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

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

References

[1] Kim JG, Shin S, Park J. Comparison between mononucleotide and dinucleotide marker panels in gastric cancer with loss of hMLH1 or hMSH2 expression. Int J Biol Markers 2017; 32(3): e352–e356

[2] Hamzehzadeh L, Yousefi M, Ghaffari SH. Colorectal cancer screening: a comprehensive review to recent non-invasive methods. Int J Hematol Oncol Stem Cell Res 2017; 11(3): 250–261

[3] Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357(6349): 409–413

[4] Vanderwalde A, Spetzler D, Xiao N, Gatalica Z, Marshall J. Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med 2018; 7(3): 746–756

[5] Chen W, Swanson BJ, Frankel WL. Molecular genetics of microsatellite-unstable colorectal cancer for pathologists. Diagn Pathol 2017; 12(1): 24

[6] Katona BW, Rustgi AK. Gastric cancer genomics: advances and future directions. Cell Mol Gastroenterol Hepatol 2017; 3(2): 211–217

[7] Yuza K, Nagahashi M, Watanabe S, Takabe K, Wakai T. Hypermutation and microsatellite instability in gastrointestinal cancers. Oncotarget 2017; 8(67): 112103–112115

[8] Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010; 138(6):2073–2087.e3

[9] Egoavil C, Alenda C, Castillejo A, Paya A, Peiro G, Sánchez-Heras AB, Castillejo MI, Rojas E, Barberá VM, Cigüenza S, Lopez JA, Piñero O, Román MJ, Martínez-Escoriza JC, Guarinos C, Perez-Carbonell L, Aranda FI, Soto JL. Prevalence of Lynch syndrome among patients with newly diagnosed endometrial cancers. PLoS One 2013; 8(11): e79737

[10] Liu X, Yang Z, Latchoumanin O, Qiao L. Antagonizing programmed death-1 and programmed death ligand-1 as a therapeutic approach for gastric cancer. Therap Adv Gastroenterol 2016; 9(6): 853–860

[11] Dawood S. The evolving role of immune oncology in colorectal cancer. Chin Clin Oncol 2018; 7(2): 17

[12] Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372(26): 2509–2520

[13] Böger C, Behrens HM, Mathiak M, Krüger S, Kalthoff H, Röcken C. PD-L1 is an independent prognostic predictor in gastric cancer of Western patients. Oncotarget 2016; 7(17): 24269–24283

[14] Hile SE, Shabashev S, Eckert KA. Tumor-specific microsatellite instability: do distinct mechanisms underlie the MSI-L and EMAST phenotypes? Mutat Res 2013; 743-744: 67–77

[15] Carethers JM. Microsatellite instability pathway and EMAST in colorectal cancer. Curr Colorectal Cancer Rep 2017; 13(1): 73–80

[16] Liu X, Meltzer SJ. Gastric cancer in the era of precision medicine. Cell Mol Gastroenterol Hepatol 2017; 3(3): 348–358

[17] Watson MM, Lea D, Rewcastle E, Hagland HR, Søreide K. Elevated microsatellite alterations at selected tetranucleotides in early-stage colorectal cancers with and without high-frequency microsatellite instability: same, same but different? Cancer Med 2016; 5(7): 1580–1587

[18] Devaraj B, Lee A, Cabrera BL, Miyai K, Luo L, Ramamoorthy S, Keku T, Sandler RS, McGuire KL, Carethers JM. Relationship of EMAST and microsatellite instability among patients with rectal cancer. J Gastrointest Surg 2010; 14(10): 1521–1528

[19] Laiho P, Launonen V, Lahermo P, Esteller M, Guo M, Herman JG, Mecklin JP, Järvinen H, Sistonen P, Kim KM, Shibata D, Houlston RS, Aaltonen LA. Low-level microsatellite instability in most colorectal carcinomas. Cancer Res 2002; 62(4): 1166–1170

[20] Pepiński W, Sołtyszewski I, Skawrońska M, Rogowski M, Zalewska R, Kozłowski L, Filipowski T, Janica J. Loss of heterozygosity (LOH)—implications for human genetic identification. Folia Histochem Cytobiol 2009; 47(1): 105–110

[21] Xiao C, Peng Z, Chen F, Yan H, Zhu B, Tai Y, Qiu P, Liu C, Song X, Wu Z, Chen L. Mutation analysis of 19 commonly used short tandem repeat loci in a Guangdong Han population. Leg Med (Tokyo) 2018; 32: 92–97

[22] Zhao SM, Li CT, Zhang SH, Li L. Application of number of matched STR loci and identical alleles in individual discrimination of colorectal cancer. J Foren Med (Fa Yi Xue Za Zhi) 2009;25(6):412–416, 420 (in China)

