Top

Published in:

Open Access 01-12-2021 | Colorectal Cancer | Research

Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer

Authors: Zijian Chen, Zenghong Huang, Yanxin Luo, Qi Zou, Liangliang Bai, Guannan Tang, Xiaolin Wang, Guangwen Cao, Meijin Huang, Jun Xiang, Huichuan Yu

Published in: Journal of Translational Medicine | Issue 1/2021

Abstract

Background

Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC).

Methods

An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP).

Results

The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma.

Conclusions

This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.

Available only for authorised users

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2018;68(6):394–424.CrossRef

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMed

Mahar AL, Compton C, Halabi S, Hess KR, Weiser MR, Groome PA. Personalizing prognosis in colorectal cancer: a systematic review of the quality and nature of clinical prognostic tools for survival outcomes. J Surg Oncol. 2017;116(8):969–82.PubMedPubMedCentralCrossRef

Kocarnik JM, Shiovitz S, Phipps AI. Molecular phenotypes of colorectal cancer and potential clinical applications. Gastroenterol Rep. 2015;3(4):269–76.

Abdel Ghafar MT, Gharib F, Abdel-Salam S, Elkhouly RA, Elshora A, Shalaby KH, et al. Role of serum Metadherin mRNA expression in the diagnosis and prediction of survival in patients with colorectal cancer. Mol Biol Rep. 2020;47(4):2509–19.PubMedCrossRef

Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol. 2017;35(10):1086–95.PubMedPubMedCentralCrossRef

Wolff RK, Hoffman MD, Wolff EC, Herrick JS, Sakoda LC, Samowitz WS, et al. Mutation analysis of adenomas and carcinomas of the colon: early and late drivers. Genes Chromosomes Cancer. 2018;57(7):366–76.PubMedPubMedCentralCrossRef

Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358(11):1148–59.PubMedCrossRef

Chang SY, Kuo CC, Wu CC, Hsiao CW, Hu JM, Hsu CH, et al. NKX6.1 hypermethylation predicts the outcome of stage II colorectal cancer patients undergoing chemotherapy. Genes Chromosomes Cancer. 2018;57(5):268–77.PubMedCrossRef

10.

Graule J, Uth K, Fischer E, Centeno I, Galvan JA, Eichmann M, et al. CDX2 in colorectal cancer is an independent prognostic factor and regulated by promoter methylation and histone deacetylation in tumors of the serrated pathway. Clin Epigenet. 2018;10(1):120.CrossRef

11.

Luo Y, Kaz AM, Kanngurn S, Welsch P, Morris SM, Wang J, et al. NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer. PLoS Genet. 2013;9(7):e1003552.PubMedPubMedCentralCrossRef

12.

Khotskaya YB, Holla VR, Farago AF, Mills Shaw KR, Meric-Bernstam F, Hong DS. Targeting TRK family proteins in cancer. Pharmacol Ther. 2017;173:58–66.PubMedCrossRef

13.

Scott LJ. Larotrectinib: first global approval. Drugs. 2019;79(2):201–6.PubMedCrossRef

14.

Cho YA, Chung JM, Ryu H, Kim EK, Cho BC, Yoon SO. Investigating Trk protein expression between oropharyngeal and non-oropharyngeal squamous cell carcinoma: clinical implications and possible roles of human papillomavirus infection. Cancer Res Treat. 2019;51(3):1052–63.PubMedCrossRef

15.

Kamiya A, Inokuchi M, Otsuki S, Sugita H, Kato K, Uetake H, et al. Prognostic value of tropomyosin-related kinases A, B, and C in gastric cancer. Clin Transl Oncol. 2016;18(6):599–607.PubMedCrossRef

16.

Leveque R, Corbet C, Aubert L, Guilbert M, Lagadec C, Adriaenssens E, et al. ProNGF increases breast tumor aggressiveness through functional association of TrkA with EphA2. Cancer Lett. 2019;449:196–206.PubMedCrossRef

17.

Xu Z. Tumor-derived exosomes educate fibroblasts to promote salivary adenoid cystic carcinoma metastasis via NGF-NTRK1 pathway. Oncol Lett. 2019;18(4):4082–91.PubMedPubMedCentral

18.

Yang X, Shen H, Buckley B, Chen Y, Yang N, Mussell AL, et al. NTRK1 is a positive regulator of YAP oncogenic function. Oncogene. 2019;38(15):2778–87.PubMedCrossRef

19.

Youssef G, Gillett C, Rampling D, Chagtai T, Virasami A, Barton J, et al. The presence of Y674/Y675 phosphorylated NTRK1 via TP53 repression of PTPN6 expression as a potential prognostic marker in neuroblastoma. Hum Pathol. 2019;86:182–92.PubMedCrossRef

20.

