Somatic mutations of APC gene in carcinomas from hereditary non-polyposis colorectal cancer patients

Huang, Jian; Jin, Shen-hang; Zhang, Suzhan

doi:10.3748/wjg.v10.i6.834

Cited by 16 publications

(11 citation statements)

References 22 publications

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“…6,34). Surprisingly, in HNPCC-MSS tumors, small deletions/insertions in repetitive sequences account for 70% of mutations, mimicking the mutation profile of HNPCC-MSI-H (34,35). The data indicate that factors other than MMR deficiency might account for this mutation profile.…”

Section: Discussionmentioning

confidence: 79%

Molecular Analysis of Colorectal Cancer Tumors from Patients with Mismatch Repair–Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways

Sánchez-de-Abajo

Hoya

Puijenbroek

et al. 2007

Clinical Cancer Research

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Purpose: A subset of colorectal cancers (CRC) arises in families that, despite fulfilling clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC), do not show evidence of a mismatch repair (MMR) deficiency. The main objective of this study was to characterize these tumors at the molecular level. Experimental Design: After comprehensive germ line mutation scanning, microsatellite analysis, and MMR protein expressions, we selected a well-defined cohort of 57 colorectal tumors with no evidence of MMR defects. In this group of tumors, we analyzed KRAS, BRAF, and APC somatic mutations, as well as methylguanine methyltransferase (MGMT) and h-catenin expression.We correlated these alterations with clinicopathologic data and explored the relationship between KRAS G > A transitions and lack of MGMTexpression. Results:The mutation profile at the RAS/RAF/MAPK pathway mimics sporadic microsatellitestable CRCs. We found an average age of diagnosis 10 years older in KRAS-mutated patients (P = 0.001). In addition, we show that KRAS G > A transitions are actively selected by tumors, regardless of MGMT status. Similarities with HNPCC high^microsatellite instability tumors are observed when APC data are analyzed. The APC mutation rate was low and small insertions/ deletions accounted for 70% of the alterations. In addition, we found a low frequency of h-catenin nuclear staining. Finally, we did not find evidence of tumors arising in individuals from the same family sharing molecular features. Conclusions: We show evidence that CRC tumors arising in HNPCC families without MMR alterations have distinctive molecular features. Overall, our work shows that systematic analysis of somatic alterations in a well-defined subset of CRCs is a good approach to provide new insights into the mechanisms of colorectal carcinogenesis.Approximately 5% of all colorectal cancers (CRC) are diagnosed in the context of known Mendelian syndromes, principally, hereditary nonpolyposis colon cancer (HNPCC) and familial adenomatous polyposis. When considering HNPCC as a syndrome linked to mismatch repair (MMR) gene mutations, the frequency range is from 0.3% to 3% of the total CRC burden (1). Tumors from patients with MMR mutations frequently show high -microsatellite instability (MSI-H; ref.2). The MSI-H phenotype is also found in 10% to 15% of sporadic CRCs, although these tumors differ from their hereditary counterparts at the molecular level (3, 4). For instance, the MMR deficiency seen in sporadic tumors is mainly due to hMLH1 promoter hypermethylation. Apart from MSI, less wellcharacterized genetic instability phenotypes may contribute to colorectal carcinogenesis. For example, epigenetic silencing of methylguanine methyltransferase (MGMT), leading to an excess of G > A transitions, is a common event (5).Early genetic events in colorectal carcinogenesis involve the deregulation of the WNT and RAS/RAF/MAPK pathways. The mutation profile of a particular tumor is related to the underlying phenotype instability. For example, in MSI...

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Section: Discussionmentioning

confidence: 79%

Molecular Analysis of Colorectal Cancer Tumors from Patients with Mismatch Repair–Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways

Sánchez-de-Abajo

Hoya

Puijenbroek

et al. 2007

Clinical Cancer Research

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“…Germline mutations in the tumor suppressor APC gene cause familial adenomatous polyposis, and somatic mutations are common in sporadic CRC (45). Hypermethylation of the APC promoter has been reported in early steps of carcinogenesis in several tumors (46).…”

Section: Discussionmentioning

confidence: 99%

Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer

et al. 2016

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Abstract. DNA methylation is the most frequent epigenetic alteration. Using methylation-specific polymerase chain reaction (MSP), the methylation status of the adenomatous polyposis coli (APC) and Ras association domain family 1 isoform A (RASSF1A) genes was examined in cell-free circulating DNA from 155 plasma samples obtained from patients with early and advanced colorectal cancer (CRC). APC and RASSF1A hypermethylation was frequently observed in both early and advanced disease, and was significantly associated with a poorer disease outcome. The methylation status of the APC and RASSF1A promoters was investigated in cell-free DNA of patients with CRC. Using MSP, the promoter methylation status of APC and RASSF1A was examined in 155 blood samples obtained from patients with CRC, 88 of whom had operable CRC (oCRC) and 67 had metastatic CRC (mCRC). The frequency of APC methylation in patients with oCRC was 33%. Methylated APC promoter was significantly associated with older age (P= 0.012), higher stage (P= 0.014) and methylated RASSF1A status (P= 0.050). The frequency of APC methylation in patients with mCRC was 53.7%. In these patients, APC methylation was significantly associated with methylated RASSF1A status (P=0.016). The frequency of RASSF1A methylation in patients with oCRC was 25%. Methylated RASSF1A in oCRC was significantly associated with higher stage (P=0.021). The frequency of RASSF1A methylation in mCRC was 44.8%. Methylated RASSF1A in mCRC was associated with moderate differentiation (P=0.012), high levels of carcinoembryonic antigen (P=0.023) and methylated APC status (P=0.016). Patients with an unmethylated APC gene had better survival in both early (81±5 vs. 27±4 months, P<0.001) and advanced disease (37±7 vs. 15±3 months, P<0.001), compared with patients with methylated APC. Patients with an unmethylated RASSF1A gene had better survival in both early (71±6 vs. 46±8 months, P<0.001) and advanced disease (28±4 vs. 16±3 months, P<0.001) than patients with methylated RASSF1A. The observed significant correlations between APC and RASSF1A promoter methylation status and survival may be indicative of a prognostic role for these genes in CRC, which requires additional testing in larger studies.

