Minoru Koi1, Melissa Garcia2, Chan Choi3, Hyeong-Rok Kim4, Junichi Koike5, Hiromichi Hemmi6, Takeshi Nagasaka7, Yoshinaga Okugawa8, Yuji Toiyama9, Takahito Kitajima9, Hiroki Imaoka9, Masato Kusunoki9, Yin-Hsiu Chen10, Bhramar Mukherjee10, C Richard Boland11, John M Carethers12. 1. Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas. Electronic address: mkoi@med.Umich.edu. 2. Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas. 3. Department of Pathology, Chonnam National University Medical School, Gwangju, Korea. 4. Department of Surgery, Chonnam National University Medical School, Gwangju, Korea. 5. Department of Surgery, Toho University Faculty of Medicine, Tokyo, Japan. 6. Department of Molecular Immunology, Toho University Faculty of Medicine, Tokyo, Japan. 7. Department of Gastroenterological Surgery and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. 8. Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; Department of Gastrointestinal and Pediatric Surgery, Graduate School of Medicine Mie University, Mie, Japan. 9. Department of Gastrointestinal and Pediatric Surgery, Graduate School of Medicine Mie University, Mie, Japan. 10. Department of Biostatistics School of Public Health, University of Michigan, Ann Arbor, Michigan. 11. Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas. Electronic address: RickBo@BaylorHealth.edu. 12. Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Electronic address: jcarethe@med.umich.edu.
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.
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.
Authors: Arnaud D Roth; Sabine Tejpar; Mauro Delorenzi; Pu Yan; Roberto Fiocca; Dirk Klingbiel; Daniel Dietrich; Bart Biesmans; György Bodoky; Carlo Barone; Enrique Aranda; Bernard Nordlinger; Laura Cisar; Roberto Labianca; David Cunningham; Eric Van Cutsem; Fred Bosman Journal: J Clin Oncol Date: 2009-12-14 Impact factor: 44.544
Authors: John M Carethers; Bhavya Murali; Bing Yang; Ryan T Doctolero; Akihiro Tajima; Ranor Basa; E Julieta Smith; Monte Lee; Ryan Janke; Tina Ngo; Ruth Tejada; Ming Ji; Matthew Kinseth; Betty L Cabrera; Katsumi Miyai; Temitope O Keku; Christopher F Martin; Joseph A Galanko; Robert S Sandler; Kathleen L McGuire Journal: PLoS One Date: 2014-06-23 Impact factor: 3.240
Authors: Stephanie S Tseng-Rogenski; Heekyung Chung; Maike B Wilk; Shuai Zhang; Moriya Iwaizumi; John M Carethers Journal: PLoS One Date: 2012-11-30 Impact factor: 3.240
Authors: Hafeez Afolabi; Salzihan Md Salleh; Zaidi Zakaria; Ch'ng Ewe Seng; Siti Norasikin Binti Mohd Nafil; Ahmad Aizat Bin Abdul Aziz; Yusuf Wada; Ahmad Irekeola Journal: Biomed Res Int Date: 2022-06-23 Impact factor: 3.246
Authors: Stephanie S Tseng-Rogenski; Koji Munakata; Daniel Y Choi; Paul K Martin; Supal Mehta; Minoru Koi; Wei Zheng; Yang Zhang; John M Carethers Journal: Mol Cell Biol Date: 2020-06-15 Impact factor: 4.272
Authors: Kjetil Søreide; Martin M Watson; Dordi Lea; Oddmund Nordgård; Jon Arne Søreide; Hanne R Hagland Journal: J Transl Med Date: 2016-06-29 Impact factor: 5.531