Microsatellite instability

Microsatellites are repetitive DNA sequences dispersed throughout the genome. The repetition renders them susceptible to slippage mutations. To counter this, there are a family of mismatch repair (MMR) genes which correct these errors. These repair genes include MLH1, PMS2, MSH2 and MSH6. Defective MMR genes lead to accumulation of mutations in microsatellite regions, known as microsatellite instability (MSI).

hereditary non-polyposis colorectal carcinoma (HNPCC) is associated with early onset carcinoma of colorectum , endometrium, small bowel, renal pelvis and ureter, ovary, hepatobiliary system, brain and skin. 90% of patients with HNPCC have mutations of either MLH1 or MSH2; most of the remainder have mutations of PMS2 or MSH6. HNPCC in women confers a 42% to 60% lifetime probability of developing endometrial carcinoma.

Colonic and endometrial carcinomas in HNPCC can be demonstrated to have MSI. MSI can also be found in 17% to 23% of non-familial endometrial carcinomas: this MSI is attributable to silencing of the MLH1 gene by promoter methylation.

MSI is associated with a favorable clinical outcome in endometrial carcinoma.

MSI can be demonstrated by polymerase chain reaction. However, in routine diagnostic practice, monoclonal antibodies demonstrating loss of staining for at least some MMR gene proteins have good sensitivity and specificity for predicting MSI. Some mutant proteins remain detectable by IHC, giving false results.

Immunohistochemical expression

For colonic neoplasms:

Abnormal (loss of staining)	MSI-high by PCR	not MSI-high by PCR	sensitivity of IHC for MSI	specificity of IHC for MSI
MLH1	5/412	1/612	123%2	98%2
MSH2	25/402	0/622	63%2	100%2
MSH6	20/372	0/602	54%2	100%2

For endometrial carcinomas:

Abnormal (loss of staining)	MSI-high by PCR	not MSI-high by PCR	sensitivity of IHC for MSI	specificity of IHC for MSI
MLH1	24/451	1/401	53%1	98%1
PMS2	31/451	1/401	69%1	98%1
MSH2	7/451	0/401	18%1	100%1
MSH6	12/451	6/401	27%1	85%1

In another study, MSI phenotype was observed in a small subset of mainly advanced-stage endometrial carcinomas, frequently showing mucinous differentiation, areas of solid-cribriform pattern, and necrosis. It was often associated with loss of MLH1 expression, which may be a prognostic marker, but only rarely with defects of MSH23.

Diagnostic utility

Diagnosis of HNPCC families. As a screening procedure, a four antibody panel gives the highest sensitivity, albeit with reduced specificity.

References

1 Modica I, Soslow RA, Black D, et al. Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma. Am J Surg Pathol 2007; 31:744-51

2 Shia J, Klimstra DS, Nafa K, et al. Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms. Am J Surg Pathol 2005; 29:96-104

3 Peiro G, Diebold J, Lohse P, et al. Microsatellite instability, loss of heterozygosity, and loss of hMLH1 and hMSH2 protein expression in endometrial carcinoma. Hum Pathol 2002; 33:347-54

This page last revised 5.6.2007.