Low somatic K-ras mutation frequency in colorectal cancer diagnosed under the age of 45 years

Alsop, Kathryn; Mead, Leeanne J.; Smith, Letitia; Royce, Simon G.; Tesoriero, Andrea; Young, Joanne; Haydon, Andrew; Grubb, Garry; Giles, Graham G.; Jenkins, Mark A.; Hopper, John L.; Southey, Melissa C.

doi:10.1016/j.ejca.2006.02.023

Cited by 26 publications

(18 citation statements)

References 20 publications

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“…Recently, a population-based study published a very low KRAS mutation rate (6%) in early onset sporadic CRC (<45 years old; ref. 31). In this regard, we observed a strong association of KRAS mutation with older age of diagnosis.…”

Section: Discussionsupporting

confidence: 52%

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: Discussionsupporting

confidence: 52%

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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“…We identified a rate for KRAS and TP53 mutations (respectively 37% and 44%) as similar to that of CIN tumors but with an absence of BRAF mutations and no evidence of a methylator phenotype [41]. The discrepancies with data from the literature on mutation rates in EOCRC might be linked to the absence of a clear distinction between MSS and MSI tumors in older studies which may have affected the mutation rates, particularly for KRAS and BRAF [39], [40]. Overall, our genetic study favors the hypothesis that sporadic EOCRC is a sub-group of CIN tumors with neither BRAF mutation nor methylator phenotype.…”

Section: Discussionmentioning

confidence: 55%

Sporadic Early-Onset Colorectal Cancer Is a Specific Sub-Type of Cancer: A Morphological, Molecular and Genetics Study

et al. 2014

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Sporadic early onset colorectal carcinoma (EOCRC) which has by definition no identified hereditary predisposition is a growing problem that remains poorly understood. Molecular analysis could improve identification of distinct sub-types of colorectal cancers (CRC) with therapeutic implications and thus can help establish that sporadic EOCRC is a distinct entity. From 954 patients resected for CRC at our institution, 98 patients were selected. Patients aged 45–60 years were excluded to help define “young” and “old” groups. Thirty-nine cases of sporadic EOCRC (patients≤45 years with microsatellite stable tumors) were compared to both microsatellite stable tumors from older patients (36 cases, patients>60 years) and to groups of patients with microsatellite instability. Each group was tested for TP53, KRAS, BRAF, PIK3CA mutations and the presence of a methylator phenotype. Gene expression profiles were also used for pathway analysis. Compared to microsatellite stable CRC from old patients, sporadic EOCRC were characterized by distal location, frequent synchronous metastases and infrequent synchronous adenomas but did not have specific morphological characteristics. A familial history of CRC was more common in sporadic EOCRC patients despite a lack of identified hereditary conditions (p = 0.013). Genetic studies also showed the absence of BRAF mutations (p = 0.022) and the methylator phenotype (p = 0.005) in sporadic EOCRC compared to older patients. Gene expression analysis implicated key pathways such as Wnt/beta catenin, MAP Kinase, growth factor signaling (EGFR, HGF, PDGF) and the TNFR1 pathway in sporadic EOCRC. Wnt/beta catenin signaling activation was confirmed by aberrant nuclear beta catenin immunostaining (p = 0.01). This study strongly suggests that sporadic EOCRC is a distinct clinico-molecular entity presenting as a distal and aggressive disease associated with chromosome instability. Furthermore, several signaling pathways including the TNFR1 pathway have been identified as potential biomarkers for both the diagnosis and treatment of this disease.

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“…27,28 Tumor DNA was tested for the p.V600E BRAF mutation (N=1,948) using a fluorescent allele-specific PCR assay as described previously; 29 this mutation accounts for ~90% of BRAF mutations in CRC. 30 Mutations in KRAS codons 12 and 13 were identified through forward and reverse sequencing of amplified tumor DNA (N=1,894); 8,31 mutations in this hotspot region account for ~80% of KRAS mutations in CRC. 32,33 CIMP testing was completed for a large subset of cases (N=1,508) based on a validated quantitative DNA methylation assay using a five-gene panel ( CACNA1G , IGF2 , NEUROG1 , RUNX3 , SOCS1 ).…”

Section: Methodsmentioning

confidence: 99%

Association Between Molecular Subtypes of Colorectal Cancer and Patient Survival

et al. 2015

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Background and Aims. Colorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival. Methods. Participants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (n=2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI] high, CpG island methylator phenotype [CIMP] positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI-low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1-3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history. Results. Compared to participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR=2.20, 95% CI: 1.47-3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR=1.32, 95% CI: 1.07-1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR=0.30, 95% CI: 0.14-0.66). Associations with overall mortality were similar to those with disease-specific mortality. Conclusions. Based on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC.

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Low somatic K-ras mutation frequency in colorectal cancer diagnosed under the age of 45 years

Cited by 26 publications

References 20 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

Sporadic Early-Onset Colorectal Cancer Is a Specific Sub-Type of Cancer: A Morphological, Molecular and Genetics Study

Association Between Molecular Subtypes of Colorectal Cancer and Patient Survival

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