Is Microsatellite Instability Important

Is Microsatellite Instability Important in Response to Radiotherapy in Patients with Rectal Cancer?

A B S T R A C T

MSI is the indicator of a DNA repair error that may lead to mutation accumulation formed in the cell. Although there are conflicting studies in the literature, in many studies it has been revealed that MSI has predictive and prognostic effect on response to RT in rectal cancer.

Keywords

Microsatellite instability, radiotherapy, rectal cancer


Cancer is a disease that is as a result of the accumulation of many genetic alterations. As a result of these genetic alterations, genomic instability occurs in both nuclear and mitochondrial genome. One of the best indicators of the genomic instability is microsatellite instability. Microsatellites are formations distributed throughout the human genome and that do not encode proteins in their DNA structure in the form of mono, di, tri, tetra, penta dinucleotide repeats, but whose present functions are not known precisely. As the number of the repeats increases in microsatellites, the possibility of error occurrence as insertion or deletion during DNA replication also increases [1-3].

In a normal cell, these errors are recognized by mismatch repair genes (MMR) and directed to the cell repair or apoptosis. Microsatellite instability (MSI) causes function incompetence in the relevant proteins as a result of the mutation or epigenetic alteration in any of the genes (MLH1, MSH2, MSH6, PMS1, PMS2, MLH3, EXO1) encoding proteins that play role in the mismatch repair. It is argued that MSI occurs in the early stages of carcinogenesis and predisposes to consecutive mutations of other responsible genes [1-5]. MSI is detected in 90% of familial colorectal cancers and 75% of endometrium cancers. MSI is also observed in 15% of sporadic colorectal cancers, 2-8% of rectal cancers and 9-45% of sporadic endometrium cancers. It has also been stated that it is seen in solid tumors such as ovary cancer and malignant melanoma [1, 4-7]. It is also thought that frequent detection of MSI outside the specific patient group may lead to new approaches in screening, diagnosis, staging and treatment.

There is a worldwide consensus that the prognostic value of MSI establishes a prediction for treatment. However, the knowledge is limited, and the field is open to the research. In recent years it has been reported that there is also an increase in sporadic cases about colorectal cancer development via MSI. It has been revealed that MSI is both prognostic and predictive in these cases [4, 5, 7]. In a systematic analysis by Popat et al., it is emphasized that MSI tumors in colorectal cancers have better prognosis, tend to metastasize less and respond chemotherapy better when compared to stable tumors. According to the result of this analysis, MSI increases prognostic value in colorectal cancers [4]. MSI presence in endometrium cancer has been shown to be associated with poor prognosis as distinct from colon and gastric cancers [7-9]. It is unclear whether MSI is a sensitivity predictor of radiotherapy (RT). There are few studies in the literature. In a study conducted by Demes et al., the positivity of MSI in rectal cancers was in 8% of the cases, and it was reported that these cases did not respond chemoradiotherapy [6]. In addition, they emphasized in another study that MSI did not have role as a predictor for the treatment in local advanced stage rectal cancer patients who received neoadjuvant RT, but it had prognostic significance in lymph node-negative patients [2]. Bilbao-Sieyro et al. reported that patients with MSI among diploid tumors in endometrioid endometrial cancer were found to have worse survival rates and lower RT responses [9].

As a consequence, the interest in the significance of genetic alterations in cancer has been increasing day by day and the obtained results seem to be encouraging. MSI is the indicator of a DNA repair error that may lead to mutation accumulation formed in the cell. Although there are conflicting studies in the literature, in many studies it has been revealed that MSI has predictive and prognostic effect on response to RT in rectal cancer. There is a need for large-scale, randomized and prospective multivariate studies to form a consensus on this issue.

Download PDF View PDF


Article Info

Article Type
Mini Review

Publication history

Received:

Accepted:

Published:


Copyright

© 2023 Yasemin Benderli Cihan. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.

DOI: 10.31487/j.IJCST.2020.01.03


Author Info

Yasemin Benderli Cihan


Corresponding Author
Yasemin Benderli Cihan
Department of Radiation Oncology, Kayseri City Education and Research Hospital, Kocasinan/Kayseri, Turkey
  1. Kubeček O, Kopecký J (2016) Microsatellite instability in melanoma: a comprehensive review. Melanoma Res 26: 545-550. [Crossref]
  2. Du C, Zhao J, Xue W, Dou F, Gu J (2013) Prognostic value of microsatellite instability in sporadic locally advanced rectal cancer following neoadjuvant radiotherapy. Histopathology 62: 723-730. [Crossref]
  3. De Schutter H, Spaepen M, Van Opstal S, Poorten VV, Verbeken E et al. (2009) The prevalence of microsatellite instability in head and neck squamous cell carcinoma. J Cancer Res Clin Oncol 135: 485-490. [Crossref]
  4. Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23: 609-618. [Crossref]
  5. Lim SH, Chua W, Henderson C, Ng W, Shin J et al. (2015) Predictive and prognostic biomarkers for neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Crit Rev Oncol Hematol 96: 67-80. [Crossref]
  6. Demes M, Scheil Bertram S, Bartsch H, Fisseler Eckhoff A (2013) Signature of microsatellite instability, KRAS and BRAF gene mutations in German patients with locally advanced rectal adenocarcinoma before and afte rneoadjuvant 5-FU radiochemotherapy. J Gastrointest Oncol 4: 182-192. [Crossref]
  7. Yan H, Hao L, Jin H, Xing Q, Xue G et al. (2008) Clinical features and mismatch repair genes analyses of Chinese suspected hereditary non-polyposis colorectal cancer: a cost-effective screening strategy proposal. Cancer Sci 99: 770-780. [Crossref]
  8. Fadhil W, Kindle K, Jackson D, Zaitoun A, Lane N et al. (2014) DNA content analysis of colorectal cancer defines a distinct 'microsatellite and chromosome stable' group but does not predict response to radiotherapy. Int J Exp Pathol 95: 16-23. [Crossref]
  9. Bilbao C, Lara PC, Ramírez R, Henríquez Hernández LA, Rodríguez G et al. (2010) Microsatellite instability predicts clinical outcome in radiation-treated endometrioid endometrial cancer. Int J Radiat Oncol Biol Phys 76: 9-13. [Crossref]