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“…The percentages reported next to a subset of scores indicate the proportion of tumor cells presenting with that particular score. Huang et al (1996Huang et al ( , 2004, Homfray et al (1996), Kitaeva et al (1997), Muller et al (1998), Miyaki et al (1999) (Tables 1 and 2). Among the MSI-H tumors, CTNNB1 mutations appeared to be more frequent in HNPCC MMR deficient than in sporadic MSI-H carcinomas (4/ 12 versus 1/10).…”

Section: Mutation Frequenciesmentioning

confidence: 99%

“…APC mutations have been found in the majority of MSS (microsatellite stable) tumors and in 20-50% of MSI-High cancers, both from sporadic and HNPCC (hereditary nonpolyposis colorectal cancer) patients carrying germline mutations in MMR genes (Huang et al, 1996(Huang et al, , 2004Homfray et al, 1998;Rowan et al, 2000). Colorectal tumors with an intact APC gene, mostly MSI-H, often carry oncogenic b-catenin (CTNNB1) mutations which make the resulting protein resistant to proteolytic degradation (Kitaeva et al, 1997;Mirabelli-Primdahl et al, 1999;Morin et al, 1997;Muller et al, 1998;Sparks et al, 1998;Miyaki et al, 1999;Lovig et al, 2002;Johnson et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…To address these issues in a more systematic fashion, we have performed somatic mutation analyses of the APC, CTNNB1, and AXIN2 genes in a cohort of 52 colorectal tumors stratified by their sporadic or hereditary nature, MSI status, and anatomical location. In parallel, we performed a meta analysis by employing the mutation analysis data from colorectal tumors, stratified by MSI status and anatomical location, reported to date in the scientific literature (Aoki et al, 1994;Huang et al, 1996Huang et al, , 2004Kitaeva et al, 1997;Olschwang et al, 1997;Yagi et al, 1997;Homfray et al, 1998;Muller et al, 1998;Otori et al, 1998;Miyaki et al, 1999;Salahshor et al, 1999;Rowan et al, 2000;Shitoh et al, 2001;Aust et al, 2002;Lovig et al, 2002;Shimizu et al, 2002;Smith et al, 2002;Miyaki et al, 2003;Giaretti et al, 2004;Johnson et al, 2005;Suraweera et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Colorectal cancers show distinct mutation spectra in members of the canonical WNT signaling pathway according to their anatomical location and type of genetic instability

Albuquerque

Baltazar

Filipe

et al. 2010

Genes Chromosomes & Cancer

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It is unclear whether the mutation spectra in WNT genes vary among distinct types of colorectal tumors. We have analyzed mutations in specific WNT genes in a cohort of 52 colorectal tumors and performed a meta-analysis of previous studies. Notably, significant differences were found among the mutation spectra. We have previously shown that in familial adenomatous polyposis, APC somatic mutations are selected to provide the "just-right" level of WNT signaling for tumor formation. Here, we found that APC mutations encompassing at least two beta-catenin down-regulating motifs (20 a.a. repeats) are significantly more frequent in microsatellite unstable (MSI-H) than in microsatellite stable (MSS) tumors where truncations retaining less than two repeats are more frequent (P = 0.0009). Moreover, in cases where both APC hits are detected, selection for mutations retaining a cumulative number of two 20 a.a. repeats became apparent in MSI-H tumors (P = 0.001). This type of mutations were also more frequent in proximal versus distal colonic tumors, regardless of MSI status (P = 0.0008). Among MSI-H tumors, CTNNB1 mutations were significantly more frequent in HNPCC than in sporadic lesions (28% versus 6%, P < 10-6) and were preferentially detected in the proximal colon, independently of MSI status (P = 0.017). In conclusion, the observed spectra of WNT gene mutations in colorectal tumors are likely the result from selection of specific levels of beta-catenin signaling, optimal for tumor formation in the context of specific anatomical locations and forms of genetic instability. We suggest that this may underlie the preferential location of MMR deficient tumors in the proximal colon.

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Somatic mutations of APC gene in carcinomas from hereditary non-polyposis colorectal cancer patients

Abstract: AIM:To investigate the mutational features of adenomatous polyposis coli (APC) gene and its possible arising mechanism in hereditary non-polyposis colorectal cancers (HNPCC).

Cited by 16 publications

References 22 publications

Molecular Analysis of Colorectal Cancer Tumors from Patients with Mismatch Repair–Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways

Molecular Analysis of Colorectal Cancer Tumors from Patients with Mismatch Repair–Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways

Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer

Colorectal cancers show distinct mutation spectra in members of the canonical WNT signaling pathway according to their anatomical location and type of genetic instability

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