Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer

Abstract

Purpose: Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status.

Methods: MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed.

Results: Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases.

Conclusion: MSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.

FIG 1.

Distribution of microsatellite instability (MSI) status across cancer types. Tumor types are indicated on the x-axis. (A) Bar graphs demonstrate the percentage of tumors that are high-frequency MSI (MSI-H; blue) and indeterminate MSI (MSI-I; red) by cancer type. (B) MSIsensor score is indicated on the y-axis. Box and whisker plots illustrate that the majority of tumors were microsatellite stable (MSS; 93.2%), with MSIsensor score < 3, and teal dots indicate individual tumor MSIsensor scores for MSI-H (score ≥ 10) and MSI-I (score ≥ 3 to < 10) tumors. Dark orange dots indicate patients in whom germline mismatch repair (MMR) pathogenic variants were identified. The one germline MMR mutation (dark orange dot) seen in Other Tumor Type was in an adenocarcinoma of unknown primary. Bladder/urothelial category includes renal pelvis, ureter, bladder, and urethral cancers. CNS tumors category includes glioma, astrocytoma, embryonal, and miscellaneous brain tumors. Other tumor type category includes less common tumors, including ampullary carcinoma, anal carcinoma, appendiceal carcinoma, osteosarcoma, peripheral nerve sheath tumor, choriocarcinoma, cervical cancer, neuroendocrine tumor, neuroblastoma, thymic tumor, pheochromocytoma, vaginal carcinoma, Wilms tumor, cancer of unknown primary, head and neck cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, Ewing sarcoma, non-Hodgkin lymphoma, leukemia, and retinoblastoma.

FIG 2.

Distribution and prevalence of germline mismatch repair (MMR) gene mutations by microsatellite instability (MSI) status and by MMR gene type. (A) Bar graph and pie charts represent overall prevalence of pathogenic or likely pathogenic germline mutations in the DNA MMR genes, diagnostic of Lynch syndrome (LS), among high-frequency MSI (MSI-H; red), indeterminate MSI (MSI-I; blue), and microsatellite stable (MSS; gray) groups (16.3%, 1.9%, and 0.3%, respectively; P < .001). Tumor types are indicated in the bar within the pie graphs by individual colors, highlighting the distinct tumor types composing each group. (B) MMR genes are indicated on the x-axis and number of individual patients with pathogenic or likely pathogenic variants are indicated on the y-axis. Red, blue, and gray bars represent mutations found in MSI-H, MSI-I, and MSS cohorts across each MMR gene, respectively. ACC, adrenocortical carcinoma; BRC, breast; CRC, colorectal; EC, endometrial; GAST, gastric; GC, germ cell tumor; HAN, head and neck cancer; HBC, hepatobiliary; LUN, lung; MEL, melanoma; MESO, mesothelioma; OST, osteosarcoma; PDAC, pancreatic ductal adenocarcinoma; PROS, prostate; RCC, renal cell carcinoma; SB, small bowel; STS, soft tissue sarcoma; THY, thyroid cancer; UNK, unknown primary; URO, urothelial.

FIG 3.

Concordance of immunohistochemical staining (IHC) for the mismatch repair proteins with high-frequency microsatellite instability (MSI-H) or indeterminate MSI (MSI-I) status in patients with Lynch syndrome (LS). (A) Of 53 MSI-H tumors in patients with LS, IHC was performed on 89% (47 of 53) of tumors, with 98% concordance. One MSI-H colorectal tumor (MSIsensor score, 42) had intact expression of mismatch repair proteins. Among MSI-I tumors of patients with LS, IHC was performed on 77% (10 of 13), with 100% concordance. (B) IHC on a urothelial tumor of a patient with LS with an MSH2 germline mutation. Top panels demonstrate intact protein expression of MLH1 (left) and PMS2 (right), and bottom panels demonstrate absence of protein expression of MSH2 (left) and MSH6 (right). CRC, colorectal cancer.

FIG 4.

Tumor signatures of patients with Lynch syndrome by microsatellite instability (MSI) and mismatch repair (MMR) gene mutation status. Pie chart indicates the overall amount of all tumor types among microsatellite stable (MSS) group (blue; n = 14,020) and high-frequency microsatellite instability (MSI-H) and indeterminate MSI (MSI-I) group (gray; n = 1,025). Tumor type indicated on the x-axis. MSIsensor score indicated on the y-axis. Each point corresponds to a patient tumor in which germline analysis revealed an underlying MMR gene pathogenic or likely pathogenic variant. Color of each point indicates the specific MMR gene in which the variant was found, and shape of each point indicates the dominant tumor mutational signature (circle, MMR-deficiency [MMR-D] signature; triangle, could not be determined; square, other non–MMR-D signature). Among patients with Lynch syndrome in the MSI-H/I group (top panel), the majority (87.9%) of tumors had MMR-D dominant tumor mutational signatures, whereas the majority of patients with Lynch syndrome in the MSS group (89.2%; bottom panel) did not have MMR-D tumor signatures.