A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases

Objective DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer. Loss of DACH1 expression is associated with poor prognostic features and reduced overall survival in uterine cancer. In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population. Methods We obtained clinical and genomic data for 65 patients with endometrial cancer from the Markey Cancer Center (MCC). We examined the clinical attributes of the cancers by DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). Results Kentucky women with endometrial cancer had an increased frequency of DACH1 mutations (12/65 patients, 18.5%) compared to The Cancer Genome Atlas (TCGA) endometrial cancer population (25/586 patients, 3.8%) with p-value = 1.04E-05. DACH1 mutations were associated with increased tumor mutation count in both TCGA (median 65 vs. 8972, p-value = 7.35E-09) and our Kentucky population (490 vs. 2160, p-value = 6.0E-04). DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (24 vs. 6.02, p-value = 4.29E-05). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, and PMS2. DACH1 mutations were not associated with an increase in microsatellite instability at MCC (MSI-H) (p-value = 0.1342). Conclusions DACH1 mutations are prevalent in Kentucky patients with endometrial cancer. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 may be a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.

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Characteristics of Pan-Cancer Patients With Ultrahigh Tumor Mutation Burden

Frontiers in Oncology ◽

10.3389/fonc.2021.682017 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hong Yuan ◽

Jun Ji ◽

Min Shi ◽

Yan Shi ◽

Jing Liu ◽

...

Keyword(s):

Dna Damage ◽

Microsatellite Instability ◽

Dna Damage Repair ◽

Oncogenic Signaling ◽

Tumor Mutation Burden ◽

Dna Mismatch ◽

Damage Repair ◽

Mutation Burden ◽

Number Variation ◽

Group A

BackgroundTumor mutation burden has been proven to be a good predictor for the efficacy of immunotherapy, especially in patients with hypermutation. However, most research focused on the analysis of hypermutation in individual tumors, and there is a lack of integrated research on the hypermutation across different cancers. This study aimed to characterize hypermutated patients to distinguish between these patients and non-hypermutated patients.MethodsA total of 5,980 tumor samples involving 23 types of solid tumors from the in-house database were included in the study. Based on the cutoff value of tumor mutation burden (TMB), all samples were divided into hypermutated or non-hypermutated groups. Microsatellite instability status, PD-L1 expression and other mutation-related indicators were analyzed.ResultsAmong the 5,980 tumor samples, 1,164 were selected as samples with hypermutation. Compared with the non-hypermutated group, a significant increase in the mutation rates of DNA mismatch repair genes and polymerase genes was detected in the hypermutated group, and there was an overlap between high TMB and high microsatellite instability or high PD-L1. In addition, we found that EGFR, KRAS and PIK3CA had a high frequency of both single nucleotide variation and copy number variation mutations. These identified mutant genes were enriched in the oncogenic signaling pathway and the DNA damage repair pathway. At the same time, the somatic cell characteristics and distribution of the two groups were significantly different.ConclusionsThis study identified genetic and phenotypic characteristics of hypermutated tumors and demonstrated that DNA damage repair is critically involved in hypermutation.

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Impact of MLH1, PMS2, MSH2, and MSH6 alterations on tumor mutation burden (TMB) and PD-L1 expression in 1,057 microsatellite instability-high (MSI-H) tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.3572 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 3572-3572 ◽

Cited By ~ 2

Author(s):

Mohamed E. Salem ◽

Axel Grothey ◽

Edward S. Kim ◽

Joanne Xiu ◽

Richard M. Goldberg ◽

...

Keyword(s):

Microsatellite Instability ◽

Tumor Mutation Burden ◽

Mutation Burden

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A pan-cancer analysis of microsatellite instability as a predictor of Lynch syndrome in Chinese population.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1574 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1574-1574

Author(s):

Pinzhu Huang ◽

Yanhong Deng ◽

Jianwei Zhang ◽

Meijin Huang ◽

Jun Huang ◽

...

Keyword(s):

Lynch Syndrome ◽

Microsatellite Instability ◽

Chinese Population ◽

Germline Mutations ◽

Tumor Type ◽

Exact Test ◽

Targeted Next Generation Sequencing ◽

Repair Deficiency ◽

Mutation Burden ◽

Pan Cancer

1574 Background: Microsatellite instability (MSI) and mismatch repair deficiency (dMMR) are primarily tested in colorectal (CRC) and endometrial cancer (EC) to aid Lynch Syndrome (LS) diagnosis. A pan-cancer study presented at 2018 ASCO, however, revealed that up to 50% of LS patients had tumors not typically associated with LS, suggesting that patients with an MSI-high (MSI-H) phenotype should proceed to germline testing regardless of tumor type or family history. We thus set out to examine this potentially practice changing notion in Chinese population. Methods: MSI status and germline mutations in MLH1, MSH2, MSH6 and PMS2 genes were determined using a targeted next generation sequencing panel covering 100 MSI loci as well as MMR genes. Tumor mutation burden (TMB) levels were calculated for LS patients with MSI-H and MSS tumors, and intergroup differences were assessed using Mann Whitney U test or Fisher’s exact test. Results: Of 6,288 advanced tumors spanning > 27 cancers, 0.8% (48/6,288) were EC, 21.6% (1,362/6,288) were CRC, and 77.6% (4,878/6,288) were other malignancies. 3.6% (224/6,288) of the samples were found to be MSI-H and 3.5% (217/6,288) harbored MMR mutations (somatic and germline). Germline mutations indicative of LS were identified in 0.1% (8/6,064) of the MSS group and 17% (38/224) of the MSI-H group (p < 0.001). In contrast with the 2018 ASCO report, up to 63.8% of the 224 MSI-H tumors were CRC/EC, and only 8.9% (3/38) of the LS patients had MSI-H non-CRC/EC tumors (1 ovarian clear cell, 1 small bowel, and 1 gastric cancer). LS patients with non-CRC/EC tumors were more likely to be MSS compared to those with CRC/EC (70.0% vs 2.7%, p < 0.001). Alterations in MLH1/ MSH2 were present in 78.3% (36/46) of the LS patients, and they demonstrated significantly better correlation with a MSI-H phenotype than MSH6/PMS2 alterations (94.4% vs. 40.0%, p = 0.0005). Additionally, in line with previous reports showing co-ocurrence of MSI-H and high TMB in gastrointestinal cancers, the LS patients with MSS tumors had a significantly lower median TMB compared with the MSI-H population (4.6 muts/Mb vs. 91.8 muts/Mb, p < 0.001). Conclusions: Our study showed that in Chinese population, CRC/EC still predominated among LS-associated cancers, while non-CRC/EC LS patients were more likely to present with an MSS phenotype. The value of MSI-H/dMMR as a predictor of LS across different tumor types warrant further investigation.

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