Xu Y, Jiang WG, Wang HC, Martin T, Zeng YX, Zhang J, Qi YS. BDNF activates TrkB/PLCγ1 signaling pathway to promote proliferation and invasion of ovarian cancer cells through inhibition of apoptosis. Eur Rev Med Pharmacol Sci. 2019;23:5093–100.PubMed

21.

Zhou Y, Sinha S, Schwartz JL, Adami GR. A subtype of oral, laryngeal, esophageal, and lung, squamous cell carcinoma with high levels of TrkB-T1 neurotrophin receptor mRNA. BMC Cancer. 2019;19(1):607.PubMedPubMedCentralCrossRef

22.

Contreras-Zarate MJ, Day NL, Ormond DR, Borges VF, Tobet S, Gril B, et al. Estradiol induces BDNF/TrkB signaling in triple-negative breast cancer to promote brain metastases. Oncogene. 2019;38(24):4685–99.PubMedPubMedCentralCrossRef

23.

Li W, Lu Y, Yu X, Yong M, Ma D, Gao Q. Detection of exosomal tyrosine receptor kinase B as a potential biomarker in ovarian cancer. J Cell Biochem. 2019;120(4):6361–9.PubMedCrossRef

24.

Wang X, Xu Z, Chen X, Ren X, Wei J, Zhou S, et al. A tropomyosin receptor kinase family protein, NTRK2 is a potential predictive biomarker for lung adenocarcinoma. PeerJ. 2019;7:e7125.PubMedPubMedCentralCrossRef

25.

Deluche E, Bessette B, Durand S, Caire F, Rigau V, Robert S, et al. CHI3L1, NTRK2, 1p/19q and IDH status predicts prognosis in glioma. Cancers. 2019;11(4):544.PubMedCentralCrossRef

26.

Meng L, Liu B, Ji R, Jiang X, Yan X, Xin Y. Targeting the BDNF/TrkB pathway for the treatment of tumors. Oncol Lett. 2019;17(2):2031–9.PubMed

27.

Thomaz A, Pinheiro KV, Souza BK, Gregianin L, Brunetto AL, Brunetto AT, et al. Antitumor activities and cellular changes induced by TrkB inhibition in medulloblastoma. Front Pharmacol. 2019;10:698.PubMedPubMedCentralCrossRef

28.

Jin W, Kim GM, Kim MS, Lim MH, Yun C, Jeong J, et al. TrkC plays an essential role in breast tumor growth and metastasis. Carcinogenesis. 2010;31(11):1939–47.PubMedCrossRef

29.

Bu JY, Lv WZ, Liao YF, Xiao XY, Lv BJ. Long non-coding RNA LINC00978 promotes cell proliferation and tumorigenesis via regulating microRNA-497/NTRK3 axis in gastric cancer. Int J Biol Macromol. 2019;123:1106–14.PubMedCrossRef

30.

Bouzas-Rodriguez J, Cabrera JR, Delloye-Bourgeois C, Ichim G, Delcros JG, Raquin MA, et al. Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis. J Clin Invest. 2010;120(3):850–8.PubMedPubMedCentralCrossRef

31.

Foerster Y, Stover T, Wagenblast J, Diensthuber M, Balster S, Gabrielpillai J, et al. Relevance of neurotrophin receptors CD271 and TrkC for prognosis, migration, and proliferation in head and neck squamous cell carcinoma. Cells. 2019;8(10):1167.PubMedCentralCrossRef

32.

Behrouz Sharif S, Hashemzadeh S, Mousavi Ardehaie R, Eftekharsadat A, Ghojazadeh M, Mehrtash AH, et al. Detection of aberrant methylated SEPT9 and NTRK3 genes in sporadic colorectal cancer patients as a potential diagnostic biomarker. Oncol Lett. 2016;12(6):5335–43.PubMedPubMedCentralCrossRef

33.

Li Z, Takenobu H, Setyawati AN, Akita N, Haruta M, Satoh S, et al. EZH2 regulates neuroblastoma cell differentiation via NTRK1 promoter epigenetic modifications. Oncogene. 2018;37(20):2714–27.PubMedPubMedCentralCrossRef

34.

Palani M, Arunkumar R, Vanisree AJ. Methylation and expression patterns of tropomyosin-related kinase genes in different grades of glioma. Neuromol Med. 2014;16(3):529–39.CrossRef

35.

Chmelarova M, Dvorakova E, Spacek J, Laco J, Mzik M, Palicka V. Promoter methylation of GATA4, WIF1, NTRK1 and other selected tumour suppressor genes in ovarian cancer. Folia Biol. 2013;59(2):87–92.

36.

