Both BRAF and KRAS mutations are rare in colorectal carcinomas from patients with hereditary nonpolyposis colorectal cancer

Miyaki, Michiko; Iijima, Takeru; Yamaguchi, Tatsuro; Kadofuku, Tsuyoki; Funata, Nobuaki; Mori, Takeo

doi:10.1016/j.canlet.2004.01.027

Cited by 58 publications

(73 citation statements)

References 16 publications

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“…No germ line mutations were seen in these nine individuals (including three of the individuals whose tumors harbored APC mutations). Whereas APC mutations are known to occur in a subset of HNPCC-associated unstable tumors (12), their presence in sporadic unstable tumors has been controversial (8, 13), especially because it had been very difficult to completely exclude a germ line HNPCC mutation. Using our surrogate markers of CIMP-high, BRAF mutations and hMLH1 methylation (and, in many cases, evaluation of the germ line itself for mismatch repair gene mutations), we can be fairly certain that this subset of tumors is sporadic and that some do harbor APC mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, there is some controversy about whether APC mutations occur in sporadic microsatellite-unstable colon cancers; a subset of unstable tumors associated with hereditary nonpolyposis colon cancer (HNPCC) are known to harbor APC mutations (12), but the literature has been divided on whether these mutations are seen in sporadic unstable colon cancers (8,13). Studies also have differed on whether the spectrum of APC mutations in microsatellite-unstable tumors differs from that seen in stable tumors (13,14).…”

Section: Introductionmentioning

confidence: 99%

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APC Mutations and Other Genetic and Epigenetic Changes in Colon Cancer

Samowitz¹,

Slattery

Sweeney

et al. 2007

Molecular Cancer Research

139

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Relationships between adenomatous polyposis coli (APC) mutations, BRAF V600E mutations, and the CpG island methylator phenotype (CIMP) in colon cancer have not been explored. In addition, controversies exist about the proportion of tumors with APC mutations in the mutation cluster region (MCR); how commonly APC, Ki-ras, and p53 mutations occur in the same tumor; and whether APC mutations occur in sporadic microsatellite-unstable tumors. The APC gene was therefore sequenced in 90 colonic adenocarcinomas previously evaluated for CIMP, microsatellite instability, BRAF, Ki-ras, and p53. APC mutations were inversely related to BRAF mutations (P = 0.0003) and CIMP (P = 0.02) and directly related to p53 and Ki-ras mutations (P = 0.04). Slightly more than half of APC mutations occurred outside of the MCR, and frameshift mutations were more likely than nonsense mutations to occur in the MCR (21 of 28 versus 12 of 40, P = 0.0003). APC mutations were found in sporadic microsatellite-unstable tumors and were more likely to be frameshifts in short nucleotide repeats (P = 0.007). The occurrence of APC, Ki-ras, and p53 mutations together in the same tumor was uncommon (11.1%).In conclusion, an analysis restricted to the MCR will miss more than half of APC mutations as well as mischaracterize their mutational spectrum. The conventional wisdom that most colon cancers contain APC, Ki-ras, and p53 mutations is incorrect. Microsatellite instability may precede acquisition of APC mutations in sporadic microsatellite-unstable tumors. The relationships of APC mutations to other genetic and epigenetic alterations add to the already impressive genetic heterogeneity of colon cancer. (Mol Cancer Res 2007;5(2):165 -70)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

APC Mutations and Other Genetic and Epigenetic Changes in Colon Cancer

Samowitz¹,

Slattery

Sweeney

et al. 2007

Molecular Cancer Research

139

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“…In hereditary nonpolyposis colorectal cancer (HNPCC) caused by mutations of mismatch-repair genes, BRAF mutations are equally rare as they are in sporadic microsatellite stable colorectal cancer, indicating that the methylation pattern rather than mismatch-repair deficiency is associated with increased BRAF mutations. [20][21][22][23][24] Our study shows that the frequency of BRAF mutations and microsatellite instability in UC-related cancers is similar to that in sporadic colorectal cancers. 4,18,20 Microsatellite instability in these UC-related cancers was associated with a loss of hMLH1 (2 of 3 cases) or hMSH6 protein (1 of 3 cases); the loss of hMLH1 can be attributed to promoter hypermethylation in both cases.…”

Section: Discussionmentioning

confidence: 81%

“…Interestingly, microsatellite instability due to the hypermethylation of the hMLH1 promoter correlated significantly with BRAF mutations, but microsatellite instability due to mutations of the mismatch-repair genes did not, indicating that the methylation pattern rather than mismatch-repair deficiency is associated with increased BRAF mutations. [20][21][22][23][24] Nothing is known about the frequency of BRAF mutations in UC-related cancers, whereas KRAS mutations were studied in UCrelated neoplasia by a number of authors. There is concordance in that the frequency of KRAS mutations is lower in UC-related than in sporadic colorectal cancer.…”

