Microsatellite instability testing
MSI; mismatch repair deficiency; MMR-IHC; dMMR; MSI-PCR; Lynch screening
Microsatellite instability (MSI) reflects loss of function of the DNA mismatch-repair (MMR) machinery — MLH1, MSH2, MSH6 and PMS2 — leading to accumulation of insertion-deletion errors at short tandem-repeat sequences (microsatellites). MSI is the molecular signature of Muir-Torre / Lynch syndrome. Two complementary tests are used: MMR immunohistochemistry (MLH1, MSH2, MSH6, PMS2 — loss of any nuclear protein implies dMMR) and MSI-PCR (microsatellite-loci comparison of tumour vs germline DNA). In skin oncology MSI testing is the gateway to Lynch screening triggered by sebaceous neoplasms (adenoma, sebaceoma, sebaceous carcinoma, cystic sebaceous tumour); it is also an emerging predictive biomarker for ICI response in solid cancers (high MSI = high TMB = good ICI response).
Biology — the MMR system
- The MMR system corrects single-base mismatches and short insertion-deletion loops introduced during DNA replication.
- Four core proteins:
- MLH1 and PMS2 form a heterodimer (MutLα).
- MSH2 and MSH6 form a heterodimer (MutSα).
- Loss of one protein typically destabilises its partner — MLH1 loss → PMS2 loss; MSH2 loss → MSH6 loss.
- MMR deficiency causes accumulation of mutations at microsatellite repeats (high MSI) and a markedly elevated overall mutational burden (high TMB).
- Inherited Lynch syndrome — germline variant in one MMR gene + somatic loss of the other allele = MMR-deficient tumour. Sporadic MMR deficiency — most often through MLH1 promoter methylation (associated with BRAF V600E in colorectal tumours).
MMR-IHC vs MSI-PCR
- MMR-IHC — IHC for MLH1, MSH2, MSH6, PMS2; loss of nuclear staining in tumour cells (with retained internal control staining) indicates dMMR.
- Pattern of loss — MLH1+PMS2 loss most common in sporadic colorectal cancer (BRAF / MLH1 promoter methylation); MSH2+MSH6 loss most often Lynch syndrome.
- Isolated MSH6 or PMS2 loss — Lynch syndrome variants.
- Widely available; rapid; well-tolerated by pathology workflows.
- MSI-PCR — multiplex PCR of standardised microsatellite loci (Bethesda panel: BAT-25, BAT-26, NR-21, NR-24, MONO-27 mononucleotide repeats) compared between tumour and germline DNA.
- Tumours classified MSI-high (≥ 2/5 loci unstable), MSI-low (1/5), or MSS (microsatellite stable).
- More specialised; usually performed when MMR-IHC equivocal or for advanced indications.
- The two tests have ~ 95% concordance. MMR-IHC has the advantage of identifying which protein is lost (guides germline testing); MSI-PCR detects MSI in IHC-equivocal cases.
Role in skin oncology — Muir-Torre / Lynch
- Any sebaceous neoplasm — sebaceous adenoma, sebaceoma, sebaceous carcinoma, cystic sebaceous tumour — triggers MMR-IHC on the lesion in many UK pathology services as a Muir-Torre screening test.
- MMR-IHC loss in a sebaceous neoplasm — patient referred to clinical genetics for germline Lynch testing.
- Refer for genetic counselling and Lynch surveillance (colonoscopy from age 25–30; gynae and urology per local protocol; aspirin chemoprevention discussion).
- Multiple sebaceous neoplasms, lesions on the trunk, age < 60, or relevant family / personal cancer history particularly increase Muir-Torre likelihood.
- Some labs use a risk-adjusted approach (Mayo score / MTS scoring) to decide which sebaceous lesions warrant MMR-IHC.
MSI and immune checkpoint inhibitor response
- High-MSI / dMMR tumours have a substantially elevated tumour mutational burden — generating many neoantigens recognised by the immune system.
- This translates clinically to substantially improved response to pembrolizumab and other anti-PD-1 therapy.
- Pembrolizumab is approved (FDA tumour-agnostic; NICE specific cancers) for unresectable / metastatic dMMR / MSI-high solid tumours that have progressed after prior treatment.
- In skin oncology — most cSCC and melanoma are MSS (microsatellite stable) — high TMB in melanoma is driven by UV signature rather than MMR deficiency. But MMR-deficient melanoma (rare) has very high ICI response rates.
- MMR / MSI testing increasingly relevant beyond Lynch screening as treatment-decision biomarker.
References
- Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology; 2010.
- Le DT et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med; 2015.
- NICE NG151. Colorectal cancer. London: NICE; 2020 (last updated 15 December 2021; reviewed 29 April 2026).
- Royal College of Pathologists. Dataset for histopathological reporting of primary cutaneous adnexal carcinomas and regional lymph nodes. G127. London: RCPath; February 2019; updated Appendix A for UICC TNM9, November 2025.
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