Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit

doi:10.1007/s11684-019-0698-4

Front. Med.

2020, Vol. 14

Issue (1) : 101-111 https://doi.org/10.1007/s11684-019-0698-4

RESEARCH ARTICLE

Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit

Anqi Chen^1,², Suhua Zhang², Jixi Li¹, Chaoneng Ji¹, Jinzhong Chen¹(

), Chengtao Li²(

)

¹. State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, China
². Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Institute of Forensic Sciences, Ministry of Justice, Shanghai 200063, China

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Abstract

Growing evidence suggests that somatic hypermutational status and programmed cell death-1 overexpression are potential predictive biomarkers indicating treatment benefits from immunotherapy using immune checkpoint inhibitors. However, biomarker-matched trials are still limited, and many of the genomic alterations remain difficult to target. To isolate the potential somatic hypermutational tumor from microsatellite instability low/microsatellite stability (MSI-L/MSS) cases, we employed two commercial kits to determine MSI and forensic short tandem repeat (STR) alternations in 250 gastrointestinal (GI) tumors. Three types of forensic STR alternations, namely, allelic loss, Aadd, and Anew, were identified. 62.4% (156/250) of the patients with GI exhibited STR alternation, including 100% (15/15) and 60% (141/235) of the microsatellite high instability and MSI-L/MSS cases, respectively. 30% (75/250) of the patients exhibited STR instability with more than 26.32% (26.32%–84.21%) STR alternation. The cutoff with 26.32% of the STR alternations covered all 15 MSI cases and suggested that it might be a potential threshold. Given the similar mechanism of the mutations of MSI and forensic STR, the widely used forensic identifier STR kit might provide potential usage for identifying hypermutational status in GI cancers.

Keywords mismatch repair protein deficiency (MMR-D) microsatellite instability (MSI) short tandem repeats (STR) gastrointestinal tumor hypermutability

Corresponding Author(s): Jinzhong Chen,Chengtao Li

Just Accepted Date: 24 June 2019 Online First Date: 01 August 2019 Issue Date: 02 March 2020

Cite this article:

Anqi Chen,Suhua Zhang,Jixi Li, et al. Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit[J]. Front. Med., 2020, 14(1): 101-111.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0698-4
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I1/101

Fig.1 MSI analysis of control and tumor DNA samples by using 6-monomorphic mononucleotide repeat loci markers, namely, NR-21, BAT-26, NR-27, BAT-25, NR-24, and MONO-27. (A) MSI positive sample (Sample No. 48). (B) MSI negative sample (Sample No. 237). The vertical and horizontal axes refer to allele sizes and fluorescence intensity, respectively.

Fig.2 Electropherogram of the STR abnormalities. (A) Electropherogram of L at locus D8S1179 (Sample No. 130). Upper panel, reference DNA showing a profile of alleles of 13 and 14; lower panel, partial loss of allele 14. (B) Electropherogram of Aadd at locus D16S539 (Sample No. 106). Upper panel, reference DNA showing a profile of alleles of 10 and 12; lower panel, additional allele 13. (C) Electropherogram of Anew at locus D18S51 (Sample No. 165). Upper panel, reference DNA showing a profile of alleles of 15 and 16; lower panel, new alleles of 13 and 14. The vertical and horizontal axes refer to allele sizes and fluorescence intensity, respectively.

Fig.3 STR analysis of control and tumor DNA of an MSI-positive sample by using 19 autosomal STR markers (Sample No. 48). The vertical and horizontal axes refer to allele sizes and fluorescence intensity, respectively.

Tab.1 Frequency of MSI in 250 gastrointestinal cancer samples

Tab.2 STR status of all investigated MSI positive samples (n = 19)

Tab.3 Difference of STR over the three types of alternation type in all investigated cancer types

Tab.4 Difference of MSI over the six loci in all investigated cancer types

Tab.5 STR alternations per locus in 250 GI samples

Tab.6 Characteristics of 19 STR loci

Fig.4 Frequency of genetic instabilities at each STR locus.

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