Inactivation of O6-methylguanine-DNA methyltransferase in soft tissue sarcomas: association with K-ras mutations

Kim, Jeung Il; Suh, Jeung Tak; Choi, Kyung Un; Kang, Hyun Jeong; Shin, Dong Hoon; Lee, In Sook; Moon, Tae Yong; Kim, Won Taek

doi:10.1016/j.humpath.2009.01.005

« Previous Next »Human Pathology
Volume 40, Issue 7 , Pages 934-941, July 2009

Inactivation of O⁶-methylguanine-DNA methyltransferase in soft tissue sarcomas: association with K-ras mutations

Jeung Il Kim, MD
- Department of Orthopedics, School of Medicine, Pusan National University, Busan 602-739, Republic of Korea
Jeung Tak Suh, MD
- Department of Orthopedics, School of Medicine, Pusan National University, Busan 602-739, Republic of Korea
Kyung Un Choi, MD
- Department of Pathology, School of Medicine, Pusan National University, Busan 602-739, Republic of Korea
- Corresponding author.
Hyun Jeong Kang, MD
- Department of Pathology, School of Medicine, Pusan National University, Busan 602-739, Republic of Korea
Dong Hoon Shin, MD
- Department of Pathology, School of Medicine, Pusan National University, Busan 602-739, Republic of Korea
In Sook Lee, MD
- Department of Radiology, School of Medicine, Pusan National University, Busan 602-739, Republic of Korea
Tae Yong Moon, MD
- Department of Radiology, School of Medicine, Pusan National University, Busan 602-739, Republic of Korea
Won Taek Kim, MD
- Department of Therapeutic Radiology and Oncology, School of Medicine, Pusan National University, Busan 602-739, Republic of Korea

Received 1 October 2008; received in revised form 5 January 2009; accepted 9 January 2009. published online 08 April 2009.

Summary

The DNA-repair protein O⁶-methylguanine-DNA methyltransferase removes alkyl adducts from the O⁶-position of guanine. The adducts can mispair with T during DNA replication, resulting in a G-to-A mutation. Epigenetic inactivation of O⁶-methylguanine-DNA methyltransferase has been found in human neoplasia and is considered one of the implicated factors in chemoresistance. Sixty-two patients with soft tissue sarcomas were analyzed with regard to the status of O⁶-methylguanine-DNA methyltransferase protein expression status using immunohistochemistry and promoter hypermethylation of the MGMT gene using methylation-specific PCR. G-to-A transitions in codons 12 and 13 of the K-ras oncogene were investigated using PCR and direct automated sequencing analysis. A loss of O⁶-methylguanine-DNA methyltransferase expression was noted in 20 (32.3%) cases of 62 total soft tissue sarcomas. The MGMT promoter hypermethylation rate was 33.9% (21/62 cases). Of the 54 sarcomas evaluated, K-ras mutations were found in only 2 (3.7%) cases. Loss of O⁶-methylguanine-DNA methyltransferase expression and MGMT promoter hypermethylation showed a significant association with high American Joint Committee on Cancer stage, high French Federation of Cancer Centers grade, and aggressive behavior. On multivariate analysis, these were not an independently significant prognostic factors. However, when the group receiving chemotherapy was analyzed (n = 27), loss of O⁶-methylguanine-DNA methyltransferase expression was correlated with worse survival on multivariate analysis (P = .024). MGMT promoter hypermethylation status had a strong correlation with loss of O⁶-methylguanine-DNA methyltransferase expression (P = .000). Our results suggest that MGMT promoter hypermethylation and loss of O⁶-methylguanine-DNA methyltransferase expression tend to be associated with poor prognosis and that the loss of O⁶-methylguanine-DNA methyltransferase protein expression frequently occurs via MGMT promoter hypermethylation. However, MGMT promoter hypermethylation was not significantly associated with point mutations of K-ras at codons 12 and 13 in sarcomas.