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Large-scale analysis of KMT2 mutations defines a distinctive molecular subset with treatment implication in gastric cancer

Oncogene volume 40, pages 4894–4905 (2021)Cite this article

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Abstract

Frequent mutations of genes in the histone-lysine N-methyltransferase 2 (KMT2) family members were identified in gastric cancers (GCs). Understanding how gene mutations of KMT2 family affect cancer progression and tumor immune microenvironment may provide new treatment strategies. A total of 1245 GCs were analyzed using next-generation sequencing, whole transcriptome sequencing, immunohistochemistry (Caris Life Sciences, Phoenix, AZ). The overall mutation rate of genes in the KMT2 family was 10.6%. Compared to KMT2-wild-type GCs, genes involved in epigenetic modification, receptor tyrosine kinases/MAPK/PI3K, and DNA damage repair (DDR) pathways had higher mutation rates in KMT2-mutant GCs (p < 0.05). Significantly higher rates of high tumor mutational burden, microsatellite instability-high/mismatch-repair deficiency (dMMR), and PD-L1 positivity were observed in KMT2-mutant GCs (p < 0.01), compared to KMT2-wild-type GCs. The association between PD-L1 positivity and KMT2 mutations remained significant in the proficient-MMR and microsatellite stable subgroup. Based on transcriptome data from the TCGA, cell cycle, metabolism, and interferon-α/β response pathways were significantly upregulated in KMT2-mutant GCs than in KMT2-wild-type GCs. Patients with KMT2 mutation treated with immune checkpoint inhibitors had longer median overall survival compared to KMT2-wild-type patients with metastatic solid tumors (35 vs. 16 months, HR = 0.73, 95% CI: 0.62–0.87, p = 0.0003). In conclusion, this is the largest study to investigate the distinct molecular features between KMT2-mutant and KMT2-wild-type GCs to date. Our data indicate that GC patients with KMT2 mutations may benefit from ICIs and drugs targeting DDR, MAPK/PI3K, metabolism, and cell cycle pathways.

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Fig. 1: Overview of KMT2 mutations in GC.
Fig. 2: Molecular characteristics of KMT2-MT vs. KMT2-WT GC in the CARIS database.
Fig. 3: Genomic and transcriptomic characteristics of KMT2-MT vs. KMT2-WT GCs in the TCGA database.
Fig. 4: The association of KMT2 mutations with the efficacy of ICIs based on the MSKCC database.

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Data availability

Selected subset of analyzed data from CARIS are available on reasonable request and through collaborative investigations. The clinical information and tumor DNA/RNA sequencing data about TCGA and MSKCC cohort are available from websites (http://www.cbioportal.org, https://tcga.xenahubs.net).

References

  1. Feinberg AP, Koldobskiy MA, Gondor A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet. 2016;17:284–99.

    Article  CAS  Google Scholar 

  2. Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449–56.

    Article  CAS  Google Scholar 

  3. Zang ZJ, Cutcutache I, Poon SL, Zhang SL, McPherson JR, Tao J, et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet. 2012;44:570–4.

    Article  CAS  Google Scholar 

  4. Wang K, Yuen ST, Xu J, Lee S, Yan HHN, Shi ST, et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet. 2014;46:573–82.

    Article  CAS  Google Scholar 

  5. Ge S, Li B, Li Y, Li Z, Liu Z, Chen Z, et al. Genomic alterations in advanced gastric cancer endoscopic biopsy samples using targeted next-generation sequencing. AM J Cancer Res. 2017;7:1540–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen K, Yang D, Li X, Sun B, Song F, Cao W, et al. Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy. Proc Natl Acad Sci USA. 2015;112:1107–12.

    Article  CAS  Google Scholar 

  7. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9.

    Article  CAS  Google Scholar 

  8. Shilatifard A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem. 2006;75:243–69.

    Article  CAS  Google Scholar 

  9. Rao Rajesh C, Yali D. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat Rev Cancer. 2015;15:334–46.

    Article  CAS  Google Scholar 

  10. Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nat Biotechnol. 2010;28:1069–78.

    Article  CAS  Google Scholar 

  11. Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell. 2002;10:1107–17.

    Article  CAS  Google Scholar 

  12. Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007;7:823–33.

    Article  CAS  Google Scholar 

  13. Fagan Richard J, Dingwall Andrew K. COMPASS ascending: emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer. Cancer Lett. 2019;458:56–65.

