Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer

Sabine Meessen; Nicola Currey; Zeenat Jahan; Hannah W Parker; Mark A Jenkins; Daniel D Buchanan; John L Hopper; Eva Segelov; Jane E Dahlstrom; Maija R J Kohonen-Corish

doi:10.3390/cancers13143529

Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer

Cancers (Basel). 2021 Jul 14;13(14):3529. doi: 10.3390/cancers13143529.

Authors

Sabine Meessen¹, Nicola Currey¹, Zeenat Jahan², Hannah W Parker^{2

3}, Mark A Jenkins⁴, Daniel D Buchanan^{5

6

7}, John L Hopper⁴, Eva Segelov⁸, Jane E Dahlstrom⁹, Maija R J Kohonen-Corish^{1

2

3

10

11}

Affiliations

¹ Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
² The Woolcock Institute of Medical Research, The University of Sydney, Sydney, NSW 2037, Australia.
³ Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia.
⁴ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC 3000, Australia.
⁵ Department of Clinical Pathology, University of Melbourne, Melbourne, VIC 3010, Australia.
⁶ University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, VIC 3010, Australia.
⁷ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Melbourne, VIC 3010, Australia.
⁸ Department of Oncology, Monash University and Monash Health, Melbourne, VIC 3168, Australia.
⁹ ACT Pathology, The Canberra Hospital and Australian National University Medical School, Canberra, ACT 2605, Australia.
¹⁰ Microbiome Research Centre, St George & Sutherland Clinical School, UNSW Sydney, Sydney, NSW 2217, Australia.
¹¹ School of Medicine, Western Sydney University, Sydney, NSW 2751, Australia.

Abstract

MSH3 gene or protein deficiency or loss-of-function in colorectal cancer can cause a DNA mismatch repair defect known as "elevated microsatellite alterations at selected tetranucleotide repeats" (EMAST). A high percentage of MSI-H tumors exhibit EMAST, while MSI-L is also linked with EMAST. However, the distribution of CpG island methylator phenotype (CIMP) within the EMAST spectrum is not known. Five tetranucleotide repeat and five MSI markers were used to classify 100 sporadic colorectal tumours for EMAST, MSI-H and MSI-L according to the number of unstable markers detected. Promoter methylation was determined using methylation-specific PCR for MSH3, MCC, CDKN2A (p16) and five CIMP marker genes. EMAST was found in 55% of sporadic colorectal carcinomas. Carcinomas with only one positive marker (EMAST-1/5, 26%) were associated with advanced tumour stage, increased lymph node metastasis, MSI-L and lack of CIMP-H. EMAST-2/5 (16%) carcinomas displayed some methylation but MSI was rare. Carcinomas with ≥3 positive EMAST markers (13%) were more likely to have a proximal colon location and be MSI-H and CIMP-H. Our study suggests that EMAST/MSI-L is a valuable prognostic and predictive marker for colorectal carcinomas that do not display the high methylation phenotype CIMP-H.

Keywords: CDKN2A; CIMP; EMAST; MCC; MSH3; MSI-H; MSI-L; colorectal cancer.

Abstract

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