Yamada Y, Toyota M, Hirokawa Y, Suzuki H, Takagi A, Matsuzaki T, et al. Identification of differentially methylated CpG islands in prostate cancer. Int J Cancer. 2004;112(5):840–5.PubMedCrossRef

37.

Cancer Genome Atlas. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7.CrossRef

38.

Kwon Y, Park M, Jang M, Yun S, Kim WK, Kim S, et al. Prognosis of stage III colorectal carcinomas with FOLFOX adjuvant chemotherapy can be predicted by molecular subtype. Oncotarget. 2017;8(24):39367–81.PubMedPubMedCentralCrossRef

39.

Hu Y, Gaedcke J, Emons G, Beissbarth T, Grade M, Jo P, et al. Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery. Genes Chromosomes Cancer. 2018;57(3):140–9.PubMedCrossRef

40.

Marisa L, de Reynies A, Duval A, Selves J, Gaub MP, Vescovo L, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013;10(5):e1001453.PubMedPubMedCentralCrossRef

41.

Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, et al. Neoadjuvant modified FOLFOX6 with or without radiation versus fluorouracil plus radiation for locally advanced rectal cancer final results of the Chinese FOWARC Trial. J Clin Oncol. 2019;37(34):3223–33.PubMedPubMedCentralCrossRef

42.

Benson AB, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, et al. NCCN Guidelines Insights: colon Cancer, Version 2.2018. J Natl Compr Canc Netw. 2018;16(4):359–69.PubMedCrossRef

43.

Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, et al. NCCN Guidelines Insights: rectal Cancer, Version 6.2020. J Natl Compr Canc Netw. 2020;18(7):806–15.PubMedCrossRef

44.

Yu H, Bai L, Tang G, Wang X, Huang M, Cao G, et al. Novel assay for quantitative analysis of DNA methylation at single-base resolution. Clin Chem. 2019;65(5):664–73.PubMedCrossRef

45.

Luo Y, Tsuchiya KD, Il Park D, Fausel R, Kanngurn S, Welcsh P, et al. RET is a potential tumor suppressor gene in colorectal cancer. Oncogene. 2012;32:2037.PubMedPubMedCentralCrossRef

46.

Fu XH, Chen ZT, Wang WH, Fan XJ, Huang Y, Wu XB, et al. KRAS G12V mutation is an adverse prognostic factor of Chinese gastric cancer patients. J Cancer. 2019;10(4):821–8.PubMedPubMedCentralCrossRef

47.

Weiser MR, Landmann RG, Kattan MW, Gonen M, Shia J, Chou J, et al. Individualized prediction of colon cancer recurrence using a nomogram. J Clin Oncol. 2008;26(3):380–5.PubMedCrossRef

48.

Weiser MR, Gönen M, Chou JF, Kattan MW, Schrag D. Predicting survival after curative colectomy for Cancer: individualizing colon cancer staging. J Clin Oncol. 2011;29(36):4796–802.PubMedPubMedCentralCrossRef

49.

Deckers IA, Schouten LJ, Van Neste L, van Vlodrop IJ, Soetekouw PM, Baldewijns MM, et al. Promoter methylation of CDO1 identifies clear-cell renal cell cancer patients with poor survival outcome. Clin Cancer Res. 2015;21(15):3492–500.PubMedPubMedCentralCrossRef

50.

Zhao S, Fan NF, Chen XH, Zhuo CH, Xu CW, Lin RB. Long noncoding RNA PVT1-214 enhances gastric cancer progression by upregulating TrkC expression in competitively sponging way. Eur Rev Med Pharmacol Sci. 2019;23:4173–84.PubMed

51.

Marino FZ, Pagliuca F, Ronchi A, Cozzolino I, Montella M, Berretta M, et al. NTRK fusions, from the diagnostic algorithm to innovative treatment in the era of precision medicine. Int J Mol Sci. 2020;21(10):3718.CrossRef

Title: Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer
Authors: Zijian Chen
Zenghong Huang
Yanxin Luo
Qi Zou
Liangliang Bai
Guannan Tang
Xiaolin Wang
Guangwen Cao
Meijin Huang
Jun Xiang
Huichuan Yu
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Journal of Translational Medicine / Issue 1/2021
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-021-02740-6

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Retraction Note to: microRNA-128 mediates CB1 expression and regulates NF-KB/p-JNK axis to influence the occurrence of diabetic bladder disease

Effect of antibiotic-induced intestinal dysbacteriosis on bronchopulmonary dysplasia and related mechanisms

A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation

Gene alterations as predictors of radiation-induced toxicity in head and neck squamous cell carcinoma

Correction to: Identification of key biomarkers and immune infiltration in systemic lupus erythematosus by integrated bioinformatics analysis

Identification of prognostic values defined by copy number variation, mRNA and protein expression of LANCL2 and EGFR in glioblastoma patients

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials