Mutations in BRAF and KRAS Differentially Distinguish Serrated versus Non-Serrated Hyperplastic Aberrant Crypt Foci in Humans

Abstract

We previously reported that colon carcinomas, adenomas, and hyperplastic polyps exhibiting a serrated histology were very likely to possess BRAF mutations, whereas when these same advanced colonic lesions exhibited non-serrated histology, they were wild type for BRAF; among hyperplastic polyps, KRAS mutations were found mainly in a non-serrated variant. On this basis, we predicted that hyperplastic aberrant crypt foci (ACF), a putative precancerous lesion found in the colon, exhibiting a serrated phenotype would also harbor BRAF mutations and that non-serrated ACF would not. In contrast, KRAS mutations would be found more often in the nonserrated ACF. We examined 55 ACF collected during screening colonoscopy from a total of 28 patients. Following laser capture microdissection, DNA was isolated, and mutations in BRAF and KRAS were determined by direct PCR sequencing. When hyperplastic lesions were further classified into serrated and non-serrated histologies, there was a strong inverse relationship between BRAF and KRAS mutations: a BRAF V600E mutation was identified in 10 of 16 serrated compared with 1 of 33 non-serrated lesions (P = 0.001); conversely, KRAS mutations were present in 3 of 16 serrated compared with 14 of 33 non-serrated lesions. Our finding of a strong association between BRAF mutations and serrated histology in hyperplastic ACF supports the idea that these lesions are an early, sentinel, or a potentially initiating step on the serrated pathway to colorectal carcinoma. [Cancer Res 2007;67(8):3551-4]

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

“…17,49 Although these colorectal mucosa samples were macroscopically normal, it is conceivable that they contained aberrant cryptic foci. Indeed, the presence of the BRAF V600E mutation, 50,51 as well as methylation of numerous genes including MLH1, [52][53][54] have previously been identified in these benign lesions. Nevertheless, the occurrence of these molecular event may represent a 'field defect' that underlies the development of metachronous colorectal neoplasia in some patients.…”

Genetic and epigenetic changes in aberrant crypt foci and serrated polyps

“…higher in non-serrated hyperplastic ACF than in serrated hyperplastic ACF (Table 2). (70) This mutually exclusive relationship between K-ras and BRAF mutations suggests the existence of distinct pathways to hyperplastic ACF as shown in Figure 2.…”

“…K-ras mutation 36 (10/28) Chan et al (59) 88 (28/32) Takayama et al (26) 93 (50/56) Otori et al (64) 19 (3/16) 42 (14/33) Rosenberg et al (70) BRAF mutation 4 (1/26) Beach et al (19) 63 (10/26) 3 (1/33) Rosenberg et al (70) Chromosome 1p loss 10 (2/20) Chan et al (59) MGMT methylation 13 (3/24) Chan et al (59) CIM 50 (14/28) Chan et al (59) CIMP-high 11 (3/28) Chan et al (59) CIM, CpG island methylation of MINT1, MINT2, MINT31, p16, MGMT and/or hMLH1; CIMP, CpG island methylator phenotype; CRC, colorectal cancer. (73) 0 (0/9) Chan et al (41) 24 ( (19) 100 (9/9) Chan et al (41) 62 ( …”

BRAF V600E mutations in bile duct adenomas

“…BRAF mutations also seem to occur early during carcinogenesis, as observed in the serrated pathway of colon cancer. 6 In conclusion, we have identified a high frequency of BRAF V600E mutations in BDAs, suggesting that they are true neoplasms and that they may be important precursors for the subset of ICC exhibiting BRAF mutations. Our findings support an adenoma to carcinoma sequence associated with BRAF mutations in intrahepatic biliary carcinogenesis.…”

“…6 HCV case finding and treatment in prison could provide a substantial boost to "treatment as prevention" in the community, precisely because individuals with an ongoing risk of transmitting infection to others may be detected and treated. To date, however, the duration of HCV treatment, problems of ensuring continuity of care in the community, and average durations of imprisonment have mitigated against scaling up HCV treatment in the prison setting.…”