CpG Island Methylator Phenotype is Associated with the Efficacy of Sequential Oxaliplatin- and Irinotecan-based Chemotherapy and EGFR-related Gene Mutation in Japanese Patients with Metastatic Colorectal Cancer

Overview

Journal Int J Clin Oncol

Specialty Oncology

Date 2016 Jul 21

PMID 27435270

Citations 13

Authors

Xiaofei Zhang

Hideki Shimodaira

Hiroshi Soeda

Keigo Komine

Hidekazu Takahashi

Kota Ouchi

Masahiro Inoue

Masanobu Takahashi

Shin Takahashi

Chikashi Ishioka

Affiliations

Soon will be listed here.

Abstract

Background: The CpG island methylator phenotype (CIMP) with multiple promoter methylated loci has been observed in a subset of human colorectal cancer (CRC) cases. CIMP status, which is closely associated with specific clinicopathological and molecular characteristics, is considered a potential predictive biomarker for efficacy of cancer treatment. However, the relationship between the effect of standard chemotherapy, including cytotoxic drugs and anti-epidermal growth factor receptor (EGFR) antibodies, and CIMP status has not been elucidated.

Methods: In 125 metastatic colorectal cancer (mCRC) patients, we investigated how clinical outcome of chemotherapy was related to CIMP status as detected by methylation-specific PCR (MSP) and to genetic status in five EGFR-related genes (KRAS, BRAF, PIK3CA, NRAS, and AKT1) as detected by direct sequencing.

Results: CIMP-positive status was significantly associated with proximal tumor location and peritoneum metastasis (all P values <0.05). The progression-free survival of patients with CIMP-positive tumors receiving sequential therapy with FOLFOX as the first-line treatment followed by irinotecan-based therapy as the second-line treatment (median = 6.6 months) was inferior to that of such patients receiving the reverse sequence (median = 15.2 months; P = 0.043). Furthermore, CIMP-positive tumors showed higher mutation frequencies for the five EGFR-related genes (74.1 %) than the CIMP-negative tumors did (50.0 %). Among the KRAS wild-type tumors, CIMP-positive tumors were associated with a worse clinical outcome than CIMP-negative tumors following anti-EGFR antibody therapy.

Conclusion: Sequential FOLFOX followed by an irinotecan-based regimen is unfavorable in patients with CIMP-positive tumors. High frequencies of mutation in EGFR-related genes in CIMP-positive tumors may cause the lower response to anti-EGFR antibody therapy seen in patients with wild-type KRAS and CIMP-positive tumors.

Citing Articles

Genome-wide DNA methylation status is a predictor of the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer: Translational research of the EPIC trial.

Ouchi K, Takahashi S, Sasaki K, Yoshida Y, Taniguchi S, Kasahara Y Int J Colorectal Dis. 2024; 39(1):89.

PMID: 38862615 PMC: 11166830. DOI: 10.1007/s00384-024-04659-y.

The CpG Island Methylator Phenotype Status in Synchronous and Solitary Primary Colorectal Cancers: Prognosis and Effective Therapeutic Drug Prediction.

Weng Y, Huang M Int J Mol Sci. 2024; 25(10).

PMID: 38791280 PMC: 11121449. DOI: 10.3390/ijms25105243.

A Multi-Omics Overview of Colorectal Cancer to Address Mechanisms of Disease, Metastasis, Patient Disparities and Outcomes.

Yang G, Yu X, Weisenberger D, Lu T, Liang G Cancers (Basel). 2023; 15(11).

PMID: 37296894 PMC: 10251979. DOI: 10.3390/cancers15112934.

Epigenome-Wide DNA Methylation Profiling in Colorectal Cancer and Normal Adjacent Colon Using Infinium Human Methylation 450K.

Baharudin R, Ishak M, Muhamad Yusof A, Saidin S, Syafruddin S, Nazarie W Diagnostics (Basel). 2022; 12(1).

PMID: 35054365 PMC: 8775085. DOI: 10.3390/diagnostics12010198.

Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma.

Tomicic M, Dawood M, Efferth T Cancers (Basel). 2021; 13(16).

PMID: 34439227 PMC: 8394868. DOI: 10.3390/cancers13164072.

