Protein expression profiles of deoxyribonucleic acid mismatch repair genes: Association with clinicopathological characteristics of Malaysian Lynch syndrome patients

Abstract

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, accounts for approximately 1–5% of all colorectal cancers. Germline mutations in a group of deoxyribonucleic acid (DNA) mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS1, and PMS2) are responsible for Lynch syndrome cases. This study focuses on the determination of MMR (MLH1, MSH2, MSH6, and PMS2) protein expression profile by immunohistochemical analysis and its association with clinicopathological characteristics in clinically diagnosed Malaysian Lynch syndrome patients. Fifty patients who fulfilled any of the revised Bethesda Guidelines criteria were recruited from four collaborating centers in Malaysia. Clinicopathological information of clinically diagnosed Lynch syndrome cases that underwent bowel resection was reviewed. Immunohistochemical analysis for MLH1, MSH2, MSH6, and PMS2 proteins were performed on paraffin-embedded carcinomatous tissues. Colorectal cancer protein expression analysis for MLH1, MSH2, MSH6, and PMS2 antigens showed absence of expression of any MMR proteins in 18 out of 50 clinically diagnosed Lynch syndrome patients (36.0%). There was a significant association between abnormal MMR protein expression with tumor size (p = 0.012), histological differentiation of cancers (p = 0.012), and growth pattern of tumor (p = 0.01). Abnormal expression of MMR protein in colorectal cancers in clinically diagnosed Lynch syndrome patients was associated with specific clinicopathological characteristics such as tumor size, histological differentiation of cancers, and growth pattern of tumor. Immunohistochemical analysis proved to be an advantageous pre-screening tool for Lynch syndrome in Malaysian patients and highly predictive of a germline mutation in DNA MMR genes.

Keywords:

• Colorectal cancer
• Immunohistochemistry
• Lynch syndrome
• Mismatch repair protein

Acknowledgments

The authors would like to thank the patients and their family members who participated in this project. Also, the authors wish to acknowledge the assistance and support of Dr. Muhammad Radzi Abu Hassan (Hospital Sultanah Bahiyah, Alor Star, Kedah), Dr. Ahmad Shanwani Mohd Sidek (Hospital Raja Perempuan Zainab II, Kota Bharu, Kelantan), and Dr. Harjinder Singh (Queen Elizabeth Hospital, Kota Kinabalu, Sabah) in recruiting the study subjects. Lastly, the authors would like to thank the staff at Clinical Research Centre, Hospital Sultanah Bahiyah, Alor Setar, Kedah, Malaysia and Surgical Department, Hospital Raja Perempuan Zainab II, Kota Bharu, Kelantan, Malaysia for their contribution to this study, Mariam Azmi, Advanced Medical and Dental Institute, Universiti Sains Malaysia and Shazana Hilda Shamsuddin, Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia Health Campus for their technical expertise in immunohistochemistry.