Analysis of Hereditary Nonpolyposis Colorectal Cancer in Malay Cohorts using Immunohistochemical Screening

  • Juhari, Wan Khairunnisa Wan (Department of Paediatric, Universiti Sains Malaysia, Health Campus) ;
  • Rahman, Wan Faiziah Wan Abdul (Department of Pathology, Universiti Sains Malaysia, Health Campus) ;
  • Sidek, Ahmad Shanwani Mohd (Surgery Department, Hospital Raja Perempuan Zainab 2) ;
  • Hassan, Muhammad Radzi Abu (Clinical Research Centre, Hospital Sultanah Bahiyah) ;
  • Noordin, Khairul Bariah Ahmad Amin (School of Dental Sciences, Universiti Sains Malaysia) ;
  • Zakaria, Andee Dzulkarnaen (Department of Surgery, School of Medical Sciences, Universiti Sains Malaysia, Health Campus) ;
  • Macrae, Finlay (Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital) ;
  • Zilfalil, Bin Alwi (Department of Paediatric, Universiti Sains Malaysia, Health Campus)
  • Published : 2015.05.18


Background: Lynch syndrome (LS) is an inherited predisposition to colorectal, endometrial (uterine) and other cancers. Although most cancers are not inherited, about 5 percent (%) of people who have colorectal or endometrial cancer have the Lynch syndrome. It involves the alteration of mismatch repair (MMR) genes; MLH1, MSH2, MSH6 or PMS2. In this study, we analyzed the expression of MMR proteins in colorectal cancer in a Malay cohort by immunohistochemistry. Materials and Methods: A total of 17 patients were selected fulfilling one of the Bethesda criteria: colorectal cancer diagnosed in a patient aged less than 50 years old, having synchronous and metachronous colorectal cancer or with a strong family history. Immunohistochemical staining was performed on paraffin embedded tumour tissue samples using four antibodies: MLH1, MSH2, MSH6 and PMS2. Results: Twelve out of 17 patients (70.6%) were noted to have a family history. A total of 41% (n=7) of the patients had abnormal immunohistochemical staining with one or more of the four antibodies. Loss of expression were noted in 13 tumour tissues with a negative staining score <4. Of 13 tumour tissues, four showed loss expression of MLH1. For PMS2, loss of expression were noted in five cases. Both MSH2 and MSH6 showed loss of expression in two tumour tissues respectively. Conclusions: Revised Bethesda criteria and immunohistochemical analysis constituted a convenient approach and is recommended to be a first-line screening for Lynch syndrome in Malay cohorts.


Colorectal carcinoma;HNPCC;Lynch syndrome;immunohistochemistry;MMR


  1. Amira AT, Mouna T, Ahlem B, et al (2014). Immunohistochemical expression pattern of MMR protein can specifically identify patients with colorectal cancer microsatellite instability. Tumor Biol, 35, 6283-91.
  2. Arends M, Ibrahim M, Happerfield L, et al (2008). Interpretation of immunohistochemical analysis of mismatch repair (mmr) protein expression in tissue sections for investigation of suspected Lynch/hereditary non-polyposis colorectal cancer (HNPCC) syndrome. UK NEQAS ICC & ISH Recommendations, 1.
  3. Barrow E, Jagger E, Brierley J, et al (2010). Semiquantitative assessment of immunohistochemistry for mismatch repair proteins in Lynch syndrome. Histopathology, 56, 331-44.
  4. Cheah PL, Looi LM, Teoh KH, et al (2014). Colorectal carcinoma in Malaysians: DNA mismatch repair pattern in a multiethnic population. Asian Pac J Cancer Prev, 15, 3287-91.
  5. Coggins RP, Cawkwell L, Bell SM, et al (2005). Association between family history and mismatch repair in colorectal cancer. Gut, 54, 636-42.
  6. Goh KLl, Quek KFf, Yeo GTSts, et al (2005). Colorectal cancer in Asians: a demographic and anatomic survey in Malaysian patients undergoing colonoscopy. Aliment Pharm Therap, 22, 859-864.
  7. Haghighi MM, Vahedi M, Mohebbi SR, et al (2009). Comparison of survival between patients with hereditary non polyposis colorectal cancer (HNPCC) and sporadic colorectal cancer. Asian Pac J Cancer Prev, 10, 497-500.
  8. Lynch HT, de la Chapelle A (2003). Hereditary colorectal cancer. N Engl J Med, 348, 919-32.
  9. Murad NAA, Othman Z, Khalid M, et al (2012). Missense mutations in MLH1, MSH2, KRAS, and APC genes in colorectal cancer patients in Malaysia. Digest Dis Sci, 57, 2863-72.
  10. Pinol V, Castells A, Andreu M, et al (2005). Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA, 293,16, 1986-1994.
  11. Southey MC, Jenkins MA, Mead L, et al (2005). Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol, 23, 6524-6532.
  12. Thibodeau SN, French AJ, Roche PC, et al (1996). Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res, 56, 4836-40.
  13. Toft NJ, Arends MJ (1998). DNA mismatch repair and colorectal cancer. J Pathol, 185, 123-9.<123::AID-PATH62>3.0.CO;2-P
  14. Vasen HF, Moslein G, Alonso A, et al (2007). Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet, 44, 353-62.
  15. Yusoff HM, Daud N, Noor NM, et al (2012). Participation and barriers to colorectal cancer screening in Malaysia. Asian Pac J Cancer Prev, 13, 3983-7.
  16. Zahary MN, Kaur G, Hassan MRA, Singh H, Naik VR, Ankathil R (2012). Germline mutation analysis of MLH1 and MSH2 in Malaysian Lynch syndrome patients. World J Gastroenterol, 18, 814.