BRAF Mutations in Aberrant Crypt Foci and Hyperplastic Polyposis

Abstract

Patients with hyperplastic polyposis have multiple hyperplastic polyps (HPs) and increased risk of colorectal carcinomas. Aberrant crypt foci (ACF) are postulated to be the earliest precursor lesions in colorectal carcinogenesis. We evaluated BRAF mutations by DNA sequencing in 53 ACF from patients with sporadic colorectal carcinomas and familial adenomatous polyposis, in 18 sporadic HPs from patients with resected colorectal cancer, and in 70 HPs, 4 serrated adenomas, 3 admixed hyperplastic-adenomatous polyps, 10 tubular adenomas, and 6 carcinomas from 17 patients with multiple/large HPs and/or hyperplastic polyposis. BRAF mutation status was compared with clinicopathological features and other genetic alterations by marginal logistic regression. BRAF mutation was present in only 2% of ACF and 6% of sporadic HPs. In contrast, BRAF mutation was present in 43% of HPs (P = 0.01 versus sporadic HPs), 75% of serrated adenomas, 33% of admixed hyperplastic-adenomatous polyps, 30% of tubular adenomas, and 33% of carcinomas from patients with multiple/large HPs and/or hyperplastic polyposis. BRAF mutation status in patients with multiple/large HPs and/or hyperplastic polyposis correlated with HPs from the same patient (odds ratio, 5.8; P = 0.0002) but associated with younger age (odds ratio, 0.83; P = 0.006 compared to older age), with a large HP (odds ratio, 22.5; P = 0.01 compared with patients with multiple HPs), with location of HPs in the right colon (odds ratio, 3.0; P = 0.03), and with methylation of the p16 gene and the MINT31 locus [odds ratio, 12.2 (P = 0.0001) and 4.4 (P = 0.02), respectively]. Our study shows that BRAF mutation status is heterogeneous among patients with multiple/large HPs and/or hyperplastic polyposis, suggesting differences in pathogenesis of HPs that indicate subsets within this phenotype.

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

“…K-ras mutation 0 (0/24) 50 (2/4) Chan et al (59) 64 (18/28) Otori et al (64) 13 (1/8) 64 (7/11) Takayama et al (26) BRAF mutation 0 (0/21) 0 (0/3) Beach et al (19) Chromosome 1p loss 0 (0/24) 0 (0/3) Chan et al …”

“…(1) Most colorectal cancers (CRC) develop from adenomatous polyps (tubular adenoma) and show morphological and genetic progression through an adenomacarcinoma sequence, even in hereditary colorectal cancer syndromes. (2)(3)(4) Sporadic HP are usually present in the left colon, are small, and are generally regarded as harmless lesions with no potential for malignancy.(5,6) However, adenocarcinoma arising in the setting of colorectal HP or serrated adenomas (SA), especially in patients with hyperplastic polyposis (HPP), which is characterized by the presence of numerous HP or large HP, have been described.(7-11) Indeed, patients with HPP have an increased risk of CRC.(11-18) Serrated polyps (SP) include HP, SA, and admixed hyperplastic-adenomatous polyps (AHAP), (19,20) and are considered a morphological continuum encompassing non-dysplastic (heteroplastic) aberrant crypt foci (ACF), HP, AHAP, and SA. (21) SA are composed of dysplastic epithelium but with the sawtooth configuration that is typical of HP.…”

“…(2) BRAF mutations tend to occur in a mutually exclusive relationship with K-ras mutations. (19,(36)(37)(38) BRAF mutations have been found in HP, SA (including some from patients with HPP) and colorectal carcinomas. (39)(40)(41) A subset of CRC show a characteristic mutator phenotype that leads to microsatellite instability (MSI) and mutations of other genes, such as TGFβRII (42) and BAX.…”

“…(7)(8)(9)(10)(11) Indeed, patients with HPP have an increased risk of CRC. (11)(12)(13)(14)(15)(16)(17)(18) Serrated polyps (SP) include HP, SA, and admixed hyperplastic-adenomatous polyps (AHAP), (19,20) and are considered a morphological continuum encompassing non-dysplastic (heteroplastic) aberrant crypt foci (ACF), HP, AHAP, and SA. (21) SA are composed of dysplastic epithelium but with the sawtooth configuration that is typical of HP.…”