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Pietrantonio F, Randon G, Romagnoli D, Di Donato S, Benelli M, de Braud F. Biomarker-guided implementation of the old drug temozolomide as a novel treatment option for patients with metastatic colorectal cancer. Cancer Treat Rev 2020; 82:101935. [DOI: 10.1016/j.ctrv.2019.101935] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 11/21/2019] [Accepted: 11/22/2019] [Indexed: 12/21/2022]
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Liu X, Fu J, Bi H, Ge A, Xia T, Liu Y, Sun H, Li D, Zhao Y. DNA methylation of SFRP1, SFRP2, and WIF1 and prognosis of postoperative colorectal cancer patients. BMC Cancer 2019; 19:1212. [PMID: 31830937 PMCID: PMC6909551 DOI: 10.1186/s12885-019-6436-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 12/05/2019] [Indexed: 12/24/2022] Open
Abstract
Background As biomarkers, DNA methylation is used to detect colorectal cancer (CRC) and make assessment of CRC prognosis. The published findings showed the association between the methylation of SFRP1, SFRP2, and WIF1, located in the Wnt signaling pathway, and the prognosis of CRC were not consistent. Our study aimed to explore the potential possibility of SFRP1, SFRP2, and WIF1 concomitant promoter methylation as prognostic biomarkers of postoperative CRC patients. Methods As a total of 307 sporadic postoperative CRC patients were followed up, we detected SFRP1, SFRP2, and WIF1 methylation obtained from tumor tissues and adjacent non-tumor tissues respectively on the basis of methylation-sensitive high resolution melting analysis. Univariate and multivariate Cox regressions were carried out so as to assess the potential possibility of SFRP1, SFRP2, and WIF1 promoter methylation as predictors of prognosis. Confounders in our study were controlled by Propensity Score (PS) analysis. Results The SFRP1, SFRP2, and WIF1 methylation levels in tumor tissues were significantly higher than that in adjacent non-tumor tissues (P < 0.001). SFRP2 hypermethylation was significantly associated with a favorable clinical outcome at the hazard ratio (HR) of 0.343 [95% confidence intervals (CI): 0.164–0.718, P = 0.005] and 0.410 (95% CI: 0.200–0.842, P = 0.015) in multivariate Cox regression and PS analysis, respectively. Co-hypermethylation of SFRP1 and SFRP2 was significantly associated with a favorable clinical outcome at the HR of 0.333 (95% CI: 0.159–0.694, P = 0.003) and 0.398 (95% CI: 0.192–0.821, P = 0.013) in multivariate Cox regression and PS analysis, respectively. Co-hypermethylation of SFRP1, SFRP2 and WIF1 was significantly associated with a favorable clinical outcome at the HR of 0.326 (95% CI: 0.117–0.908, P = 0.032) and 0.401 (95% CI: 0.146–1.106, P = 0.077) in multivariate Cox regression and PS analysis, respectively. Conclusions SFRP1, SFRP2, and WIF1 were frequently hypermethylated in CRC tumor tissues. It was apparent that the promoter hypermethylation of SFRP2 and co-hypermethylation of SFRP1 and SFRP2 might be considered as independent prognostic predictors for survival advantage of postoperative CRC patients.
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Affiliation(s)
- Xinyan Liu
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150086, Heilongjiang Province, People's Republic of China
| | - Jinming Fu
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150086, Heilongjiang Province, People's Republic of China
| | - Haoran Bi
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150086, Heilongjiang Province, People's Republic of China
| | - Anqi Ge
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150086, Heilongjiang Province, People's Republic of China
| | - Tingting Xia
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150086, Heilongjiang Province, People's Republic of China
| | - Yupeng Liu
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150086, Heilongjiang Province, People's Republic of China
| | - Hongru Sun
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150086, Heilongjiang Province, People's Republic of China
| | - Dapeng Li
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150086, Heilongjiang Province, People's Republic of China
| | - Yashuang Zhao
- Department of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150086, Heilongjiang Province, People's Republic of China.
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Harada H, Hosoda K, Moriya H, Mieno H, Ema A, Ushiku H, Washio M, Nishizawa N, Ishii S, Yokota K, Tanaka Y, Kaida T, Soeno T, Kosaka Y, Watanabe M, Yamashita K. Cancer-specific promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene as an important prognostic biomarker of gastric cancer. PLoS One 2019; 14:e0214872. [PMID: 30934021 PMCID: PMC6443169 DOI: 10.1371/journal.pone.0214872] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 03/21/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND There have been few available prognostic biomarkers in gastric cancer. We rigorously assessed the clinical relevance of promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene, a cancer-specific aberration, in human gastric cancer. METHODS Quantitative CDO1 methylation value (TaqMeth V) was initially calculated in 138 gastric cancer patients operated in 2005, and its clinical significance was elucidated. As a subsequent expanded set, 154 gastric cancer patients with pathological stage (pStage) II / III with no postoperative therapy were validated between 2000 and 2010. RESULTS (1) Median TaqMeth V of CDO1 gene methylation of gastric cancer was 25.6, ranging from 0 to 120.9. As pStage progressed, CDO1 TaqMeth V became higher (p < 0.0001). (2) The optimal cut-off value was determined to be 32.6; gastric cancer patients with high CDO1 gene methylation showed a significantly worse prognosis than those with low CDO1 gene methylation (p < 0.0001). (3) A multivariate cox proportional hazards model identified high CDO1 gene methylation (p = 0.033) as an independent prognostic factor. (4) The results were recapitulated in the expanded set in pStage III, where high CDO1 gene methylation group had a significantly worse prognosis than low CDO1 gene methylation group (p = 0.0065). Hematogenous metastasis was unique in pStage III with high CDO1 gene methylation (p = 0.0075). (5) Anchorage independent growth was reduced in several gastric cancer cell lines due to forced expression of the CDO1 gene, suggesting that abnormal CDO1 gene expression may represent distant metastatic ability. CONCLUSIONS Promoter DNA hypermethylation of CDO1 gene was rigorously validated as an important prognostic biomarker in primary gastric cancer with specific stage.
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Affiliation(s)
- Hiroki Harada
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Kei Hosoda
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Hiromitsu Moriya
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Hiroaki Mieno
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Akira Ema
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Hideki Ushiku
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Marie Washio
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Nobuyuki Nishizawa
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Satoru Ishii
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Kazuko Yokota
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Yoko Tanaka
- Department of Breast and Endocrine Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Takeshi Kaida
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Takafumi Soeno
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Yoshimasa Kosaka
- Department of Breast and Endocrine Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Masahiko Watanabe
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Keishi Yamashita
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
- Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
- * E-mail:
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4
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Greytak SR, Engel KB, Zmuda E, Casas-Silva E, Guan P, Hoadley KA, Mungall AJ, Wheeler DA, Doddapaneni HV, Moore HM. National Cancer Institute Biospecimen Evidence-Based Practices: Harmonizing Procedures for Nucleic Acid Extraction from Formalin-Fixed, Paraffin-Embedded Tissue. Biopreserv Biobank 2018; 16:247-250. [PMID: 29920119 DOI: 10.1089/bio.2018.0046] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Affiliation(s)
| | | | - Erik Zmuda
- 3 Cytogenetics/Molecular Genetics Laboratory at Nationwide Children's Hospital , Columbus, Ohio
| | - Esmeralda Casas-Silva
- 4 Biorepositories and Biospecimen Research Branch, Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute , Bethesda, Maryland
| | - Ping Guan
- 4 Biorepositories and Biospecimen Research Branch, Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute , Bethesda, Maryland
| | - Katherine A Hoadley
- 5 Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill , Chapel Hill, North Carolina
| | - Andrew J Mungall
- 6 Canada's Michael Smith Genome Sciences Center , BC Cancer Agency, Vancouver, Canada
| | - David A Wheeler
- 7 Human Genome Sequencing Center , Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Harsha V Doddapaneni
- 7 Human Genome Sequencing Center , Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Helen M Moore
- 4 Biorepositories and Biospecimen Research Branch, Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute , Bethesda, Maryland
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Kojima K, Nakamura T, Ohbu M, Katoh H, Ooizumi Y, Igarashi K, Ishii S, Tanaka T, Yokoi K, Nishizawa N, Yokota K, Kosaka Y, Sato T, Watanabe M, Yamashita K. Cysteine dioxygenase type 1 (CDO1) gene promoter methylation during the adenoma-carcinoma sequence in colorectal cancer. PLoS One 2018; 13:e0194785. [PMID: 29746493 PMCID: PMC5944981 DOI: 10.1371/journal.pone.0194785] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 03/10/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Progression of colorectal cancer (CRC) has been explained by genomic abnormalities along with the adenoma-carcinoma sequence theory (ACS). The aim of our study is to elucidate whether the promoter DNA methylation of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in CRC. METHODS The study group comprised 107 patients with CRC who underwent surgical resection and 90 adenomas treated with endoscopic resection in the Kitasato University Hospital in 2000. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1. RESULTS The methylation level increased along with the ACS process (p < 0.0001), and statistically significant differences were found between normal-appearing mucosa (NAM) and low-grade adenoma (p < 0.0001), and between low-grade adenoma and high-grade adenoma (p = 0.01), but not between high-grade adenoma and cancer with no liver metastasis. Furthermore, primary CRC cancers with liver metastasis harbored significantly higher methylation of CDO1 than those without liver metastasis (p = 0.02). As a result, the area under the curve by CDO1 promoter methylation was 0.96, 0.80, and 0.67 to discriminate cancer from NAM, low-grade adenoma from NAM, and low-grade adenoma from high-grade adenoma, respectively. CONCLUSIONS CDO1 methylation accumulates during the ACS process, and consistently contributes to CRC progression.
