Landscape of Microsatellite Instability Across 39 Cancer Types

Abstract

Purpose: Microsatellite instability (MSI) is a pattern of hypermutation that occurs at genomic microsatellites and is caused by defects in the mismatch repair system. Mismatch repair deficiency that leads to MSI has been well described in several types of human cancer, most frequently in colorectal, endometrial, and gastric adenocarcinomas. MSI is known to be both predictive and prognostic, especially in colorectal cancer; however, current clinical guidelines only recommend MSI testing for colorectal and endometrial cancers. Therefore, less is known about the prevalence and extent of MSI among other types of cancer.

Methods: Using our recently published MSI-calling software, MANTIS, we analyzed whole-exome data from 11,139 tumor-normal pairs from The Cancer Genome Atlas and Therapeutically Applicable Research to Generate Effective Treatments projects and external data sources across 39 cancer types. Within a subset of these cancer types, we assessed mutation burden, mutational signatures, and somatic variants associated with MSI.

Results: We identified MSI in 3.8% of all cancers assessed-present in 27 of tumor types-most notably adrenocortical carcinoma (ACC), cervical cancer (CESC), and mesothelioma, in which MSI has not yet been well described. In addition, MSI-high ACC and CESC tumors were observed to have a higher average mutational burden than microsatellite-stable ACC and CESC tumors.

Conclusion: We provide evidence of as-yet-unappreciated MSI in several types of cancer. These findings support an expanded role for clinical MSI testing across multiple cancer types as patients with MSI-positive tumors are predicted to benefit from novel immunotherapies in clinical trials.

Conflict of interest statement

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc. Russell Bonneville No relationship to disclose Melanie A. Krook No relationship to disclose Esko A. Kautto No relationship to disclose Jharna Miya No relationship to disclose Michele R. Wing No relationship to disclose Hui-Zi Chen No relationship to disclose Julie W. Reeser No relationship to disclose Lianbo Yu No relationship to disclose Sameek Roychowdhury Stock and Other Ownership Interests: Johnson & Johnson (I) Research Funding: Takeda, Ignyta

Figures

Fig 1.

Prevalence of microsatellite instability (MSI) across 39 human cancer types. (A) MSI prevalence was detected across 39 tumor types. The total number of tumors and the percentage of cases called MSI-high (MSI-H) in each cohort is listed in Appendix Table A1. (B) The relative level of instability, as measured by MANTIS score, is shown across all 39 tumor types. Note that for chronic lymphocytic leukemia (CLL), the listed MSI prevalence in panel A is out of 279 patients, and all 338 tumors are shown in panel B. MANTIS threshold cutoff of 0.4 is depicted with a dashed line. ACC, adrenocortical carcinoma; AML, pediatric acute myeloid leukemia (TARGET); BLCA, bladder carcinoma; BRCA, breast carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; CTCL, cutaneous T-cell lymphoma; DLBC, diffuse large B-cell lymphoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LAML, acute myeloid leukemia (TCGA); LGG, lower-grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; MESO, mesothelioma; NBL, pediatric neuroblastoma; NPC, nasopharyngeal carcinoma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; READ, rectal adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TCGT, testicular germ cell tumor; THCA, thyroid carcinoma; THYM, thymoma; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma; UVM, uveal melanoma; WT, Wilms tumor.

Fig 2.

Kernel density plots of MANTIS scores within (A) adrenocortical carcinoma (ACC), (B) cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and (C) mesothelioma (MESO). The dotted line denotes the average distance threshold of 0.4, used by MANTIS to differentiate microsatellite instability high from microsatellite stable tumors. ACC: n = 92, kernel bandwidth (h) = 7.6e-3; CESC: n = 305, h = 9.4e-3; MESO: n = 83, h = 3.2e-3. KD plots for the other 36 cancer types analyzed are available in Appendix Fig A1.

Fig 3.

Somatic mutational burden correlates with microsatellite instability high (MSI-H) status within adrenocortical carcinoma (ACC) and cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Mutational burden is listed for (A) ACC, (B) CESC, and (C) mesothelioma (MESO). P values were calculated using the Welch two-sample t test of log-normalized absolute somatic mutation counts. Variant calling was performed by using MuTect (“Variant Calling” in Methods), and all passing variants were included (nonsynonymous or synonymous).

Fig A1.

Kernel density plots of MANTIS scores within 36 cancer types. The dotted line denotes the average distance threshold of 0.4, used by MANTIS to differentiate microsatellite instability high from microsatellite stable tumors. Uterine corpus endometrial carcinoma (UCEC): kernel bandwidth (h) = 4.89e-02. Colon adenocarcinoma (COAD): h = 1.13e-02. Stomach adenocarcinoma (STAD): h = 7.59e-03. Rectal adenocarcinoma (READ): h = 9.16e-03. Uterine carcinosarcoma (UCS): h = 4.10e-03. Pediatric high-risk Wilms tumor (WT): h = 1.27e-02. Esophageal carcinoma (ESCA): h = 5.02e-03. Breast carcinoma (BRCA): h = 7.41e-03. Kidney renal clear cell carcinoma (KIRC): h = 6.83e-03. Ovarian serous cystadenocarcinoma (OV): h = 5.23e-03. Cholangiocarcinoma (CHOL): h = 1.17e-02. Thymoma (THYM): h = 3.08e-03. Liver hepatocellular carcinoma (LIHC): h = 4.42e-03. Head and neck squamous cell carcinoma (HNSC): h = 4.25e-03. Sarcoma (SARC): h = 7.14e-03. Skin cutaneous melanoma (SKCM): h = 5.32e-03. Lung squamous cell carcinoma (LUSC): h = 7.13e-03. Prostate adenocarcinoma (PRAD): h = 5.31e-03. Lung adenocarcinoma (LUAD:): h = 5.74e-03. Bladder carcinoma (BLCA): h = 4.40e-03. Pediatric neuroblastoma (NBL:): h = 5.47e-03. Lower-grade glioma (LGG:): h = 4.32e-03. Chronic lymphocytic leukemia (CLL): h = 2.64e-03. Glioblastoma multiforme (GBM): h = 4.38e-03. Pediatric acute myeloid leukemia (AML): h = 6.13e-03. Cutaneous T-cell lymphoma (CTCL): h = 5.86e-03. Diffuse large B-cell lymphoma (DLBC): h = 6.68e-03. Kidney chromophobe (KICH): h = 3.34e-03. Kidney renal papillary cell carcinoma (KIRP): h = 5.16e-03. Acute myeloid leukemia (LAML): h = 5.28e-03. Nasopharyngeal carcinoma (NPC): h = 6.09e-03. Pancreatic adenocarcinoma (PAAD): h = 5.36e-03. Pheochromocytoma and paraganglioma (PCPG): h = 5.04e-03. Testicular germ cell tumor (TGCT): h = 3.40e-03. Thyroid carcinoma (THCA): h = 5.09e-03. Uveal melanoma (UVM): h = 3.06e-03.

Fig A2.

Patterns of mutational signatures (S) across microsatellite instability cancers: (A) adrenocortical carcinoma (ACC), (B) cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and (C) mesothelioma (MESO). Mutational signatures were called using deconstructSigs from pooled variants from all microsatellite instability high or microsatellite stable tumors within each cohort within ACC, CESC, and MESO. Unk., unknown.