    Article  CAS  Google Scholar 

  14. Cho S-J, Yoon C, Lee JH, Chang KK, Lin J, Young-Ho K, et al. KMT2C mutations in diffuse-type gastric adenocarcinoma promote epithelial-to-mesenchymal transition. Clin Cancer Res. 2018;24:6556–69.

    Article  CAS  Google Scholar 

  15. Theodoros R, Dimitris K, Margaritis A, Alexander P, Antonis K, Zoi K, et al. The lysine-specific methyltransferase KMT2C/MLL3 regulates DNA repair components in cancer. EMBO Rep. 2019;20:e46821.

    Google Scholar 

  16. Je EM, Lee SH, Yoo NJ, Lee SH. Mutational and expressional analysis of MLL genes in gastric and colorectal cancers with microsatellite instability. Neoplasma. 2012;60:188–95.

    Article  Google Scholar 

  17. Kantidakis T, Saponaro M, Mitter R, Horswell S, Kranz A, Boeing S, et al. Mutation of cancer driver MLL2 results in transcription stress and genome instability. Genes Dev. 2016;30:408–20.

    Article  CAS  Google Scholar 

  18. Wang G, Chow RD, Zhu L, Bai Z, Ye L, Zhang F, et al. CRISPR-GEMM pooled mutagenic screening identifies KMT2D as a major modulator of immune checkpoint blockade. Cancer Discov. 2020;10:1912–33.

    Article  CAS  Google Scholar 

  19. Jia Q, Wang J, He N, He J, Zhu B. Titin mutation associated with responsiveness to checkpoint blockades in solid tumors. JCI Insight. 2019;4:e127901.

    Article  Google Scholar 

  20. Li X, Pasche B, Zhang W, Chen K. Association of MUC16 mutation with tumor mutation load and outcomes in patients with gastric cancer. JAMA Oncol. 2018;4:1691–8.

    Article  Google Scholar 

  21. Chen H, Chong W, Wu Q, Yao Y, Mao M, Wang X. Association of LRP1B mutation with tumor mutation burden and outcomes in melanoma and non-small cell lung cancer patients treated with immune check-point blockades. Front Immunol. 2019;10:1113.

    Article  CAS  Google Scholar 

  22. Okamura R, Kato S, Lee S, Jimenez RE, Sicklick JK, Kurzrock R. ARID1A alterations function as a biomarker for longer progression-free survival after anti-PD-1/PD-L1 immunotherapy. J Immunother Cancer. 2020;8:e000438.

    Article  Google Scholar 

  23. Wang F, Wei XL, Wang FH, Xu N, Shen L, Dai GH, et al. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432. Ann Oncol. 2019;30:1479–86.

    Article  CAS  Google Scholar 

  24. Bang YJ, Van CE, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97.

    Article  CAS  Google Scholar 

  25. Italiano A, Soria JC, Toulmonde M, Michot JM, Lucchesi C, Varga A, et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 2018;19:649–59.

    Article  CAS  Google Scholar 

  26. Wang Lu Z, Zibo O, Patrick A, Fantini D, Marshall SA, Rendleman EJ, et al. Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy. Nat Med. 2018;24:758–69.

    Article  CAS  Google Scholar 

  27. Park Y, Chui MH, Suryo Rahmanto Y, Yu ZC, Shamanna RA, Bellani MA, et al. Loss of ARID1A in tumor cells renders selective vulnerability to combined ionizing radiation and PARP inhibitor therapy. Clin Cancer Res. 2019;25:5584–94.

    Article  CAS  Google Scholar 

  28. Yang L, Yang G, Ding Y, Huang Y, Liu S, Zhou L, et al. Combined treatment with PI3K inhibitor BKM120 and PARP inhibitor olaparib is effective in inhibiting the gastric cancer cells with ARID1A deficiency. Oncol Rep. 2018;40:479–87.

    CAS  PubMed  Google Scholar 

  29. Lv S, Wen H, Shan X, Li J, Wu Y, Yu X, et al. Loss of KMT2D induces prostate cancer ROS-mediated DNA damage by suppressing the enhancer activity and DNA binding of antioxidant transcription factor FOXO3. Epigenetics. 2019;14:1194–208.

    Article  Google Scholar 

  30. Bang YJ, Xu RH, Chin K, Lee KW, Park SH, Rha SY, et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1637–51.

    Article  CAS  Google Scholar 

  31. Mitani S, Kawakami H. Emerging targeted therapies for HER2 positive gastric cancer that can overcome trastuzumab resistance. Cancers (Basel). 2020;12:400.