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Affiliation(s)
- Keita Kojima
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Takatoshi Nakamura
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Makoto Ohbu
- Department of Pathology, Kitasato University School of Allied Health Sciences, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Hiroshi Katoh
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Yosuke Ooizumi
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Kazuharu Igarashi
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Satoru Ishii
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Toshimichi Tanaka
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Keigo Yokoi
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Nobuyuki Nishizawa
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Kazuko Yokota
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Yoshimasa Kosaka
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Takeo Sato
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Masahiko Watanabe
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
- * E-mail:
| | - Keishi Yamashita
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
- Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical Frontiers, Minami-ku, Sagamihara, Kanagawa, Japan
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6
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Calegari MA, Inno A, Monterisi S, Orlandi A, Santini D, Basso M, Cassano A, Martini M, Cenci T, de Pascalis I, Camarda F, Barbaro B, Larocca LM, Gori S, Tonini G, Barone C. A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation. Br J Cancer 2017; 116:1279-1286. [PMID: 28427088 PMCID: PMC5482728 DOI: 10.1038/bjc.2017.109] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 02/19/2017] [Accepted: 03/28/2017] [Indexed: 01/04/2023] Open
Abstract
Background: Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent. Methods: This was a multicentre, phase 2 trial, planned according to a two-stage Simon’s optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150–200 mg m−2 per day on days 1–5 every 28 days. Results: From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively. Conclusions: Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.
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Affiliation(s)
- M A Calegari
- Division of Medical Oncology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome 00168, Italy
| | - A Inno
- Medical Oncology Unit, 'Sacro Cuore Don Calabria' Hospital Cancer Care Center, Verona 37024, Italy
| | - S Monterisi
- Division of Medical Oncology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome 00168, Italy
| | - A Orlandi
- Division of Medical Oncology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome 00168, Italy
| | - D Santini
- Division of Medical Oncology, Campus Bio-medico University, Rome 00128, Italy
| | - M Basso
- Division of Medical Oncology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome 00168, Italy
| | - A Cassano
- Division of Medical Oncology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome 00168, Italy
| | - M Martini
- Institute of Pathological Anatomy, Catholic University of the Sacred Heart, Rome 00168, Italy
| | - T Cenci
- Institute of Pathological Anatomy, Catholic University of the Sacred Heart, Rome 00168, Italy
| | - I de Pascalis
- Institute of Pathological Anatomy, Catholic University of the Sacred Heart, Rome 00168, Italy
| | - F Camarda
- Division of Medical Oncology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome 00168, Italy
| | - B Barbaro
- Institute of Radiology, Catholic University of the Sacred Heart, Rome 00168, Italy
| | - L M Larocca
- Institute of Pathological Anatomy, Catholic University of the Sacred Heart, Rome 00168, Italy
| | - S Gori
- Medical Oncology Unit, 'Sacro Cuore Don Calabria' Hospital Cancer Care Center, Verona 37024, Italy
| | - G Tonini
- Division of Medical Oncology, Campus Bio-medico University, Rome 00128, Italy
| | - C Barone
- Division of Medical Oncology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 8, Rome 00168, Italy
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Galamb O, Kalmár A, Barták BK, Patai &AV, Leiszter K, Péterfia B, Wichmann B, Valcz G, Veres G, Tulassay Z, Molnár B. Aging related methylation influences the gene expression of key control genes in colorectal cancer and adenoma. World J Gastroenterol 2016; 22:10325-10340. [PMID: 28058013 PMCID: PMC5175245 DOI: 10.3748/wjg.v22.i47.10325] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 09/20/2016] [Accepted: 11/13/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To analyze colorectal carcinogenesis and age-related DNA methylation alterations of gene sequences associated with epigenetic clock CpG sites. METHODS In silico DNA methylation analysis of 353 epigenetic clock CpG sites published by Steve Horvath was performed using methylation array data for a set of 123 colonic tissue samples [64 colorectal cancer (CRC), 42 adenoma, 17 normal; GEO accession number: GSE48684]. Among the differentially methylated age-related genes, secreted frizzled related protein 1 (SFRP1) promoter methylation was further investigated in colonic tissue from 8 healthy adults, 19 normal children, 20 adenoma and 8 CRC patients using bisulfite-specific PCR followed by methylation-specific high resolution melting (MS-HRM) analysis. mRNA expression of age-related "epigenetic clock" genes was studied using Affymetrix HGU133 Plus2.0 whole transcriptome data of 153 colonic biopsy samples (49 healthy adult, 49 adenoma, 49 CRC, 6 healthy children) (GEO accession numbers: GSE37364, GSE10714, GSE4183, GSE37267). Whole promoter methylation analysis of genes showing inverse DNA methylation-gene expression data was performed on 30 colonic samples using methyl capture sequencing. RESULTS Fifty-seven age-related CpG sites including hypermethylated PPP1R16B, SFRP1, SYNE1 and hypomethylated MGP, PIPOX were differentially methylated between CRC and normal tissues (P < 0.05, Δβ ≥ 10%). In the adenoma vs normal comparison, 70 CpG sites differed significantly, including hypermethylated DKK3, SDC2, SFRP1, SYNE1 and hypomethylated CEMIP, SPATA18 (P < 0.05, Δβ ≥ 10%). In MS-HRM analysis, the SFRP1 promoter region was significantly hypermethylated in CRC (55.0% ± 8.4 %) and adenoma tissue samples (49.9% ± 18.1%) compared to normal adult (5.2% ± 2.7%) and young (2.2% ± 0.7%) colonic tissue (P < 0.0001). DNA methylation of SFRP1 promoter was slightly, but significantly increased in healthy adults compared to normal young samples (P < 0.02). This correlated with significantly increased SFRP1 mRNA levels in children compared to normal adult samples (P < 0.05). In CRC tissue the mRNA expression of 117 age-related genes were changed, while in adenoma samples 102 genes showed differential expression compared with normal colonic tissue (P < 0.05, logFC > 0.5). The change of expression for several genes including SYNE1, CLEC3B, LTBP3 and SFRP1, followed the same pattern in aging and carcinogenesis, though not for all genes (e.g., MGP). CONCLUSION Several age-related DNA methylation alterations can be observed during CRC development and progression affecting the mRNA expression of certain CRC- and adenoma-related key control genes.
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8
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Galamb O, Kalmár A, Péterfia B, Csabai I, Bodor A, Ribli D, Krenács T, Patai ÁV, Wichmann B, Barták BK, Tóth K, Valcz G, Spisák S, Tulassay Z, Molnár B. Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer. Epigenetics 2016; 11:588-602. [PMID: 27245242 PMCID: PMC4990228 DOI: 10.1080/15592294.2016.1190894] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 04/26/2016] [Accepted: 05/11/2016] [Indexed: 02/06/2023] Open
Abstract
The WNT signaling pathway has an essential role in colorectal carcinogenesis and progression, which involves a cascade of genetic and epigenetic changes. We aimed to analyze DNA methylation affecting the WNT pathway genes in colorectal carcinogenesis in promoter and gene body regions using whole methylome analysis in 9 colorectal cancer, 15 adenoma, and 6 normal tumor adjacent tissue (NAT) samples by methyl capture sequencing. Functional methylation was confirmed on 5-aza-2'-deoxycytidine-treated colorectal cancer cell line datasets. In parallel with the DNA methylation analysis, mutations of WNT pathway genes (APC, β-catenin/CTNNB1) were analyzed by 454 sequencing on GS Junior platform. Most differentially methylated CpG sites were localized in gene body regions (95% of WNT pathway genes). In the promoter regions, 33 of the 160 analyzed WNT pathway genes were differentially methylated in colorectal cancer vs. normal, including hypermethylated AXIN2, CHP1, PRICKLE1, SFRP1, SFRP2, SOX17, and hypomethylated CACYBP, CTNNB1, MYC; 44 genes in adenoma vs. NAT; and 41 genes in colorectal cancer vs. adenoma comparisons. Hypermethylation of AXIN2, DKK1, VANGL1, and WNT5A gene promoters was higher, while those of SOX17, PRICKLE1, DAAM2, and MYC was lower in colon carcinoma compared to adenoma. Inverse correlation between expression and methylation was confirmed in 23 genes, including APC, CHP1, PRICKLE1, PSEN1, and SFRP1. Differential methylation affected both canonical and noncanonical WNT pathway genes in colorectal normal-adenoma-carcinoma sequence. Aberrant DNA methylation appears already in adenomas as an early event of colorectal carcinogenesis.
