Epithelial-Specific SHP1-P2 Methylation - a Novel Universal Tumor Marker for Detection of Colorectal Cancer Lymph Node Metastasis

  • Rattanatanyong, Prakasit (Center of Excellence in Molecular Genetics of Cancer and Human Disease, Department of Anatomy, Faculty of Medicine, Chulalongkorn University) ;
  • Keelawat, Somboon (Department of Pathology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital) ;
  • Kitkumthorn, Nakarin (Department of Oral Biology, Faculty of Dentistry, Mahidol University) ;
  • Mutirangura, Apiwat (Center of Excellence in Molecular Genetics of Cancer and Human Disease, Department of Anatomy, Faculty of Medicine, Chulalongkorn University)
  • Published : 2016.08.01


Background: Methylation of promoter 2 of the SHP1 gene is epithelial cell specific, with reported potential as a lymph node metastatic marker. Objective: To demonstrate SHP1-P2 methylation-specific quantitative PCR effectiveness in detecting colorectal cancer (CRC) DNA in lymph nodes. Materials and Methods: SHP1-P2 methylation levels were measured in lymph nodes of CRC patients and compared with pathological findings and patient prognosis. Results: Lymph nodes of CRC metastatic patients without microscopically detectable cancer cells had higher SHP1-P2 methylation levels than lymph nodes of controls (p<0.001). In addition, a higher SHP1-P2 methylation level was associated with a shorter duration until adverse disease events, metastasis, recurrence and death (r2 = 0.236 and p value = 0.048). Studying two cohorts of 74 CRC patients without microscopic lymph node metastases showed that only the cohort containing samples with high SHP1-P2 methylation levels had a significant hazard ratio of 3.8 (95%CI = 1.02 to 14.2). Conclusions: SHP1-P2 methylation PCR can detect CRC DNA in lymph nodes even if cancer cells are not visible under a microscope, confirming applicability as a potential universal lymph node metastatic marker.


Supported by : Thailand Research Fund


  1. Anglim PP, Alonzo TA, Laird-Offringa IA (2008). DNA methylation-based biomarkers for early detection of nonsmall cell lung cancer: an update. Mol Cancer, 7, 81.
  2. Brock MV, Hooker CM, Ota-Machida E, et al (2008). DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med, 358, 1118-28.
  3. Chujan S, Kitkumthorn N, Siriangkul S, et al (2014). CCNA1 promoter methylation: a potential marker for grading Papanicolaou smear cervical squamous intraepithelial lesions. Asian Pac J Cancer Prev, 15, 7971-5.
  4. Huynh KT, Hoon DS (2012). Epigenetics of regional lymph node metastasis in solid tumors. Clin Exp Metastasis, 29, 747-56.
  5. Kim MS, Lee J, Sidransky D (2010). DNA methylation markers in colorectal cancer. Cancer Metastasis Rev, 29, 181-206.
  6. Kitkumthorn N, Keelawat S, Rattanatanyong P, et al (2012). LINE-1 and Alu methylation patterns in lymph node metastases of head and neck cancers. Asian Pac J Cancer Prev, 13, 4469-75.
  7. Patel A, Groopman JD, Umar A (2003). DNA methylation as a cancer-specific biomarker: from molecules to populations. Ann N Y Acad Sci, 983, 286-97.
  8. Patel V, Martin D, Malhotra R, et al (2013). DSG3 as a biomarker for the ultrasensitive detection of occult lymph node metastasis in oral cancer using nanostructured immunoarrays. Oral Oncol, 49, 93-101.
  9. Payne SR, Serth J, Schostak M, et al (2009). DNA methylation biomarkers of prostate cancer: confirmation of candidates and evidence urine is the most sensitive body fluid for noninvasive detection. Prostate, 69, 1257-69.
  10. Ruchusatsawat K, Wongpiyabovorn J, Shuangshoti S, et al (2006). SHP-1 promoter 2 methylation in normal epithelial tissues and demethylation in psoriasis. J Mol Med (Berl), 84, 175-82.
  11. Safar AM, Spencer H, Su X, et al (2007). Promoter hypermethylation for molecular nodal staging in non-small cell lung cancer. Arch Pathol Lab Med, 131, 936-41.
  12. Tiwawech D, Srisuttee R, Rattanatanyong P, et al (2014). Alu methylation in serum from patients with nasopharyngeal carcinoma. Asian Pac J Cancer Prev, 15, 9797-800.
  13. Toyooka S, Toyooka KO, Maruyama R, et al (2001). DNA methylation profiles of lung tumors. Mol Cancer Ther, 1, 61-7.
  14. Vinayanuwattikun C, Chantranuwat P, Sriuranpong V, et al (2014).The role of SHP-1 promoter 2 hypermethylation detection of lymph node micrometastasis in resectable stage I non-small cell lung cancer as a prognostic marker of disease recurrence. Int J Clin Oncol, 19, 586-92.
  15. Vinayanuwattikun C, Sriuranpong V, Tanasanvimon S, et al (2011). Epithelial-specific methylation marker: a potential plasma biomarker in advanced non-small cell lung cancer. J Thorac Oncol, 6, 1818-25.
  16. Vinayanuwattikun C, Winayanuwattikun P, Chantranuwat P, et al (2013). The impact of non-tumor-derived circulating nucleic acids implicates the prognosis of non-small cell lung cancer. J Cancer Res Clin Oncol, 139, 67-76.