Investigation of an Alternative Marker for Hypermutability Evaluation in Different Tumors.

Anqi Chen,Lei Xiong,Shihan Xi,Chengtao Li,Jixi Li,Jinzhong Chen,Ruiyang Tao,Suhua Zhang,Chong Chen

doi:10.3390/genes12020197

Anqi Chen, Lei Xiong + Show 7 more

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https://doi.org/10.3390/genes12020197

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Abstract

A growing number of studies have shown immunotherapy to be a promising treatment strategy for several types of cancer. Short tandem repeats (STRs) have been proven to be alternative markers for the evaluation of hypermutability in gastrointestinal (GI) cancers. However, the status of STRs and microsatellite instability (MSI) in other tumors have not yet been investigated. To further compare STR and MSI alterations in different tumors, a total of 407 paired DNAs were analyzed from the following eight tumor types: breast cancer (BC), hepatocellular cancer (HCC), pancreatic cancer (PC), colorectal cancer (CRC), gastric cancer (GC), lung cancer (LC), esophageal cancer (EC), and renal cell cancer (RCC). The STR alteration frequencies varied in different tumors as expected. Interestingly, none of the patients possessed MSI-low (MSI-L) or MSI-high (MSI-H), except for the GI patients. The highest STR alteration was detected in EC (77.78%), followed by CRC (69.77%), HCC (63.33%), GC (54.55%), LC (48.00%), RCC (40.91%), BC (36.11%), and PC (25.71%). The potential cutoff for hypermutability was predicted using the published objective response rate (ORR), and the cutoff of LC and HCC was the same as that of GI cancers (26.32%). The cutoffs of 31.58% and 10.53% should be selected for BC and RCC, respectively. In summary, we compared MSI and STR status in eight tumor types, and predicted the potential threshold for hypermutability of BC, HCC, CRC, GC, LC, EC, and RCC.

Highlights

Microsatellite instability (MSI) has played an essential role in tumor research [1].In 2017, programmed death 1 (PD-1) inhibitor was approved by the Food and DrugAdministration (FDA) for patients with microsatellite instability-high (MSI-H) or mismatch repair protein deficiency (MMR-D) solid tumors, regardless of tumor site or histology [2].To screen MSI-H- or MMR-D-positive individuals, several methods have been generated, such as the commonly used mono- and di-nucleotide repeats [3], elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) [4,5], and the next-generation sequencing (NGS)-based tumor mutation burden (TMB) [6]
In our previous study [9], we investigated the MSI status of GI using six microsatellite markers, but performance in other tumor samples remains unknown
Low alteration rates were shown in breast cancer (BC) (5.12% ± 4.06%), hepatocellular cancer (HCC) (10.88% ± 10.70%), pancreatic cancer (PC) (5.67% ± 2.87%), and renal cell cancer (RCC) (6.05% ± 4.80%) (Figure 1)

Summary

Introduction

Microsatellite instability (MSI) has played an essential role in tumor research [1].In 2017, programmed death 1 (PD-1) inhibitor was approved by the Food and DrugAdministration (FDA) for patients with microsatellite instability-high (MSI-H) or mismatch repair protein deficiency (MMR-D) solid tumors, regardless of tumor site or histology [2].To screen MSI-H- or MMR-D-positive individuals, several methods have been generated, such as the commonly used mono- and di-nucleotide repeats [3], elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) [4,5], and the next-generation sequencing (NGS)-based tumor mutation burden (TMB) [6]. Microsatellite instability (MSI) has played an essential role in tumor research [1]. Administration (FDA) for patients with microsatellite instability-high (MSI-H) or mismatch repair protein deficiency (MMR-D) solid tumors, regardless of tumor site or histology [2]. To screen MSI-H- or MMR-D-positive individuals, several methods have been generated, such as the commonly used mono- and di-nucleotide repeats [3], elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) [4,5], and the next-generation sequencing (NGS)-based tumor mutation burden (TMB) [6]. The overexpression of PD-L1 should enrich the response of PD-1 inhibitors; samples deemed to be PD-L1positive do not always respond to immunotherapy [7]. A study with a large sample size showed that only 5–21% of patients suffering from gastrointestinal cancers (GI) comprised. MSI-H, which was far from the actual immune check point inhibitors’ response rate (~30%) [8]. 4.0/).

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