What Is MSI-High Cancer?

## What Is Microsatellite Instability? Microsatellites are short, repetitive sequences of DNA found throughout the genome. When a cell divides, it copies its DNA — and errors in this copying are normally caught and repaired by a system called the **mismatch repair (MMR) system**. If the MMR system is defective (due to mutations in MMR genes like MLH1, MSH2, MSH6, or PMS2), errors in microsatellite sequences accumulate. This is called **microsatellite instability (MSI)**. - **MSI-H (High):** High degree of instability — mismatch repair is defective (dMMR) - **MSS (Microsatellite Stable):** Normal repair function ## Why MSI-H Matters Enormously MSI-H tumors have a very high number of mutations overall — called high **tumor mutational burden (TMB)**. This matters because: 1. Each mutation can produce abnormal proteins (neoantigens) on the cancer cell surface 2. The immune system can potentially recognize these as foreign 3. Checkpoint inhibitor immunotherapy (pembrolizumab, nivolumab) works dramatically well in MSI-H tumors **This is why MSI-H is one of the most important biomarkers in oncology today.** ## FDA-Approved Immunotherapy for MSI-H In 2017, the FDA made a historic decision — the first-ever **tumor-agnostic approval** in oncology. Pembrolizumab (Keytruda) was approved for **any MSI-H solid tumor** regardless of where in the body it originated. This means if your cancer is MSI-H — whether it's colorectal, endometrial, stomach, or another type — you are potentially eligible for pembrolizumab. ## Which Cancers Are Commonly MSI-H? | Cancer Type | Frequency of MSI-H | |---|---| | Colorectal cancer | ~15% overall; higher in earlier stages | | Endometrial (uterine) cancer | ~25–30% | | Gastric (stomach) cancer | ~10–15% | | Ovarian cancer | ~5–15% | | Prostate cancer | ~3–5% | | Pancreatic cancer | ~1–2% | ## Lynch Syndrome MSI-H can occur sporadically (random mutations) or can be inherited. **Lynch syndrome** is an inherited condition caused by germline mutations in MMR genes, leading to: - Significantly elevated lifetime risk of colorectal, endometrial, ovarian, and other cancers - All family members of a Lynch syndrome patient should be considered for genetic testing If your tumor is MSI-H, your oncologist will likely recommend **germline testing** to determine whether you have Lynch syndrome. ## How MSI Is Tested - **IHC (Immunohistochemistry):** Tests for presence of MMR proteins — "dMMR" (deficient) is equivalent to MSI-H - **PCR or next-generation sequencing (NGS):** Directly measures instability at microsatellite loci Both are done on tumor tissue from a biopsy or surgery.