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Affiliation(s)
- Orsolya Galamb
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary
| | - Alexandra Kalmár
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Bálint Péterfia
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - István Csabai
- Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary
| | - András Bodor
- Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary
| | - Dezső Ribli
- Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary
| | - Tibor Krenács
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
- Tumor Progression Research Group, Hungarian Academy of Sciences – Semmelweis University, Budapest, Hungary
| | - Árpád V. Patai
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Barnabás Wichmann
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary
| | | | - Kinga Tóth
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Gábor Valcz
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary
| | - Sándor Spisák
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Zsolt Tulassay
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Béla Molnár
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary
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Amatu A, Barault L, Moutinho C, Cassingena A, Bencardino K, Ghezzi S, Palmeri L, Bonazzina E, Tosi F, Ricotta R, Cipani T, Crivori P, Gatto R, Chirico G, Marrapese G, Truini M, Bardelli A, Esteller M, Di Nicolantonio F, Sartore-Bianchi A, Siena S. Tumor MGMT promoter hypermethylation changes over time limit temozolomide efficacy in a phase II trial for metastatic colorectal cancer. Ann Oncol 2016; 27:1062-1067. [PMID: 26916096 DOI: 10.1093/annonc/mdw071] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 02/09/2016] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Objective response to dacarbazine, the intravenous form of temozolomide (TMZ), in metastatic colorectal cancer (mCRC) is confined to tumors harboring O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylation. We conducted a phase II study of TMZ enriched by MGMT hypermethylation in archival tumor (AT), exploring dynamic of this biomarker in baseline tumor (BT) biopsy and plasma (liquid biopsy). PATIENTS AND METHODS We screened 150 mCRC patients for MGMT hypermethylation with methylation-specific PCR on AT from FFPE specimens. Eligible patients (n = 29) underwent BT biopsy and then received TMZ 200 mg/m(2) days 1-5 q28 until progression. A Fleming single-stage design was used to determine whether progression-free survival (PFS) rate at 12 weeks would be ≥35% [H0 ≤ 15%, type I error = 0.059 (one-sided), power = 0.849]. Exploratory analyses included comparison between MGMT hypermethylation in AT and BT, and MGMT methylation testing by MethylBEAMing in solid (AT, BT) and LB with regard to tumor response. RESULTS The PFS rate at 12 weeks was 10.3% [90% confidence interval (CI) 2.9-24.6]. Objective response rate was 3.4% (90% CI 0.2-15.3), disease control rate 48.3% (90% CI 32.0-64.8), median OS 6.2 months (95% CI 3.8-7.6), and median PFS 2.6 months (95% CI 1.4-2.7). We observed the absence of MGMT hypermethylation in BT in 62.7% of tumors. CONCLUSION Treatment of mCRC with TMZ driven by MGMT promoter hypermethylation in AT samples did not provide meaningful PFS rate at 12 weeks. This biomarker changed from AT to BT, indicating that testing BT biopsy or plasma is needed for refined target selection.
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Affiliation(s)
- A Amatu
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - L Barault
- Experimental Clinical Molecular Oncology Cancer Epigenetics, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy
| | - C Moutinho
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - A Cassingena
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - K Bencardino
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - S Ghezzi
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - L Palmeri
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - E Bonazzina
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - F Tosi
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - R Ricotta
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - T Cipani
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - P Crivori
- Department of Oncology, CLIOSS s.r.l., Nerviano, Milan
| | - R Gatto
- Department of Oncology, CLIOSS s.r.l., Nerviano, Milan
| | - G Chirico
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - G Marrapese
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - M Truini
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan
| | - A Bardelli
- Experimental Clinical Molecular Oncology Cancer Epigenetics, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy; Department of Oncology, University of Torino, Candiolo, Turin
| | - M Esteller
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - F Di Nicolantonio
- Experimental Clinical Molecular Oncology Cancer Epigenetics, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy; Department of Oncology, University of Torino, Candiolo, Turin
| | - A Sartore-Bianchi
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
| | - S Siena
- Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan; Department of Oncology, Università degli Studi di Milano, Milan, Italy
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