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Purpose:To analytically and clinically validate microsatellite instability (MSI) detection using cell-free DNA (cfDNA) sequencing.Experimental Design:Pan-cancer MSI detection using Guardant360 was analytically validated according to established guidelines and clinically validated using 1,145 cfDNA samples for which tissue MSI status based on standard-of-care tissue testing was available. The landscape of cfDNA-based MSI across solid tumor types was investigated in a cohort of 28,459 clinical plasma samples. Clinical outcomes for 16 patients with cfDNA MSI-H gastric cancer treated with immunotherapy were evaluated.Results:cfDNA MSI evaluation was shown to have high specificity, precision, and sensitivity, with a limit of detection of 0.1% tumor content. In evaluable patients, cfDNA testing accurately detected 87% (71/82) of tissue MSI-H and 99.5% of tissue microsatellite stable (863/867) for an overall accuracy of 98.4% (934/949) and a positive predictive value of 95% (71/75). Concordance of cfDNA MSI with tissue PCR and next-generation sequencing was significantly higher than IHC. Prevalence of cfDNA MSI for major cancer types was consistent with those reported for tissue. Finally, robust clinical activity of immunotherapy treatment was seen in patients with advanced gastric cancer positive for MSI by cfDNA, with 63% (10/16) of patients achieving complete or partial remission with sustained clinical benefit.Conclusions:cfDNA-based MSI detection using Guardant360 is highly concordant with tissue-based testing, enabling highly accurate detection of MSI status concurrent with comprehensive genomic profiling and expanding access to immunotherapy for patients with advanced cancer for whom current testing practices are inadequate.See related commentary by Wang and Ajani, p. 6887

Background: NOX-A12 is an inhibitor of the chemokine CXCL12 which prevents engagement with its receptors CXCR4 and CXCR7 and blocks the formation of chemotactic CXCL12 concentration gradients in tissue. The Opera study (NCT03168139) is a Phase 1/2 study to evaluate pharmacodynamic effects and safety of monotherapy with NOX-A12 as well as safety and efficacy of a combination with pembrolizumab in metastatic microsatellite-stable colorectal and pancreatic cancer where PD-1 inhibition alone has not shown clinical benefit. Methods: Patients received 300 mg NOX-A12 twice weekly during a 2-week monotherapy phase. Biopsies were taken from liver metastases before and after NOX-A12 monotherapy for analysis of immune cell infiltration and cytokine signature. In a combination phase, patients received repeated 21-day cycles of 300 mg NOX-A12 and 200 mg pembrolizumab until progression or intolerable toxicity. Results: 11 of the patients had CRC and 9 PaC. All patients were heavily pretreated with 5 (colorectal cancer) and 3 median lines (pancreatic cancer) of prior treatment. Best responses to last prior treatment was progressive disease for 95% of patients. The AE profile was comparable with the pembrolizumab profile or typical for the underlying diseases. Two weeks of NOX-A12 monotherapy induced Th1 cytokines (IFNγ, IL-2, IL-16) in approx. half of the patients. Comparison of tumor biopsies from before and after NOX-A12 monotherapy shows trends towards (i) agglomeration of T cells and (ii) migration of T cells towards cancer cells in the patient sub-group where NOX-A12 induced a Th1-type cytokine response. These trends are consistent with preclinical data (Feig 2013, PNAS 110:20212; Zboralski 2017, Cancer Immunol Res 5:950), suggesting that neutralization of CXCL12 signaling - either through one or both receptors - increased infiltration of effector immune cells into tumor tissue and resulted in a more effective immune response. Although there were no objective responses, 25% of patients achieved stable disease; 7 patients showed prolonged time on treatment vs. the prior line of therapy. Median progression-free survival was 1.87 months, overall survival was 42% at 6 months and 22% at 12 months. Conclusions: A trend towards agglomeration of T cells within tumors was observed in about half of the patients where NOX-A12 had induced a Th1-type cytokine response. This agglomeration was accompanied by reduced distances between T cells and cancer cells, suggesting increased infiltration of effector immune cells into tumor tissue. Treatment with NOX-A12 plus pembrolizumab in the combination therapy part of the study resulted in stable disease in 25% of patients, and prolonged time on treatment vs. prior therapy for 35% of patients. The safety profile of the combination therapy was consistent with that of pembrolizumab in advanced cancer patients. Citation Format: Niels Halama, Anja Williams, Ulrike Prüfer, Anna Frömming, Diana Beyer, Dirk Eulberg, Jarl Ulf Jungnelius, Aram Mangasarian. Phase 1/2 study with CXCL12 inhibitor NOX-A12 and pembrolizumab in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT117.

Microsatellite instability (MSI) assays are used to screen cancer patients with mismatch repair deficiency (dMMR) for immune checkpoint inhibitor therapy. However, short mononucleotide repeat (SMR) markers in current MSI assays may sometimes display subtle shifts that are difficult to interpret in certain dMMR cancers, particular non-colorectal cancers. Long mononucleotide repeat (LMR) markers that are more prone to replication errors may improve the sensitivity of MSI assays. In this study, we compared the performance of SMR and LMR markers using two panels: (1) MSI Analysis System Version 1.2 (Promega) consisting of five SMR markers (21-27 bases in length) and (2) MSI LMR System (Promega) consisting of four SMR markers from the Version 1.2 panel and four LMR markers (52-60 bases in length). We studied 20 MMR proficient (pMMR) and 18 dMMR colorectal cancers (CRC) defined by concordant immunohistochemical staining (IHC) and the Version 1.2 MSI panel, 12 pMMR and 9 dMMR endometrial cancers (EC) defined by IHC alone, and 9 dMMR prostate cancers (PC) defined by loss of MSH2 IHC staining, loss of function MSH2 mutations, and increased mutation frequency. A marker was defined as unstable if a shift of 2 or more bases was observed in the tumor sample when compared to the normal sample. When using the Version 1.2 panel, we defined MSI high (MSI-H) as 2 or more unstable markers, MSI low (MSI-L) as 1 unstable marker, and microsatellite stable (MSS) as no shifts. With the LMR panel, we defined MSI-H as 3 or more unstable markers, MSI-L as 1 or 2 unstable markers, and MSS as no shifts. In dMMR CRC, the clinical sensitivity of the LMR and Version 1.2 panels for MSI were both 100%. In pMMR CRC, MSI-H was not observed in any cases using either panel, but MSI-L was observed in 2 and 0 cases using the LMR and Version 1.2 panels, respectively. In dMMR CRC, the average size of allelic shifts in the four LMR and SMR markers from the LMR panel were 8.7 and 22.1 bases, respectively. Germline polymorphisms were observed in 47% and 1% of LMR and SMR markers, respectively. In dMMR EC, the LMR panel showed greater sensitivity than the Version 1.2 panel (100% vs 89%). In pMMR EC, MSI-H was not observed in any cases using either panel, but MSI-L was observed more often using the LMR panel when compared to the Version 1.2 panel (2 vs 0 cases). In addition, LMR markers displayed larger shifts than SMR markers (12.1 vs 4.9 bases). Polymorphisms were also more frequent in LMR markers relative to SMR markers (60% vs 2%). Likewise, in dMMR PC, the sensitivity of the LMR panel was greater than that of the Version 1.2 panel (89% vs 44%). Furthermore, shifts in LMR markers were larger than those in SMR markers (10.3 vs 3.1 bases), and polymorphisms in LMR markers were more frequent than in SMR markers (33% vs 0%). Overall, LMR markers display greater clinical sensitivity and larger shifts, indicating that LMR markers can improve MSI detection in non-colorectal cancer. Citation Format: John H. Lin, Suping Chen, Liana B. Guedes, Emmanuel S. Antonarakis, Colin C. Pritchard, Tamara L. Lotan, James R. Eshleman. Improved microsatellite instability detection in endometrial and prostate cancers using long mononucleotide repeat markers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 740.

Background: Immunotherapy, especially anti-programmed cell death protein 1 (PD-1) antibodies, has yielded significant and durable tumor response in melanoma, renal cell carcinoma, and other cancer types. In contrast, immunotherapy applied major breakthrough achievement only on patients with microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC). However, MSI-H mCRC comprised only 1.8-4% of total mCRC patients. It is crucial to investigate immune pathways to develop a new strategy for immunotherapy in treatment of microsatellite stable (MSS) mCRC. Recently, some evidences indicate that interferon (IFN)-γ pathway is critical for anti-PD-1 therapy. In this study, we emphasized on evaluating the response of MSS CRC cell lines to IFN-γ. Methods: We characterized two MSS CRC cell lines, namely SW480 (KRAS G12V mutation, BRAF wild type) and COLO320 (KRAS wild type, BRAF wild type) for our studies. The impacts of interferon-γ (IFN-γ) on cell surface expressions of different isotypes of major histocompatibility complex (MHC) class I and MHC class 1 related molecule A/B (MICA/B, the NK cell ligand) were explored. Different concentration of IFN-γ with different incubation time were also examined. Results: Both cell lines demonstrated low baseline human leukocyte antigen (HLA)-ABC and HLA-BC expression and the expression significantly increased in response to IFN-γ stimulation. We further focused on the SW480 cell line. The SW480 demonstrated low expression of all MHC class I isotypes, including HLA-ABC, HLA-BC, HLA-A, HLA-C, HLA-E, HLA-F, HLA-G and NK cell ligand MICA/B. The IFN-γ specifically stimulated the expression of HLA-A, but all other isotypes were not responsive to IFN-γ stimulation. In summary, IFN-γ significantly stimulates the expression of HLA-ABC, HLA-BC and HLA-A without stimulating HLA-C. The NK cell ligand MIC A/B was also not responsive to IFN-γ stimulation. The stimulatory effect of HLA-ABC and HLA-A in response to IFN-γ stimulation was positively correlated with IFN-γ dosage, which demonstrated highest expression level in response to 800U/ml IFN-γ stimulation. The stimulatory effect in response to IFN-γ stimulation was also positively correlated with increased incubation time with IFN-γ. Conclusion: These findings reveal that regardless of their KRAS mutation status, both MSS CRC cell lines possess a phenotype that may be not responsive to anti-PD-1 therapy due to low expression of MHC class I molecules. The IFN-γ specifically elicits the expression of stimulatory isotype, HLA-A and HLA-B, without eliciting all other inhibitory MHC class I isotypes. These results indicated that IFN-γ demonstrated pure adaptive immune stimulatory effect on CRC cell lines. Analysis of T- and NK cell-responsive immune markers along with IFN-γ signaling pathway may help us to survey possible combination therapy with anti-PD-1 treatment in CRC. Citation Format: Yi-Hsin Liang, Kuan-Yu Chan, Chang-Cheng Lee, Te-Jung Chen, Ann-Lii Cheng, Kun-Huei Yeh. IFN-γ elicits stimulatory MHC class I isotypes in human colorectal carcinoma cell lines with genetic features of microsatellite stable [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 608.

We performed an integrated clinical and bioinformatic analysis of colorectal cancers (CRCs) genotyped at our institution from 4/2014-7/2016 to comprehensively characterize genomic alterations in metastatic CRC (mCRC). We analyzed 1008 samples (474 primaries, 534 metastases) from 985 mCRC patients and 128 early stage CRCs sequenced with MSK-IMPACT, a hybridization capture next generation sequencing assay. Metastatic CRCs were divided into 3 groups by mutation burden and MSIsensor algorithm score: microsatellite stable (MSS) (n=939; 95%), microsatellite-high (MSI-H) (n=41; 4%), and ultra-mutated (n=5; 1%). Early stage CRC were enriched for MSI-H due to clinical selection and were 53% MSS, 44% MSI-H, and 4% ultra-mutated. Ultra-mutated tumors exhibited >100 mutations and harbored hotspot mutations in POLE in 8 cases and a potential novel POLE alteration in 1 case. We evaluated the frequency of oncogenic alterations in MSI-H and MSS mCRCs. The frequency of the resistance biomarkers KRAS and NRAS did not vary between MSI-H and MSS mCRCs (46% v 41%, p=0.6). Potentially actionable alterations were enriched in MSI-H tumors (78% v 33%, p Analysis of mutation frequencies in 3 MSS CRC disease states - early stage resected primary (The Cancer Genome Atlas, TCGA), primary site of mCRC, and metastatic site - found significant depletion of FBXW7 mutations in metastases. We also found significant and progressive enrichment of TP53 alterations (58% TCGA, 73% primaries of mCRC, 79% metastases) and BRAF mutations (4% TCGA, 9% primaries of mCRC, 10% metastases) in advanced disease, suggesting a role of these genes in aggressive disease. One third of the BRAF mutations in our cohorts were not V600 but known to be oncogenic. In this large dataset, we identified markers of advanced CRC and found that while MSI-H and MSS CRC have a similar frequency of resistance biomarkers, MSI-H CRC more commonly harbor actionable alterations. Citation Format: Marla Lipsyc, Walid Chatila, Jaclyn F. Hechtman, Francisco Sanchez-Vega, Sumit Middha, Andrea Cercek, Zsofia Stadler, Ritika Kundra, Aijazuddin Syed, David M. Hyman, Ahmet Zehir, Armin Shahrokni, Anna Varghese, Diane Reidy, Neil H. Segal, Efsevia Vakiani, David B. Solit, Marc Ladanyi, Michael F. Berger, Nancy Kemeny, Leonard Saltz, Nikolaus Schultz, Rona Yaeger. Integrative genomics analysis of metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4380. doi:10.1158/1538-7445.AM2017-4380

High tumor mutation load has been associated with better response to immunotherapy. Measuring mutation load via whole-genome DNA sequencing can be cost prohibitive and requires extensive analysis and data management. Targeted genomic, on the other hand, are an appealing alternative. However it is unclear how mutation load assessed using a sample of hundreds of genes relates to genome-wide mutation burden. Here we use mutation data from The Cancer Genome Atlas (TCGA) to investigate if the exonic mutation load in a small set of genes can be used to predict the genome-wide exonic mutation load. Using a gene panel composed of 315 genes, we observed a strong (R = 0.72) positive correlation between the total mutation burden and the gene panel mutation burden. To determine whether these genes allow high and low mutation burden samples to be accurately identified, we derived various classifiers on a training set of TCGA samples and evaluated their performance on held-out test data. High mutation load was defined as greater than 181 non-synonymous mutations. This threshold best distinguished microsatellite instable (MSI) high training set samples from MSI low and microsatellite stable (MSS) samples (95% true positive rate and 15% false positive rate). Receiver operating characteristic (ROC) curve analysis revealed that the 315-gene panel had excellent power to discriminate high and low mutation samples, with the area under the ROC curve evaluated on held-out test data ranging from 0.85 to 0.97 across indications. Our analysis suggests that the optimal threshold for identifying high mutation load samples may vary by indication. Our models were trained and tested using data generated by the TCGA consortium on pre-treatment patient biopsies. Direct application of our classifiers to clinical data would assume similar mutation calling sensitivity between platforms and similar underlying patient populations. To test these assumptions, we compared the mutational loads between TCGA and clinical samples within the same indication. We further performed a sensitivity analysis using a simulation-based approach which showed how deviations from these underlying assumptions would be expected to affect classification performance. These results demonstrate the feasibility of using mutation burden in a cancer related gene panel as a biomarker for genome-wide mutation load. This approach may be useful in identifying patients more likely to respond to cancer immunotherapies, but may require development be tailored to the specific sequencing platform and patient-population of interest. Citation Format: Artur Veloso, Z. Alexander Cao, Derek Y. Chiang, Hans Bitter, Kenzie D. MacIsaac. Mutation load measured using a 315 gene panel predicts genome-wide mutation load. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 854.

The BRAF (V600E) mutation in colorectal cancers that are microsatellite stable (MSS) confers a very poor patient prognosis, whereas BRAF mutant microsatellite-unstable (MSI) colorectal cancers have an excellent prognosis. BRAF wild type cancers are typically MSS and display chromosomal instability (CIN). CIN is associated with a poor prognosis but has not been extensively studied on a genome-wide basis in relation to BRAF mutational status in colorectal cancer. BRAF mutant/MSS (BRAFmut/MSS) cancers (n=33) and BRAF mutant/MSI (BRAFmut/MSI) cancers (n=30) were compared for presence of copy number aberrations (CNAs) indicative of CIN, with BRAF wild type/MSS (BRAFwt/MSS) cancers (n=18) using Illumina CytoSNP-12 arrays. BRAFmut/MSS and BRAFwt/MSS cancers showed comparable numbers of CNAs per cancer at 32.8 and 29.8 respectively. However there were distinct differences in patterns of CNA length between MSS cohorts, with BRAFmut/MSS cancers having a significantly greater proportion of focal CNAs compared to BRAFwt/MSS cancers (p These results indicate that although comparable rates of CIN occur between MSS subgroups, significant differences in their patterns of instability exist as BRAFmut/MSS cancers display a ‘focal pattern’ and BRAFwt/MSS cancers have more a ‘whole arm pattern' of CIN. This and the genomic loci more frequently affected in BRAFmut/MSS cancers may warrant extended studies to ascertain correlations with clinical data. Overall this investigation has identified that differing patterns of genomic instability exist between the two MSS colorectal subgroups and provides further evidence of the biological distinctions of the aggressive BRAFmut/MSS cancers. Citation Format: Catherine E. Bond, Derek J. Nancarrow, Leesa F. Wockner, Leanne Wallace, Grant W. Montgomery, Barbara A. Leggett, Vicki LJ Whitehall. Microsatellite stable colorectal cancers stratified by the BRAF V600E mutation show distinct patterns of chromosomal instability. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2422. doi:10.1158/1538-7445.AM2014-2422

Introduction Most of sporadic or hereditary colorectal cancers (CRC) with microsatellite instability (MSI) have a peculiar histopathologic pattern, notably with a frequent inflammatory lymphocytic component. MSI CRC are associated with a better outcome than microsatellite stable (MSS) CCR, probably in relation with a more effective immune response. The aim of our work was to highlight the inflammatory mechanisms occurring in MSI CRC, by analyzing the cytokines and the in situ immune response encountered in this tumor subtype. Methods A panel of 48 cytokines was measured from 48 MSI CRC and 62 MSS CRC using the bioplex cytokine multiplexed assay (Biorad, Hercules, CA, USA). Immunohistochemistry was performed on a tissue microarray constructed from the same tumors, with the following markers: CD3 (T lymphocytes), CD8 (cytotoxic T lymphocytes), CD45RO (memory T lymphocytes), T-bet (Th1 CD4 cells) and FoxP3 (regulatory T-cells). After immunostaining of each marker, T-cell density was assessed by image analysis. Results Analysis of the 48 cytokines allowed us to assess a higher level of IL1β, IL1-Rα, IL16, Gro-a, IL-8, Ip-10, Mig, Mip-1α, Mip-1β, Rantes and IFN-γ in MSI CRC than in MSS CRC (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 317. doi:1538-7445.AM2012-317

