BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum

Kambara, T.; Simms, L. A.; Whitehall, V. L. J.; Spring, K. J.; Wynter, C. V. A.; Walsh, M. D.; Barker, M. A.; Arnold, S.; McGivern, A.; Matsubara, N.; Tanaka, N.; Higuchi, T.; Young, J.; Jass, J. R.; Leggett, B. A.
August 2004
Gut;Aug2004, Vol. 53 Issue 8, p1137
Academic Journal
Background and aims: Mutations in BRAF hove been linked with colorectal cancers (CRC) showing high level microsatellite instability (MSI-H). However, the distribution of BRAF mutations in MSI-H cancers remains to be clarified with respect to precursor lesions and the CpG island methylator phenotype (CIMP). Methods: Forty three hyperplastic polyps (HP), nine mixed polyps (MP), five serrated adenomas (SA), 28 conventional adenomas (AD), 18 hereditary non-polyposis colorectal cancers (HNPCC), and 127 sporadic CRC (46 MSI-H and 81 non-M5I-H) were collected from patients undergoing colectomy for either CRC or hyperplastic polyposis. Twenty five of 57 serrated lesions were derived from four patients with hyperplastic polyposis. HP were further subdivided according to recently documented morphological criteria into 27 classical HP and 16 variant lesions described as "sessile serrated adenoma" (SSA). All tumours were screened for BRAF activating mutations. Results: The BRAF mutation was more frequent in SSA (75%) and MP (89%) than in classical HP (19%), SA (20%), and AD (0%) (p<0.0001), and also in sporadic MSI-H cancers (76%) compared with HNPCC (0%) and sporadic non-MSI-H cancers (9%) (p<0.0001). The BRAF mutation was identified more often in CIMP- high serrated polyps (72%) and CIMP-high CRC (77%) than in CIMP-low (30%) and CIMP-negative (13%) polyps (p=0.002) as well as CIMP-low (18%) and CIMP-negative (0%) CRC (p<0.0001). Conclusions: The BRAF mutation was frequently seen in SSA and in sporadic MSI-H CRC, both of which were associated with DNA methylation. Sporadic MSI-H cancers may originate in SSA and not adenomas, and BRAF mutation and DNA methylation are early events in this "serrated" pathway.


Related Articles

  • The CpG island methylator phenotype (CIMP) in colorectal cancer. Mojarad, Ehsan Nazemalhosseini; Kuppen, Peter JK; Aghdaei, Hamid Asadzadeh; Zali, Mohammad Reza // Gastroenterology & Hepatology from Bed to Bench;Summer2013, Vol. 6 Issue 3, p120 

    It is clear that colorectal cancer (CRC) develops through multiple genetic and epigenetic pathways. These pathways may be determined on the basis of three molecular features: (i) mutations in DNA mismatch repair genes, leading to a DNA microsatellite instability (MSI) phenotype, (ii) mutations...

  • PIK3CA Mutation in Colorectal Cancer: Relationship with Genetic and Epigenetic Alterations. Nosho, Katsuhiko; Kawasaki, Takako; Ohnishi, Mutsuko; Suemoto, Yuko; Kirkner, Gregory J.; Zepf, Dimity; Liying Yan; Longtine, Janina A.; Fuchs, Charles S.; Shuji Ogino // Neoplasia;Jun2008, Vol. 10 Issue 6, p534 

    Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN). Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. However,...

  • Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome. Morak, Monika; Koehler, Udo; Schackert, Hans Konrad; Steinke, Verena; Royer-Pokora, Brigitte; Schulmann, Karsten; Kloor, Matthias; H+ACYAIw-x00F6+ADs-chter, Wilhelm; Weingart, Josef; Keiling, Cortina; Massdorf, Trisari; Holinski-Feder, Elke // Journal of Medical Genetics;Aug2011, Vol. 48 Issue 8, p513 

    Background A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in w10e15% of cases of...

  • Analytical sensitivity and stability of DNA methylation testing in stool samples for colorectal cancer detection. Bosch, Linda; Mongera, Sandra; Droste, Jochim; Oort, Frank; Turenhout, Sietze; Penning, Maarten; Louwagie, Joost; Mulder, Chris; Engeland, Manon; Carvalho, Beatriz; Meijer, Gerrit // Cellular Oncology (2211-3428);Aug2012, Vol. 35 Issue 4, p309 

    Background: Stool-based molecular tests hold large potential for improving colorectal cancer screening. Here, we investigated the analytical sensitivity of a DNA methylation assay on partial stool samples, and estimated the DNA degradation in stool over time. In addition, we explored the...

  • Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Yamauchi, Mai; Morikawa, Teppei; Kuchiba, Aya; Yu Imamura; Qian, Zhi Rong; Nishihara, Reiko; Liao, Xiaoyun; Waldron, Levi; Hoshida, Yujin; Huttenhower, Curtis; Chan, Andrew T.; Giovannucci, Edward; Fuchs, Charles; Ogino, Shuji // Gut;Jun2012, Vol. 61 Issue 6, p847 

    Objective Colorectal cancer is typically classified into proximal colon, distal colon and rectal cancer. Tumour genetic and epigenetic features differ by tumour location. Considering a possible role of bowel contents (including microbiome) in carcinogenesis, this study hypothesised that tumour...

  • A broad band of silence. Smith, Justin S.; Costello, Joseph F. // Nature Genetics;May2006, Vol. 38 Issue 5, p504 

    Aberrant methylation of a CpG island in cancer is thought to silence a single gene but not its neighbors. A new study in colon cancer shows that transcriptional silencing can also be unexpectedly diffuse, encompassing all the genes over the 4 Mb of chromosome band 2q14.2, marked by archipelagos...

  • Low Frequency of Promoter Methylation of O6-Methylguanine DNA Methyltransferase and hMLH1 in Ulcerative Colitis-Associated Tumors: Comparison With Sporadic Colonic Tumors. Tetuo MD; Tsutomu Yoshida; Yoshiko Numata; Hiroaki Shiraishi; Kayo Araki; Marie-Christine Guiot; Jeremy Jass; Isao Okayasu // American Journal of Clinical Pathology;Mar2007, Vol. 127 Issue 3, p1 

    To cast light on the contribution of methylation to genesis of ulcerative colitis (UC)-associated tumors, promoter methylation and expression of O6-methylguanine DNA methyltransferase (MGMT), hMLH1, p16INK4, and E-cadherin were examined in 14 low-grade dysplasias (LGDs), 15 high-grade dysplasias...

  • The MRE11/RAD50/NBS1 complex destabilization in Lynch-syndrome patients. Alemayehu, Aster; Fridrichova, Ivana // European Journal of Human Genetics;Sep2007, Vol. 15 Issue 9, p922 

    Lynch syndrome is an inherited disease leading to the development predominantly of colorectal cancer (CRC). The crucial cause is malfunction of DNA mismatch repair that is characterized by high level of microsatellite instability; however, new knowledge of two MSI modes (types A and B) suggests...

  • Anticipation in Lynch Syndrome: Where We Are Where We Go. Bozzao, Cristina; Lastella, Patrizia; Stella, Alessandro // Current Genomics;Nov2011, Vol. 12 Issue 7, p451 

    Lynch syndrome (LS) is the most common form of inherited predisposition to develop cancer mainly in the colon and endometrium but also in other organ sites. Germline mutations in DNA mismatch repair (MMR) gene cause the transmission of the syndrome in an autosomal dominant manner. The management...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics