Mukherjee, Bhramar ; Boland, C. Richard ; Carethers, John M. / Microsatellite Alterations with Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis. In: Gastroenterology. 2016 ; Vol. 150, No. 4. pp. 944-955.
@article{3d8275b706584bb08a1f9727119eed98,
title = "Microsatellite Alterations with Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis",
abstract = "Background & Aims Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers (CRCs) are poorly understood. Patients with stage II or III primary CRC with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability (E/L) are more likely to have disease recurrence after treatment. Hypoxia and/or inflammation not only promote metastasis, but also induce elevated microsatellite alterations at selected tetranucleotide repeats by causing deficiency of MSH3 in the cancer cell nucleus. We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival. Methods We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan. Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity (LOH) as possible consequences of MSH3 deficiency. Highly altered loci were examined for association with E/L in liver metastases. We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L. Results LOH at several loci at chromosome 9p24.2 (9p24.2-LOH) was associated with E/L in liver metastases (odds ratio = 10.5; 95{\%} confidence interval: 2.69-40.80; P =.0007). We found no significant difference in the frequency of E/L, 9p24.2-LOH, mutations in KRAS or BRAF, or the combination of E/L and 9p24.2-LOH, between primary colorectal tumors and their matched metastases. Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival after CRC recurrence (hazard ratio = 0.25; 95{\%} CI: 0.12-0.50; P =.0001), compared with patients without with E/L and 9p24.2-LOH. E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC (hazard ratio = 0.06; 95{\%} CI: 0.01-0.57; P =.01). Conclusions E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors.",
keywords = "Colon Cancer, Microsatellite Instability, Progression, Recurrence",
author = "Minoru Koi and Melissa Garcia and Chan Choi and Kim, {Hyeong Rok} and Junichi Koike and Hiromichi Hemmi and Takeshi Nagasaka and Yoshinaga Okugawa and Yuji Toiyama and Takahito Kitajima and Hiroki Imaoka and Masato Kusunoki and Chen, {Yin Hsiu} and Bhramar Mukherjee and Boland, {C. Richard} and Carethers, {John M.}",
year = "2016",
month = "4",
day = "1",
doi = "10.1053/j.gastro.2015.12.032",
language = "English",
volume = "150",
pages = "944--955",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",

}

TY - JOUR

T1 - Microsatellite Alterations with Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis

AU - Koi, Minoru

AU - Garcia, Melissa

AU - Choi, Chan

AU - Kim, Hyeong Rok

AU - Koike, Junichi

AU - Hemmi, Hiromichi

AU - Nagasaka, Takeshi

AU - Okugawa, Yoshinaga

AU - Toiyama, Yuji

AU - Kitajima, Takahito

AU - Imaoka, Hiroki

AU - Kusunoki, Masato

AU - Chen, Yin Hsiu

AU - Mukherjee, Bhramar

AU - Boland, C. Richard

AU - Carethers, John M.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Background & Aims Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers (CRCs) are poorly understood. Patients with stage II or III primary CRC with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability (E/L) are more likely to have disease recurrence after treatment. Hypoxia and/or inflammation not only promote metastasis, but also induce elevated microsatellite alterations at selected tetranucleotide repeats by causing deficiency of MSH3 in the cancer cell nucleus. We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival. Methods We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan. Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity (LOH) as possible consequences of MSH3 deficiency. Highly altered loci were examined for association with E/L in liver metastases. We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L. Results LOH at several loci at chromosome 9p24.2 (9p24.2-LOH) was associated with E/L in liver metastases (odds ratio = 10.5; 95% confidence interval: 2.69-40.80; P =.0007). We found no significant difference in the frequency of E/L, 9p24.2-LOH, mutations in KRAS or BRAF, or the combination of E/L and 9p24.2-LOH, between primary colorectal tumors and their matched metastases. Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival after CRC recurrence (hazard ratio = 0.25; 95% CI: 0.12-0.50; P =.0001), compared with patients without with E/L and 9p24.2-LOH. E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC (hazard ratio = 0.06; 95% CI: 0.01-0.57; P =.01). Conclusions E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors.

AB - Background & Aims Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers (CRCs) are poorly understood. Patients with stage II or III primary CRC with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability (E/L) are more likely to have disease recurrence after treatment. Hypoxia and/or inflammation not only promote metastasis, but also induce elevated microsatellite alterations at selected tetranucleotide repeats by causing deficiency of MSH3 in the cancer cell nucleus. We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival. Methods We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan. Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity (LOH) as possible consequences of MSH3 deficiency. Highly altered loci were examined for association with E/L in liver metastases. We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L. Results LOH at several loci at chromosome 9p24.2 (9p24.2-LOH) was associated with E/L in liver metastases (odds ratio = 10.5; 95% confidence interval: 2.69-40.80; P =.0007). We found no significant difference in the frequency of E/L, 9p24.2-LOH, mutations in KRAS or BRAF, or the combination of E/L and 9p24.2-LOH, between primary colorectal tumors and their matched metastases. Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival after CRC recurrence (hazard ratio = 0.25; 95% CI: 0.12-0.50; P =.0001), compared with patients without with E/L and 9p24.2-LOH. E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC (hazard ratio = 0.06; 95% CI: 0.01-0.57; P =.01). Conclusions E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors.

KW - Colon Cancer

KW - Microsatellite Instability

KW - Progression

KW - Recurrence

UR - http://www.scopus.com/inward/record.url?scp=84962810218&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962810218&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2015.12.032

DO - 10.1053/j.gastro.2015.12.032

M3 - Article

C2 - 26752111

AN - SCOPUS:84962810218

VL - 150

SP - 944

EP - 955

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 4

ER -