Section: Rasmentioning

confidence: 99%

Mutations of the BRAF gene in ulcerative colitis‐related colorectal carcinoma

Aust

Haase

Dobryden

et al. 2005

Intl Journal of Cancer

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The Raf/MEK/ERK (MAPK) signal transduction cascade is an important mediator of a number of cellular fates including growth, proliferation and survival. The BRAF gene is activated by oncogenic Ras, leading to cooperative effects in cells responding to growth factor signals. Our study was performed to elucidate a possible function of BRAF in ulcerative colitis (UC)-related colorectal carcinogenesis. Mutations of BRAF and KRAS were determined in 33 UC-related colorectal cancers by direct DNA sequencing analyses after microdissection. Mismatch-repair deficiency was assessed by immunohistochemistry for major mismatch-repair proteins hMLH1, hMSH2 and hMSH6 and microsatellite analyses of the BAT25 and BAT26 loci. Hypermethylation of the hMLH1 promoter was also tested. The results obtained were correlated with histopathologic variables. Activating BRAF missense mutations were identified in 3/33 UC-related cancers (9%), 2 of which exhibited a loss of hMLH1-protein expression and hypermethylation of the hMLH1 promoter. Corresponding nondysplastic UC-mucosa of these patients did not show BRAF mutations. KRAS mutations were found in 6/33 (18%) UC cancers. All 6 UC cancers with KRAS mutations had an intact BRAF gene as the 3 cancers with BRAF mutations had an intact KRAS gene. There was no significant correlation between BRAF or KRAS status and clinicopathologic variables. Our data indicate that BRAF mutations are not an initiating event in UC-related carcinogenesis and are associated with mismatch-repair deficiency through hMLH1-promoter hypermethylation. Disruption of the Raf/MEK/ERK (MAPK) kinase pathway-either through RAS or BRAF mutation-was detected in 27% of all UC-related cancers and thus plays an important role in UC-related carcinogenesis. ' 2005 Wiley-Liss, Inc.Key words: ulcerative colitis; colorectal cancer; BRAF; KRAS; histopathology Patients with longstanding ulcerative colitis have an increased risk of developing colorectal cancer compared to an age-matched control group. The risk of developing colorectal neoplasia increases with the duration and the extent of disease.1,2 Like sporadic colorectal cancer, 3 UC-related cancer is thought to evolve through a multistep process of increasing genomic instability, accumulation of mutations and clonal expansion. Although UC-related and sporadic colorectal cancers share a common set of genomic alterations, UC-related carcinogenesis appears to differ from sporadic colorectal carcinogenesis by different frequencies of specific aberrations and by different times of onset of these alterations. 4,5 Since the discovery of the role of RAS oncogenes in tumorigenesis, we have witnessed an explosion of research in the signal transduction area.6,7 A key RAS effector pathway involves the kinase cascade RAF/MEK/ERK. In the quest to understand how RAS transmits extracellular growth signals, the MAP kinase (MAPK) pathway has emerged as an important route between membranebound RAS and the nucleus. [8][9][10] Signalling through the MAPK cascade is transduced by GTP loading of RAS leadi...

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“…Alteration of the Wnt/Wingless pathway can be observed in tumors irrespective of MSI status (29). Mutations in APC and CTNNB1 can be found in 21 and 43% of MSI tumors, respectively (30,31). In addition, the incidence of KRAS2 mutations appears to be as high as 22-31%, which is similar to the incidence observed in MSS colon cancers (32,33).…”

Section: Dna Mismatch Repair Pathway/inactivation Of Mmr Genesmentioning

confidence: 55%

Molecular Biology of Colon Cancer

Grady

Current Clinical Oncology

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SummaryColorectal cancer affects approx 140,000 people in the United States each year, resulting in more than 55,000 deaths. Colorectal cancer develops as the result of the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic epithelium to colon adenocarcinoma. The loss of genomic stability is a key molecular and pathophysiological step in this process and serves to create a permissive environment for the occurrence of alterations in tumor suppressor genes and oncogenes. Alterations in these genes, which include APC, CTNNB1, KRAS2, BRAF, MADH4/SMAD4, TP53, PI3KCA, and TGFBR2, appear to promote colon tumorigenesis by perturbing the function of signaling pathways, such as the transforming growth factor-␤ and PI3K signaling pathways, or by affecting genes that regulate genomic stability, such as the mutation mismatch repair genes.

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Both BRAF and KRAS mutations are rare in colorectal carcinomas from patients with hereditary nonpolyposis colorectal cancer

Cited by 58 publications

References 16 publications

APC Mutations and Other Genetic and Epigenetic Changes in Colon Cancer

APC Mutations and Other Genetic and Epigenetic Changes in Colon Cancer

Mutations of the BRAF gene in ulcerative colitis‐related colorectal carcinoma

Molecular Biology of Colon Cancer

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