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Prediction of sorafenib treatment–related gene expression for hepatocellular carcinoma: preoperative MRI and histopathological correlation

  • Zhi Dong
  • Kun Huang
  • Bing Liao
  • Huasong Cai
  • Yu Dong
  • Mengqi Huang
  • Xiaoqi Zhou
  • Yingmei Jia
  • Ling Xu
  • Yanji Luo
  • Zi-Ping LiEmail author
  • Shi-Ting FengEmail author
Magnetic Resonance
  • 54 Downloads

Abstract

Purpose

To investigate the feasibility of prediction for targeted therapy-related gene expression in hepatocellular carcinoma (HCC) using preoperative gadoxetic acid-enhanced magnetic resonance imaging (MRI).

Materials and methods

Ninety-one patients (81 men, mean age 53.9 ± 12 years) with solitary HCC who underwent preoperative enhanced MRI were retrospectively analyzed. Features including tumor size, signal homogeneity, tumor capsule, tumor margin, intratumoral vessels, peritumor enhancement, peritumor hypointensity, signal intensity ratio on DWI, T1 relaxation times, and the reduction rate between pre- and post-contrast enhancement images were assessed. The operation and histopathological evaluation were performed within 2 weeks after MRI examination (mean time 7 days). The expression levels of BRAF, RAF1, VEGFR2, and VEGFR3 were evaluated. The associations between these imaging features and gene expression levels were investigated.

Results

Tumor incomplete capsules or non-capsules (p = 0.001) and intratumoral vessels (p = 0.002) were significantly associated with BRAF expression, and tumor incomplete capsules or non-capsules (p = 0.001) and intratumoral vessels (p = 0.013) with RAF1 expression. There was no significant association between the expression of VEGFR2, VEGFR3, and all examined MRI features. Multivariate logistic regression showed that incomplete tumor capsule (p = 0.002) and non-capsule (p = 0.004) were independent risk factors of HCC with high BRAF expression; incomplete tumor capsule (p < 0.001) and non-capsule (p = 0.040) were independent risk factors of HCC with high RAF1 expression.

Conclusion

The presence of incomplete capsule or intratumoral vessels and the absence of capsule are potential indicators of high BRAF and RAF1 expression. Gadoxetic acid–enhanced MRI may facilitate the choice of gene therapy for patients with HCC.

Key Points

• Incomplete tumor capsule and non-capsule were independent risk factors of HCC with high BRAF and RAF1 expression.

• The presence of intratumoral vessels was a potential indicator of high BRAF and RAF1 expression.

• Gadoxetic acid-enhanced MRI may be a predictor of efficacy of treatment with sorafenib.

Keywords

Magnetic resonance imaging Hepatocellular carcinoma Gene therapy Gadoxetic acid 

Abbreviations

ADC

Apparent diffusion coefficient

DWI

Diffusion-weighted image

ECM

Extracellular matrix

HCC

Hepatocellular carcinoma

MMP

Matrix metalloproteinase

OR

Odds ratio

T1WI

T1-weighted image

T2WI

T2-weighted image

T1D%

Percentage of decrease in T1 relaxation time in the hepatocellular phase

T1E

T1 Relaxation time in the hepatocellular phase

T1N

T1 Relaxation time on non-enhanced scan

VEGFR

Vascular endothelial growth factor receptor

VIBE

Volume interpolated breath-hold examination

Notes

Funding

This work was funded by the National Natural Science Foundation of China (81771908, 81571750, 81770654).

Compliance with ethical standards

Guarantor

The scientific guarantor of this publication is Zi-Ping Li.

Conflict of interest

The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

Statistics and biometry

One of the authors has significant statistical expertise.

Informed consent

Written informed consent was obtained from all subjects (patients) in this study.

Ethical approval

Institutional Review Board approval was obtained.

