CpG island methylator phenotype and its association with malignancy in sporadic duodenal adenomas

CpG island methylator phenotype (CIMP) has been found in multiple precancerous and cancerous lesions, including colorectal adenomas, colorectal cancers, and duodenal adenocarcinomas. There are no reports in the literature of a relationship between CIMP status and clinicopathologic features of sporadic duodenal adenomas. This study sought to elucidate the role of methylation in duodenal adenomas and correlate it with KRAS and BRAF mutations. CIMP+ (with more than 2 markers methylated) was seen in 33.3% of duodenal adenomas; 61% of these CIMP+ adenomas were CIMP-high (with more than 3 markers methylated). Furthermore, CIMP+ status significantly correlated with older age of patients, larger size and villous type of tumor, coexistent dysplasia and periampullary location. MLH1 methylation was seen in 11.1% of duodenal adenomas and was significantly associated with CIMP+ tumors, while p16 methylation was an infrequent event. KRAS mutations were frequent and seen in 26.3% of adenomas; however, no BRAF mutations were detected. Furthermore, CIMP-high status was associated with larger size and villous type of tumor and race (non-white). These results suggest that CIMP+ duodenal adenomas may have a higher risk for developing malignancy and may require more aggressive management and surveillance.

[1]  R. Buettner,et al.  High-resolution melting analysis as a sensitive prescreening diagnostic tool to detect KRAS , BRAF , PIK3CA , and AKT1 mutations in formalin-fixed, paraffin-embedded tissues. , 2012, Archives of pathology & laboratory medicine.

[2]  S. Baylin,et al.  CpG Island Methylator Phenotype–Positive Tumors in the Absence of MLH1 Methylation Constitute a Distinct Subset of Duodenal Adenocarcinomas and Are Associated with Poor Prognosis , 2012, Clinical Cancer Research.

[3]  D. Chang,et al.  Filiform serrated adenoma is an unusual, less aggressive variant of traditional serrated adenoma , 2012, Pathology.

[4]  Joanne P Young,et al.  Hyperplastic polyp of the duodenum: a report of 9 cases with immunohistochemical and molecular findings. , 2011, Human pathology.

[5]  J. Herman,et al.  Sessile serrated adenomas and classical adenomas: An epigenetic perspective on premalignant neoplastic lesions of the gastrointestinal tract , 2011, International journal of cancer.

[6]  D. Chang,et al.  Molecular Features of Colorectal Hyperplastic Polyps and Sessile Serrated Adenoma/Polyps From Korea , 2011, The American journal of surgical pathology.

[7]  M. Vieth,et al.  Up and downregulation of p16Ink4a expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer , 2011, Modern Pathology.

[8]  N. Cho,et al.  Differential clinicopathological features in microsatellite instability-positive colorectal cancers depending on CIMP status , 2011, Virchows Archiv.

[9]  J. Cubiella,et al.  5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer. , 2011, Gastroenterology.

[10]  J. Herman,et al.  Colorectal cancer epigenetics: complex simplicity. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  Shuji Ogino,et al.  Prognostic significance of CDKN2A (p16) promoter methylation and loss of expression in 902 colorectal cancers: Cohort study and literature review , 2011, International journal of cancer.

[12]  M. Kloor,et al.  Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP , 2011, Modern Pathology.

[13]  A. Nakajima,et al.  Sporadic Nonampullary Duodenal Adenoma in the Natural History of Duodenal Cancer: A Study of Follow-up Surveillance , 2011, The American Journal of Gastroenterology.

[14]  E. Culver,et al.  Sporadic duodenal polyps: classification, investigation, and management , 2011, Endoscopy.

[15]  R. Wilson,et al.  Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. , 2010, Cancer cell.

[16]  J. Rigaux,et al.  Nonampullary duodenal polyps: characteristics and endoscopic management. , 2010, Gastrointestinal Endoscopy.

[17]  R. Palmqvist,et al.  The Role of the CpG Island Methylator Phenotype in Colorectal Cancer Prognosis Depends on Microsatellite Instability Screening Status , 2010, Clinical Cancer Research.

[18]  G. Ginsberg,et al.  Endoscopic predictors of successful endoluminal eradication in sporadic duodenal adenomas and its acute complications. , 2009, Gastrointestinal endoscopy.

[19]  R. Arceci Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma , 2010 .

[20]  J. Church,et al.  Outcome Based on Management for Duodenal Adenomas: Sporadic Versus Familial Disease , 2010, Journal of Gastrointestinal Surgery.

[21]  M. Bourke,et al.  EMR of large, sessile, sporadic nonampullary duodenal adenomas: technical aspects and long-term outcome (with videos). , 2009, Gastrointestinal endoscopy.

[22]  S. Kakar,et al.  Distinct CpG island methylation profiles and BRAF mutation status in serrated and adenomatous colorectal polyps , 2008, International journal of cancer.

[23]  R. Yantiss,et al.  Immunohistochemical and Molecular Features of Sporadic and FAP-associated Duodenal Adenomas of the Ampullary and Nonampullary Mucosa , 2008, The American journal of surgical pathology.

[24]  J. Pe’er,et al.  Hypermethylation of CpG island loci of multiple tumor suppressor genes in retinoblastoma. , 2008, Experimental eye research.

[25]  A. Gabbrielli,et al.  Endoscopic treatment of ampullary adenomas. , 2008, JOP : Journal of the pancreas.

[26]  S. Kakar,et al.  CpG island methylation is frequently present in tubulovillous and villous adenomas and correlates with size, site, and villous component. , 2008, Human pathology.

[27]  M. O'brien,et al.  Comparison of Microsatellite Instability, CpG Island Methylation Phenotype, BRAF and KRAS Status in Serrated Polyps and Traditional Adenomas Indicates Separate Pathways to Distinct Colorectal Carcinoma End Points , 2006, The American journal of surgical pathology.

[28]  P. Laird,et al.  CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer , 2006, Nature Genetics.

[29]  R. Wolff,et al.  Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. , 2005, Gastroenterology.

[30]  James Church,et al.  The Utility of Capsule Endoscopy Small Bowel Surveillance in Patients with Polyposis , 2005, The American Journal of Gastroenterology.

[31]  S. Tripp,et al.  Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. , 2005, Human pathology.

[32]  M. Washington,et al.  Aberrantly methylated CDKN2A, MGMT, and MLH1 in colon polyps and in fecal DNA from patients with colorectal polyps. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  J. Stoner,et al.  Multicenter Experience with Upper Gastrointestinal Polyps in Pediatric Patients with Familial Adenomatous Polyposis , 2004, American Journal of Gastroenterology.

[34]  A. Lavergne,et al.  Sporadic duodenal adenoma is associated with colorectal neoplasia , 2004, Gut.

[35]  S. Ashley,et al.  Benign nonampullary duodenal neoplasms , 2003, Journal of Gastrointestinal Surgery.

[36]  W. Bodmer,et al.  An insight into the genetic pathway of adenocarcinoma of the small intestine , 2002, Gut.

[37]  P. Laird,et al.  MethyLight: a high-throughput assay to measure DNA methylation. , 2000, Nucleic acids research.

[38]  S. Baylin,et al.  Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. , 1999, Cancer research.

[39]  J. Herman,et al.  CpG island methylator phenotype in colorectal cancer. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M. Talamini,et al.  Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. , 1997, Annals of surgery.

[41]  F. Zinzindohoué,et al.  [A radical treatment of villous tumors of the duodenum]. , 1996, Annales de chirurgie.

[42]  A. Neugut,et al.  The association between cancers of the small and large bowel. , 1993, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[43]  M. Kitagawa,et al.  Biopsy study of polyps in the duodenal bulb. , 1993, The American journal of gastroenterology.

[44]  F. Sellner,et al.  Investigations on the significance of the adenoma‐carcinoma sequence in the small bowel , 1990, Cancer.

[45]  M. Sivak,et al.  Villous Tumors of the Duodenum , 1988, Annals of surgery.

[46]  K. H. Perzin,et al.  Adenomas of the small intestine: A clinicopathologic review of 51 cases and a study of their relationship to carcinoma , 1981, Cancer.

[47]  R. Raileanu,et al.  [Benign duodenal tumors]. , 1976, Revista medico-chirurgicala a Societatii de Medici si Naturalisti din Iasi.