[23] Campanella NC, Scapulatempo-Neto C, Abrahão-Machado LF, Torres De Oliveira AT, Berardinelli GN, Guimarães DP, Reis RM. Lack of microsatellite instability in gastrointestinal stromal tumors. Oncol Lett 2017; 14(5): 5221–5228

[24] Kelly RJ. Immunotherapy for esophageal and gastric cancer. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 2017; 37:292–300

[25] Filoglu G, Bulbul O, Rayimoglu G, Yediay FE, Zorlu T, Ongoren S, Altuncul H. Evaluation of reliability on STR typing at leukemic patients used for forensic purposes. Mol Biol Rep 2014; 41(6): 3961–3972

[26] Xiao C, Peng Z, Chen F, Yan H, Zhu B, Tai Y, Qiu P, Liu C, Song X, Wu Z, Chen L. Mutation analysis of 19 commonly used short tandem repeat loci in a Guangdong Han population. Leg Med (Tokyo) 2018; 32:92–97

[27] Peloso GGP, Rosso R, Previdere C. Forensic evaluation of tetranucleotide STR instability in lung cancer. Int Congr Ser 2003; 1239(02): 719–721

[28] Edelmanna JLR, Heringb S, Hornc LC. Loss of heterozygosity and microsatellite instability of forensically used STR markers in human cervical carcinoma. International Congress Series 2004; 1261: 499–501

[29] Lin PS, Semrad TJ. Molecular testing for the treatment of advanced colorectal cancer: an overview. Methods Mol Biol 2018; 1765: 281–297

[30] Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 2017; 377(25): 2500–2501

[31] Pelotti S, Ceccardi S, Alù M, Lugaresi F, Trane R, Falconi M, Bini C, Cicognani A. Cancerous tissues in forensic genetic analysis. Genet Test 2007; 11(4): 397–400

[32] Copija A, Waniczek D, Witkoś A, Walkiewicz K, Nowakowska-Zajdel E. Clinical significance and prognostic relevance of microsatellite instability in sporadic colorectal cancer patients. Int J Mol Sci 2017; 18(1): E107

[33] George TJFGSJ, Gowen K, Kennedy M, Greenbowe JR, Schrock AB, Mahamed Ali S, Klempner SJ, Hezel AF, Ross JS, Stephens P, Miller VA, Fabrizio D. Tumor mutational burden as a potential biomarker for PD1/PD-L1 therapy in colorectal cancer. ASCO Annual Meeting Abstracts 2016; 3587

[34] Jin Z, Yoon HH. The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1. J Gastrointest Oncol 2016; 7(5): 771–788

[35] Søreide K. High-fidelity of five quasimonomorphic mononucleotide repeats to high-frequency microsatellite instability distribution in early-stage adenocarcinoma of the colon. Anticancer Res 2011; 31(3): 967–971

[36] Shemirani AIHM, Haghighi MM, Zadeh SM, Fatemi SR, Taleghani MY, Zali N, Akbari Z, Kashfi SM, Zali MR. Simplified MSI marker panel for diagnosis of colorectal cancer. Asian Pac J Cancer Prev 2011; 12(8): 2101–2104

[37] Macrae F, Harris M. Re: Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2005; 97(12): 936–937, author reply937–938

[38] Aaltonen LA, Peltomäki P, Leach FS, Sistonen P, Pylkkänen L, Mecklin JP, Järvinen H, Powell SM, Jen J, Hamilton SR, Clues to the pathogenesis of familial colorectal cancer. Science 1993; 260(5109): 812–816

[39] Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993; 260(5109): 816–819

[40] Perucho M. Correspondence re: C.R. Boland et al., A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res., 58: 5248-5257, 1998. Cancer Res 1999; 59(1): 249–256

Acknowledgements

This work was supported by the grants from National Key Research and Development Program of China (Nos. 2016YFA0500600 and 2016YFC0800703), the National Science Fund for Distinguished Young Scholars (No. 81625013), and General Program of National Natural Science Foundation of China (No. 81772028). The funders had no role in study design, data analysis, publishing decisions, or manuscript preparation.

Compliance with ethics guidelines

Anqi Chen, Suhua Zhang, Jixi Li, Chaoneng Ji, Jinzhong Chen, and Chengtao Li declare that they have no conflicts of interest. All conducted procedures were in accordance with the ethical standards of the human laboratory responsibility committee (institutions and countries).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s11684-019-0698-4 and is accessible for authorized users.

RIGHTS & PERMISSIONS

2019 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature