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PDF file - 716K, Supplementary Table 1. Somatic PIK3CA exon 9 and 20 mutations detected in 1,093 patients with sporadic CRC. Supplementary Table 2. Somatic PTEN exon 3 to 8 mutations detected in 744 patients with sporadic CRC. Supplementary Table 3. Pathogenicity predictions for PTEN missense mutations. Supplementary Table 4. Clinicopathological and molecular characteristics of sporadic CRC according to PIK3CA mutation status for microsatellite stable (n = 924) and microsatellite instability-high (n=159) cases. Supplementary Table 5. Relationship of clinicopathological and molecular characteristics of sporadic CRC with PIK3CA exon 9 or 20 mutation status, for (A) microsatellite stable (n = 923) and (B) microsatellite instability-high (n=159) cases. Supplementary Table 6. Multivariate logistic regression analysis for overall PIK3CA gene mutation relative to wild-type. Model 1 includes age at diagnosis, gender, tumor location, stage, differentiation, mucinous histology, MSI, CIMP, KRAS, BRAF and PTEN mutation status. Supplementary Table 7. Multivariate logistic regression analysis for PIK3CA exon 9 mutation relative to wild-type. Model 1 includes age at diagnosis, gender, tumor location, stage, differentiation, mucinous histology, MSI, CIMP, KRAS, BRAF and PTEN mutation status. Supplementary Table 8. Multivariate logistic regression analysis for PIK3CA exon 20 mutation relative to wild-type. Model 1 includes age at diagnosis, gender, tumor location, stage, differentiation, mucinous histology, MSI, CIMP, KRAS, BRAF and PTEN mutation status. Supplementary Table 9. Multivariate logistic regression analysis for PIK3CA exon 20 mutation relative to exon 9 mutation. Model 1 includes age at diagnosis, gender, tumor location, stage, differentiation, mucinous histology, MSI, CIMP, KRAS, BRAF and PTEN mutation status. Supplementary Table 10. Clinicopathological and molecular characteristics of sporadic CRC according to PTEN mutation status for microsatellite stable (n = 645) and microsatellite instability-high (n=98) cases. Supplementary Table 11. Multivariate logistic regression analysis for PTEN gene mutation relative to wild-type. Model 1 includes age at diagnosis, gender, tumor location, stage, differentiation, mucinous histology, MSI, CIMP, KRAS, BRAF and PTEN mutation status. Supplementary Table 12. Univariate and multivariate Cox proportionalhazards analysis of disease-free survival for patients with resected stage II or III CRC according to PIK3CA mutation status, with mutations classified into exon 9 or exon 20 mutations. * P

Purpose:PIK3CA and PTEN mutations are prevalent in colorectal cancer and potential markers of response to mitogen-activated protein/extracellular signal–regulated kinase inhibitors and anti-EGF receptor antibody therapy. Relationships between phosphoinositide 3-kinase (PI3K) pathway mutation, clinicopathologic characteristics, molecular features, and prognosis remain controversial.Experimental Design: A total of 1,093 stage I–IV colorectal cancers were screened for PIK3CA (exons 9 and 20), KRAS (codons 12–13), BRAF (codon 600) mutations, and microsatellite instability (MSI). PTEN (exons 3–8) and CpG island methylator phenotype (CIMP) status were determined in 744 and 489 cases. PIK3CA data were integrated with 17 previous reports (n = 5,594).Results:PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of colorectal cancers. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high (MSI-H), CIMP-high (CIMP-H), and BRAF mutation (P < 0.02). PIK3CA mutation was related to older age, proximal tumors, mucinous histology, and KRAS mutation (P < 0.04). In integrated cohort analysis, PIK3CA exon 9 and 20 mutations were overrepresented in proximal, CIMP-low (CIMP-L), and KRAS-mutated cancers (P ≤ 0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-H, CIMP-H, and BRAF mutation, and exon 9 mutation was associated with KRAS mutation (P ≤ 0.027). Disease-free survival for stage II/III colorectal cancers did not differ by PI3K pathway status.Conclusion: PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-H/CIMP-H/BRAFmut), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/KRASmut) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct colorectal cancer subtypes. Clin Cancer Res; 19(12); 3285–96. ©2013 AACR.

RAS mutation testing now routinely informs the optimal management of metastatic colorectal cancer (mCRC), specifically the finding of a RAS mutation defines patients who will not benefit from treatment with an epidermal growth factor receptor inhibitor. Over time more RAS genes have been tested and more sensitive techniques used.To review routine care RAS testing and results over time.A retrospective analysis of the molecular data collected prospectively in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry from 2009 to 2018 was undertaken. Patients with RAS data were further analyzed. In parallel, the RAS mutation status of patients enrolled in the Test Tailor Treat (TTT) program was examined for 2011-2018.Of 2908 patients in the TRACC registry, 1892 (65%) were tested, with 898 (47%) of tested patients found to be RAS mutant (RASmt). RAS data were available for 5935 TTT patients. Of the tested TRACC patients diagnosed in 2009 and 2010, 38% were RASmt. For each 2-year period from 2011/2012 through to 2017/2018, the prevalence of RASmt in TRACC and TTT was 42% and 40% (2011/2012), 52% and 40% (2013/2014), 47% and 49% (2015/2016), and 47% and 49% (2017/2018).Based on both TRACC and TTT data, the proportion of patients reported to have a RAS mutation increased from 2009 to 2015 but has remained relatively stable in recent years. The increased proportion of RASmt patients observed over time is likely largely driven by the uptake of extended RAS testing.

Colorectal cancer (CRC) is largely viewed as a preventable disease but the prevalence is increasing worldwide. Although many faecal and blood-based biomarkers have been proposed as potential diagnostic markers, none have been successful in large cohort studies. In this study, ELISA was used to evaluate 32 candidate protein biomarkers in a single cohort of CRC patients (n=95) and age/sex matched controls (n=50). Of these, 12 markers differed statistically between cases and controls. Receiver operating characteristic analysis identified IL8, Mac2BP, TIMP1, and OPN as the best performing markers for overall CRC diagnosis. However, further analysis determined that IL6, TGFB1, TIMP2 and IGF2 were most accurate at identifying early stage disease. We also assessed the correlation between markers and determined that the strongest correlations existed between VEGFA and TGFB1 (r=0.65, p

BACKGROUND: Lipocalin 2 has been implicated in colorectal tumorigenesis but its usefulness as a diagnostic marker for the disease has previously never been determined. METHODS: We have used ELISA immunoassay to measure the level of serum lipocalin 2 in a cohort consisting of colorectal cancer patients (n = 196) and age/gender matched controls (n = 99). RESULTS: The median concentration of lipocalin 2 was found to be significantly higher ( p< 0.0001) in the patient group (105.9 ng/mL, range 10.8–444.7 ng/mL) when compared to the control subjects (86.4 ng/mL, range 17.1–190.0 ng/mL). Additionally, no significant difference was observed between disease stage (Dukes’ or T stage) in the patient cohort. Receiver operating characteristic analysis was performed to determine its performance as a diagnostic marker. The area under the curve was found to be 0.641 (95% confidence interval 0.576–0.706). Furthermore, the sensitivity of lipocalin 2 was found to be 24% at 90% specificity. CONCLUSIONS: Our study indicates that lipocalin 2 is not a suitable serum biomarker for the diagnosis of CRC.