Background
Methods and progress of microsatellite instability detection
Detection method | Characteristics | Test items | Accuracy | Refs. |
---|---|---|---|---|
NGS | Accurate results were obtained from a small amount of sample | Nearly 100 MS loci | IMPACT™: 92% F1CDx: 94.6% | Hempelmann et al. [6] |
Fluorescent multiplex PCR and CE | Only MSI results are obtained MSI analysis system is based on this method | 5 MS sites: BAT-26, NR-21, BAT-25, MONO-27 and NR-24 | Gold standard, 100% | Arulananda et al. [11] |
IHC | Wide application and strong practicability, but only get the MMR results | The MMR protein: hMLH1, hPMS2, hMSH2, hMSH6 | 89–95% | Cheah et al. [12] |
smMIPs | Accurate and no matching of normal materials are required for certain diseases: colorectal cancer, prostate cancer, endometrial cancer | DNA from tumor tissue | 95.80% | Waalkes et al. [17] |
Next-generation sequencing (NGS)
Fluorescent multiplex PCR and CE
Immunohistochemistry (IHC)
Single-molecule molecular inversion probes (smMIPs)
MSI calculation method
Mechanism of MSI
Slipped strand mispairing
MMR deficient
Characteristics of gene mutation in MSI-H patients
Mutational characteristics in various cancers
Treatment mechanism of MSI tumors
Advances in the clinical application of microsatellite instability
MSI-H/dMMR related diseases
Diseases | MSI characteristics | Prognosis | Treatment options |
---|---|---|---|
Lynch syndrome (LS) | EpCAM immunostaining is an important factor, common in patients over 60 years old, most of them arenormal adenocarcinoma, villous adenoma, adenoma over 1 cm and highly dysplastic adenoma | MSI-H/dMMR patients with lynch syndrome have good prognosis | Aspirin/sulinda may play a preventive role in reducing the risk of Lynch syndrome-related cancer, especially in patients with hMSH2 and hMLH1 gene changes |
Colorectal cancer (CRC) | MSI-H tumors are infiltrated with dense cytotoxic T cells, generally occur on the right side | Stage I and stage II MSI CRC have good prognosis, stage III MSI CRC have bad prognosis | Stage III to IV CRC patients can use 5-FU as a chemotherapeutic, neither stage I to II CRC patients. And choose anti-PD-1/PDL-1 treatment for CRC patients at different stage |
Gastric cancer (GC) | The high expression of CD8 positive T cell molecular marker, PD-L1 gene and IFN γ gene in patients with MSI-H | MSI-H resectable primary gastric cancer have good prognosis | MSI-H GC should avoid adjuvant chemotherapy, take surgical treatment |
Breast cancer | BRCA1 mutation can cause MSI. MSI related loci D3S1766 and D2S2739 can identify MSI related breast cancer | MSI-H patients with breast cancer have bad prognosis | Olaparib can strengthen other drugs’ effect such as platinum in combination |
Prostate cancer | MSI-frequency < 1%, is closely related to pathogenic embryonic mutants carrying Lynch syndrome-related genes | MSI-H/dMMR patients with prostate cancer have good prognosis | Anti-PD-1/PDL-1 treatment |
Cholangiocarcinoma | MSI frequency < 1%, most of them are young patients with atypical tissue morphology | MSI-H/dMMR patients with cholangiocarcinoma have good prognosis | ICI (immune checkpoint inhibitor) combined with radiotherapy |
Leukemia | MSI frequency < 1%, most of them are chronic myeloid leukemia | MSI-H/dMMR patients with leukemia have good prognosis | Anti-PD-1/PDL-1 treatment |
Bladder cancer | hMSH2mutation can increase the risk of getting bladder cancer, MSI related loci D9S63, D9S156, and D9S283 can be used to screen patients with high micro bladder cancer | MSI-H/dMMR patients with bladder cancer have good prognosis | Anti-PD-1/PDL-1 treatment |
Ovarian cancer | An increased number of CD8+, PD-1+, and TILS in MSI Ovarian cancer patients | the MSI-H patients with Clear-cell ovarian carcinoma (CCOCs) are suitable for immunotherapy | Anti-PD-1/PD-L1 drugs |
Endometrial Carcinoma (EC) | UCEC patients with MSI has higher immune components, CD3+ and CD8 + TIL | MSI-H EC in the middle and late stage is associated with bad prognosis | Use anti-PD-1/ PD-L1 drugs and chemotherapeutic drugs such as temozolomide and cisplatin. |
Pancreatic ductal adenocarcinoma (PDAC) | HMLH1 and hMSH2 are mostly inactivated | MSI-H/dMMR patients with PDAC have good prognosis | Anti-PD-1/PD-L1 drugs |
Follicular thyroid cancer (FTC) | Advanced FTC associated with MMR inactivation | MSI-H patients with FTC have a prolonged survival time | Anti-PD-1/PD-L1 drugs |
Adrenocortical cancer (ACC) | MSI-H/dMMR patients with ACC have high variation load, ACC is closely related to the deletion mutations of hMSH2 | no relevant literature about the effect of MSI on the prognosis of cortical carcinoma | ACC is not effective in immunotherapy of dendritic cells without immune response |
Lynch syndrome
Colorectal cancer
Gastric cancer
Breast cancer
Prostate cancer
Cholangiocarcinoma
Leukemia
Bladder cancer
Ovarian cancer
Endometrial carcinoma
Pancreatic ductal adenocarcinoma
Thyroid cancers
Adrenocortical carcinoma
Preventive measures for MSI-H/dMMR related diseases
The treatment of MSI-H/dMMR related diseases
Drug | Target | Indications | Remarks | Refs. |
---|---|---|---|---|
Fluorouracil | Nucleic acid | Stage III to IV CRC | Chemotherapy | Kwon et al. [81] |
Nivolumab | PD-L1 | Patients with advanced metastatic CRC over the age of 12 years with MSI-H/dMMR; BRAF mutation caused by dMMR/MSI-H metastatic CRC | Based on the chemotherapy drug treatment | Overman et al. [87] |
Ipilimumab | CTLA4 | Combined treatment with Nivolumab for metastatic CRC aggravated by MSI-H/dMMR after oxaliplatin, irinotecan and fluorouracil | Low dose ipilimumab combined with nivolumab can reduce side effects in patients | Overman et al. [89] |
Pembrolizumab | PD-L1 | Advanced anti-PD-L1 positive CRC patients | Based on the chemotherapy drug treatment | O’Neil et al. [91] |
Bevacizumab | VEGF | Patients with MSI-H tumor | Based on the chemotherapy drug treatment | Innocenti et al. [92] |