    Article  Google Scholar 

  32. Alam HT, Ming M, Mayinuer D, Shilpa S, Kumar M, Han CY, et al. KMT2D deficiency impairs super-enhancers to confer a glycolytic vulnerability in lung cancer. Cancer Cell. 2020;37:599–617.

    Article  CAS  Google Scholar 

  33. Mardis ER. Neoantigens and genome instability: impact on immunogenomic phenotypes and immunotherapy response. Genome Med. 2019;11:71.

    Article  Google Scholar 

  34. Witt DA, Donson AM, Amani V, Moreira DC, Sanford B, Hoffman LM, et al. Specific expression of PD-L1 in RELA-fusion supratentorial ependymoma: Implications for PD-1-targeted therapy. Pediatr Blood Cancer. 2018;65:e26960.

    Article  Google Scholar 

  35. Tokunaga R, Xiu J, Johnston C, Goldberg RM, Philip PA, Seeber A, et al. Molecular profiling of appendiceal adenocarcinoma and comparison with right-sided and left-sided colorectal cancer. Clin Cancer Res. 2019;25:3096–103.

    Article  CAS  Google Scholar 

  36. Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21:1353–65.

    Article  CAS  Google Scholar 

  37. Becht E, Giraldo NA, Lacroix L, Buttard B, Elarouci N, Petitprez F. et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 2016;17:218.

    Article  Google Scholar 

  38. Salem ME, Puccini A, Xiu J, Raghavan D, Lenz HJ, Korn WM, et al. Comparative molecular analyses of esophageal squamous cell carcinoma, esophageal adenocarcinoma, and gastric adenocarcinoma. Oncologist. 2018;23:1319–27.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank the staff members of the TCGA Research Network and MSKCC and the cBioportal; as well as all the authors for making their valuable research data public.

Funding

This work was supported by the National Cancer Institute [P30CA 014089 to H-JL], Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, the V Foundation for Cancer Research, Eddie Money Research Fund.

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Authors and Affiliations

  1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China

    Jingyuan Wang

  2. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Jingyuan Wang, Francesca Battaglin, Hiroyuki Arai, Natsuko Kawanishi, Shivani Soni, Wu Zhang & Heinz-Josef Lenz

  3. Caris Life Sciences, Phoenix, AZ, USA

    Joanne Xiu, Yasmine Baca, Zoran Gatalica & W. Michael Korn

  4. Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Joshua Millstein

  5. Department of Translational Genomics, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Bodour Salhia

  6. West Virginia University Cancer Institute, Morgantown, WV, USA

    Richard M. Goldberg

  7. Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Philip A. Philip & Anthony F. Shields

  8. Department of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria

    Andreas Seeber

  9. Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA

    Jimmy J. Hwang

  10. Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    John L. Marshall

  11. Fox Chase Cancer Center, Philadelphia, PA, USA

    Igor Astsaturov

  12. University of Miami/Sylvester Comprehensive Cancer Center, Miami, FL, USA

    A. Craig Lockhart

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Contributions

Conception and design: JW, JX, YB, WMK, and H-JL. Development of methodology: JW, JX, YB, WZ, and H-JL. Acquisition of data (carried out experiments, acquired, and managed patients, provided facilities, etc.): JW, JX, YB, BS, RMG, PAP, AS, JJH, AFS, JLM, IA, ACL, ZG, WMK, FB, HA, NK, SS, WZ, and H-JL. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): JW, JX, YB, WZ, WMK, and H-JL. Writing, review, and/or revision of the manuscript: JW, JX, BS, WMK, FB, HA, NK, SS, WZ, JM, and H-JL. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): JW, JX, and H-JL. Study supervision: H-JL.

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Correspondence to Heinz-Josef Lenz.

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Conflict of interest

H-JL reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. JX, YB, ZG, and WMK are employees of Caris Life Sciences. AFS reports funding for research, travel, and the speakers bureau from Caris Life Sciences. All remaining authors have declared no conflicts of interest.

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Wang, J., Xiu, J., Baca, Y. et al. Large-scale analysis of KMT2 mutations defines a distinctive molecular subset with treatment implication in gastric cancer. Oncogene 40, 4894–4905 (2021). https://doi.org/10.1038/s41388-021-01840-3

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