References

Ogino S, Cantor M, Kawasaki T, Brahmandam M, Kirkner G, Weisenberger D . CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies. Gut. 2006; 55(7):1000-6. PMC: 1856352. DOI: 10.1136/gut.2005.082933. View

Min B, Bae J, Lee E, Yu H, Kim Y, Kyung Chang D . The CpG island methylator phenotype may confer a survival benefit in patients with stage II or III colorectal carcinomas receiving fluoropyrimidine-based adjuvant chemotherapy. BMC Cancer. 2011; 11:344. PMC: 3162585. DOI: 10.1186/1471-2407-11-344. View

Jover R, Nguyen T, Perez-Carbonell L, Zapater P, Paya A, Alenda C . 5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer. Gastroenterology. 2010; 140(4):1174-81. PMC: 3073650. DOI: 10.1053/j.gastro.2010.12.035. View

Barault L, Charon-Barra C, Jooste V, Vega M, Martin L, Roignot P . Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res. 2008; 68(20):8541-6. DOI: 10.1158/0008-5472.CAN-08-1171. View

Herman J, Graff J, Myohanen S, Nelkin B, Baylin S . Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996; 93(18):9821-6. PMC: 38513. DOI: 10.1073/pnas.93.18.9821. View

Shiovitz S, Bertagnolli M, Renfro L, Nam E, Foster N, Dzieciatkowski S . CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer. Gastroenterology. 2014; 147(3):637-45. PMC: 4143495. DOI: 10.1053/j.gastro.2014.05.009. View

Ouchi K, Takahashi S, Yamada Y, Tsuji S, Tatsuno K, Takahashi H . DNA methylation status as a biomarker of anti-epidermal growth factor receptor treatment for metastatic colorectal cancer. Cancer Sci. 2015; 106(12):1722-9. PMC: 4714671. DOI: 10.1111/cas.12827. View

Kim J, Shin S, Kwon H, Cho N, Kang G . Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers. Virchows Arch. 2009; 455(6):485-94. DOI: 10.1007/s00428-009-0857-0. View

Sharma S, Kelly T, Jones P . Epigenetics in cancer. Carcinogenesis. 2009; 31(1):27-36. PMC: 2802667. DOI: 10.1093/carcin/bgp220. View

10.

Lievre A, Bachet J, Le Corre D, Boige V, Landi B, Emile J . KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006; 66(8):3992-5. DOI: 10.1158/0008-5472.CAN-06-0191. View

11.

Samowitz W, Albertsen H, Herrick J, Levin T, Sweeney C, Murtaugh M . Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology. 2005; 129(3):837-45. DOI: 10.1053/j.gastro.2005.06.020. View

12.

Esteller M . Epigenetics in cancer. N Engl J Med. 2008; 358(11):1148-59. DOI: 10.1056/NEJMra072067. View

13.

Han S, Lee H, Bae J, Cho N, Lee K, Kim T . Methylation and microsatellite status and recurrence following adjuvant FOLFOX in colorectal cancer. Int J Cancer. 2012; 132(9):2209-16. DOI: 10.1002/ijc.27888. View

14.

Iacopetta B, Kawakami K, Watanabe T . Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracil-responsive subgroup?. Int J Clin Oncol. 2008; 13(6):498-503. DOI: 10.1007/s10147-008-0854-3. View

15.

Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D . FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2003; 22(2):229-37. DOI: 10.1200/JCO.2004.05.113. View

16.

Jonker D, OCallaghan C, Karapetis C, Zalcberg J, Tu D, Au H . Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007; 357(20):2040-8. DOI: 10.1056/NEJMoa071834. View

17.

Eads C, Danenberg K, Kawakami K, Saltz L, Blake C, Shibata D . MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res. 2000; 28(8):E32. PMC: 102836. DOI: 10.1093/nar/28.8.e32. View

18.

Weisenberger D, Siegmund K, Campan M, Young J, Long T, Faasse M . CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006; 38(7):787-93. DOI: 10.1038/ng1834. View

19.

Gibson T, Ranganathan A, Grothey A . Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clin Colorectal Cancer. 2006; 6(1):29-31. DOI: 10.3816/CCC.2006.n.01. View

20.

Soeda H, Shimodaira H, Watanabe M, Suzuki T, Gamoh M, Mori T . Clinical usefulness of KRAS, BRAF, and PIK3CA mutations as predictive markers of cetuximab efficacy in irinotecan- and oxaliplatin-refractory Japanese patients with metastatic colorectal cancer. Int J Clin Oncol. 2012; 18(4):670-7. DOI: 10.1007/s10147-012-0422-8. View