BRAF mutant colorectal cancers can be stratified according to the presence of microsatellite instability (MSI). MSI cancers with a BRAF mutation are associated with an excellent patient prognosis. By contrast, in microsatellite stable (MSS) cancers, a BRAF mutation confers a very poor patient prognosis. The causes of such a detrimental outcome are yet to be thoroughly determined. We have previously reported that BRAF mutant, MSS cancers (BRAFmut/MSS) have a significantly higher rate of p53 mutation and present at more advanced stages than MSI cancers. Frequencies of these features in the BRAFmut/MSS cancers are similar to those observed in BRAF wild type, MSS cancers (BRAFwt/MSS). Chromosomal instability (CIN) is a dominant feature of BRAFwt/MSS cancers, whilst MSI cancers are considered to be diploid. In MSS cancers, CIN has been associated with a worse prognosis. We therefore hypothesised that CIN would be common in BRAF mutant/MSS cancers. BRAFmut/MSS (n=60), and BRAFwt/MSS cancers (n=90) were investigated for CIN using Loss of Heterozygosity (LOH) analysis over 12 loci encompassing chromosomal regions 5q, 8p, 17p and 18q. CIN was assigned if at least 1 marker was positive for LOH, and a cancer was reported as showing no loss if at least 5 markers were informative and none demonstrated LOH. CIN was frequently found in BRAFmut/MSS cancers (41/57, 72%), and this rate was comparable to that observed in BRAFwt/MSS cancers (74/90, 82%). The greatest rate of CIN in BRAFmut/MSS cancers occurred at 8p (26/44, 59%), and the least at 5q (19/49, 39%). BRAFwt/MSS cancers showed most CIN at 17p (43/65, 66.2%), and the least at 5q (43/80, 53.8%). Within the BRAFmut/MSS cancer subgroup, CIN was highly correlated with the CpG Island Methylator Phenotype (17/23, 74%). CIN in BRAFmut/MSS cancers was significantly predominant in those at advanced (15/17, 88%), compared to early AJCC stages of presentation (6/13, 46%) (p=0.02). BRAFmut/MSS cancers with CIN at 18q and 8p significantly associated with worse survival compared to those with no loss (p=0.003, p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 106. doi:1538-7445.AM2012-106

Background: Several pathways for colorectal cancer (CRC) have been described. The well-known adenoma-to-carcinoma pathway usually results in microsatellite stable tumors and accounts for about 75% of CRC. Less is established about the origins of microsatellite unstable (MSI) CRC. These tumors are more often in the right colon and commonly characterized as having a CpG Island Methylator Phenotype (CIMP). Objective: We aimed to better understand precursors for MSI colorectal tumors by determining the correlation between CIMP-status and polyp type. Methods: We conducted a case-case comparison of CIMP status among participants aged 24-79 of a colonoscopy-based study, who were diagnosed with colorectal adenomas or hyperplastic polyps (HPs). During colonoscopy, polyps were biopsied, fixed in paraffin, and H&E slides prepared. All participants underwent a standard pathology review to confirm the diagnosis, determine the percent of lesional tissue in the block, and classify each polyp as tubular adenoma, tubulovillous adenoma, HP (both goblet cell and microvesicular), sessile serrated polyp, or serrated adenoma. Medical records were abstracted to ascertain polyp location and size; tissue blocks from polyps at least 3 mm in diameter and containing at least 80% lesional tissue were selected for CIMP analyses. DNA methylation was quantified in 905 polyps by real-time PCR (MethyLight) using a validated CIMP marker panel (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1). ALU was used to monitor DNA quality. Of the 905 polyps tested, 752 (83%) had an ALU cycle threshold Results: Of 434 adenomatous polyps, including 113 tubulovillous adenomas, only 2 ( Discussion: Until recently, sessile serrated polyps were classified as hyperplastic polyps and therefore, were thought to have little clinical significance. However, our investigation suggests that these polyps, like MSI CRC tumors, are commonly CIMP-positive. Adenomatous polyps, in contrast, were largely CIMP-negative. This finding supports other investigations suggesting MSI CRC is not likely to have an adenomatous precursor, and probably arises from serrated polyps. If confirmed by longitudinal studies, this will have important implications for CRC surveillance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3762. doi:10.1158/1538-7445.AM2011-3762