Methodology

• retrospective

• observational

• performed at one institution

Supplementary material

330_2018_5882_MOESM1_ESM.docx (24 kb)
ESM 1 (DOCX 24 kb)

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108Google Scholar
  2. 2.
    Chen W, Zheng R, Baade PD et al (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66(2):115–132CrossRefGoogle Scholar
  3. 3.
    Kudo M (2012) Treatment of advanced hepatocellular carcinoma with emphasis on hepatic arterial infusion chemotherapy and molecular targeted therapy. Liver Cancer 1(2):62–70CrossRefGoogle Scholar
  4. 4.
    Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390CrossRefGoogle Scholar
  5. 5.
    Cheng AL, Kang YK, Chen Z et al (2009) Efficacy and safety of Sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10(1):25–34CrossRefGoogle Scholar
  6. 6.
    Cammà C, Cabibbo G, Petta S et al (2013) Cost-effectiveness of sorafenib treatment in field practice for patients with hepatocellular carcinoma. Hepatology 57(3):1046–1054CrossRefGoogle Scholar
  7. 7.
    Burrell RA, Mcgranahan N, Bartek J, Swanton C (2013) The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501(7467):338–345Google Scholar
  8. 8.
    Bedard PL, Hansen AR, Ratain MJ, Siu LL (2013) Tumour heterogeneity in the clinic. Nature 501(7467):355–364Google Scholar
  9. 9.
    Colombino M, Sperlongano P, Izzo F et al (2012) BRAF and PIK3CA genes are somatically mutated in hepatocellular carcinoma among patients from South Italy. Cell Death Dis 3:e259CrossRefGoogle Scholar
  10. 10.
    Chiang DY, Villanueva A, Hoshida Y et al (2008) Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 68(16):6779–6788CrossRefGoogle Scholar
  11. 11.
    Kan Z, Zheng H, Liu X et al (2013) Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res 23(9):1422–1433CrossRefGoogle Scholar
  12. 12.
    Lei J, Zhong J, Hao J et al (2016) Hepatocellular carcinoma cases with high levels of c-Raf-1 expression may benefit from postoperative adjuvant sorafenib after hepatic resection even with high risk of recurrence. Oncotarget 7(27):42598–42607CrossRefGoogle Scholar
  13. 13.
    Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109CrossRefGoogle Scholar
  14. 14.
    Wan PT, Garnett MJ, Roe SM et al (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116(6):855–867CrossRefGoogle Scholar
  15. 15.
    Peng S, Wang Y, Peng H et al (2014) Autocrine vascular endothelial growth factor signaling promotes cell proliferation and modulates sorafenib treatment efficacy in hepatocellular carcinoma. Hepatology 60(4):1264–1277CrossRefGoogle Scholar
  16. 16.
    Friemel J, Rechsteiner M, Frick L et al (2015) Intratumor heterogeneity in hepatocellular carcinoma. Clin Cancer Res 21(8):1951–1961CrossRefGoogle Scholar
  17. 17.
    Stigliano R, Marelli L, Yu D, Davies N, Patch D, Burroughs AK (2007) Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev 33(5):437–447Google Scholar
  18. 18.
    Silva MA, Hegab B, Hyde C, Guo B, Buckels JA, Mirza DF (2008) Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut 57(11):1592–1596Google Scholar
  19. 19.
    Ahn SS, Kim MJ, Lim JS, Hong HS, Chung YE, Choi JYl (2010) Added value of gadoxetic acid-enhanced hepatobiliary phase MR imaging in the diagnosis of hepatocellular carcinoma. Radiology 255(2):459–466Google Scholar
  20. 20.
    Kogita S, Imai Y, Okada M et al (2010) Gd-EOB-DTPA-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading and portal blood flow. Eur Radiol 20(10):2405–2413CrossRefGoogle Scholar
  21. 21.
    Segal E, Sirlin CB, Ooi C et al (2007) Decoding global gene expression programs in liver cancer by noninvasive imaging. Nat Biotechnol 25(6):675–680CrossRefGoogle Scholar
  22. 22.
    Thaiss WM, Kaufmann S, Kloth C, Nikolaou K, Bösmüller H, Horger M (2016) VEGFR-2 expression in HCC, dysplastic and regenerative liver nodules, and correlation with pre-biopsy dynamic contrast enhanced CT. Eur J Radiol 85(11):2036–2041Google Scholar
  23. 23.
    Purysko AS, Remer EM, Coppa CP, Leão Filho HM, Thupili CR, Veniero JC (2012) LI-RADS: a case-based review of the new categorization of liver findings in patients with end-stage liver disease. Radiographics 32:1977–1995Google Scholar
  24. 24.
    Choi JY, Lee JM, Sirlin CB (2014) CT and MR imaging diagnosis and staging of hepatocellular carcinoma: part I. development, growth, and spread: key pathologic and imaging aspects. Radiology 272(3):635–654CrossRefGoogle Scholar
  25. 25.
    Elsayes KM, Hooker JC, Agrons MM et al (2017) 2017 version of LI-RADS for CT and MR imaging: an update. Radiographics 37(7):1994–2017CrossRefGoogle Scholar
  26. 26.
    Schreck R, Rapp UR (2006) Raf kinases: oncogenesis and drug discovery. Int J Cancer 119(10):2261–2271CrossRefGoogle Scholar
  27. 27.
    Leicht DT, Balan V, Kaplun A et al (2007) Raf kinases: function, regulation and role in human cancer. Biochim Biophys Acta 1773(8):1196–1212CrossRefGoogle Scholar
  28. 28.
    Zebisch A, Troppmair J (2006) Back to the roots: the remarkable RAF oncogene story. Cell Mol Life Sci 63(11):1314–1330CrossRefGoogle Scholar
  29. 29.
    Wellbrock C, Karasarides M, Marais R (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5(11):875–885CrossRefGoogle Scholar
  30. 30.
    Yue P, Gao ZH, Xue X et al (2011) Des-gamma-carboxyl prothrombin induces matrix metalloproteinase activity in hepatocellular carcinoma cells by involving the ERK1/2 MAPK signalling pathway. Eur J Cancer 47(7):1115–1124CrossRefGoogle Scholar
  31. 31.
    Vu TH, Werb Z (2000) Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev 14(17):2123–2133CrossRefGoogle Scholar
  32. 32.
    Wang B, Ding YM, Fan P, Wang B, Xu JH, Wang WX (2014) Expression and significance of MMP2 and HIF-1alpha in hepatocellular carcinoma. Oncol Lett 8(2):539–546Google Scholar
  33. 33.
    Sun MH, Han XC, Jia MK et al (2005) Expressions of inducible nitric oxide synthase and matrix metalloproteinase-9 and their effects on angiogenesis and progression of hepatocellular carcinoma. World J Gastroenterol 11(38):5931–5937CrossRefGoogle Scholar
  34. 34.
    McPhillips F, Mullen P, MacLeod KG et al (2006) Raf-1 is the predominant Raf isoform that mediates growth factor-stimulated growth in ovarian cancer cells. Carcinogenesis 27(4):729–739CrossRefGoogle Scholar
  35. 35.
    Galabova-Kovacs G, Matzen D, Piazzolla D et al (2006) Essential role of B-Raf in ERK activation during extraembryonic development. Proc Natl Acad Sci U S A 103(5):1325–1330CrossRefGoogle Scholar
  36. 36.
    Senger DR, Davis GE (2011) Angiogenesis. Cold Spring Harb Perspect Biol 3(8):a005090CrossRefGoogle Scholar
  37. 37.
    Beliveau A, Mott JD, Lo A et al (2010) Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo. Genes Dev 24(24):2800–2811CrossRefGoogle Scholar
  38. 38.
    Lee JH, Lee JM, Kim SJ et al (2012) Enhancement patterns of hepatocellular carcinomas on multiphasic multidetector row CT: comparison with pathological differentiation. Br J Radiol 85(1017):E573–E583CrossRefGoogle Scholar
  39. 39.
    Huang Z, Meng X, Xiu J et al (2014) MR imaging in hepatocellular carcinoma: correlations between MRI features and molecular marker VEGF. Med Oncol 31(12):313Google Scholar
  40. 40.
    Narita M, Hatano E, Arizono S et al (2009) Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. J Gastroenterol 44(7):793–798CrossRefGoogle Scholar

Copyright information

© European Society of Radiology 2018

Authors and Affiliations

  1. 1.Department of Radiology, The First Affiliated HospitalSun Yat-Sen UniversityGuangzhouChina
  2. 2.Department of RadiologyGuizhou Provincial People’s HospitalGuiyangChina
  3. 3.Department of Pathology, The First Affiliated HospitalSun Yat-Sen UniversityGuangzhouChina
  4. 4.Faculty of Medicine and DentistryUniversity of Western AustraliaCrawleyAustralia

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