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      Noninvasive Biomarkers of Colorectal Cancer: Role in Diagnosis and Personalised Treatment Perspectives

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          Abstract

          Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. It has been estimated that more than one-third of patients are diagnosed when CRC has already spread to the lymph nodes. One out of five patients is diagnosed with metastatic CRC. The stage of diagnosis influences treatment outcome and survival. Notwithstanding the recent advances in multidisciplinary management and treatment of CRC, patients are still reluctant to undergo screening tests because of the associated invasiveness and discomfort (e.g., colonoscopy with biopsies). Moreover, the serological markers currently used for diagnosis are not reliable and, even if they were useful to detect disease recurrence after treatment, they are not always detected in patients with CRC (e.g., CEA). Recently, translational research in CRC has produced a wide spectrum of potential biomarkers that could be useful for diagnosis, treatment, and follow-up of these patients. The aim of this review is to provide an overview of the newer noninvasive or minimally invasive biomarkers of CRC. Here, we discuss imaging and biomolecular diagnostics ranging from their potential usefulness to obtain early and less-invasive diagnosis to their potential implementation in the development of a bespoke treatment of CRC.

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          Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans.

          During C. elegans development, the temporal pattern of many cell lineages is specified by graded activity of the heterochronic gene Lin-14. Here we demonstrate that a temporal gradient in Lin-14 protein is generated posttranscriptionally by multiple elements in the lin-14 3'UTR that are regulated by the heterochronic gene Lin-4. The lin-14 3'UTR is both necessary and sufficient to confer lin-4-mediated posttranscriptional temporal regulation. The function of the lin-14 3'UTR is conserved between C. elegans and C. briggsae. Among the conserved sequences are seven elements that are each complementary to the lin-4 RNAs. A reporter gene bearing three of these elements shows partial temporal gradient activity. These data suggest a molecular mechanism for Lin-14p temporal gradient formation: the lin-4 RNAs base pair to sites in the lin-14 3'UTR to form multiple RNA duplexes that down-regulate lin-14 translation.
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            Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.

            Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.
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              A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.

              In December 1997, the National Cancer Institute sponsored "The International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition," to review and unify the field. The following recommendations were endorsed at the workshop. (a) The form of genomic instability associated with defective DNA mismatch repair in tumors is to be called microsatellite instability (MSI). (b) A panel of five microsatellites has been validated and is recommended as a reference panel for future research in the field. Tumors may be characterized on the basis of: high-frequency MSI (MSI-H), if two or more of the five markers show instability (i.e., have insertion/deletion mutations), and low-frequency MSI (MSI-L), if only one of the five markers shows instability. The distinction between microsatellite stable (MSS) and low frequency MSI (MSI-L) can only be accomplished if a greater number of markers is utilized. (c) A unique clinical and pathological phenotype is identified for the MSI-H tumors, which comprise approximately 15% of colorectal cancers, whereas MSI-L and MSS tumors appear to be phenotypically similar. MSI-H colorectal tumors are found predominantly in the proximal colon, have unique histopathological features, and are associated with a less aggressive clinical course than are stage-matched MSI-L or MSS tumors. Preclinical models suggest the possibility that these tumors may be resistant to the cytotoxicity induced by certain chemotherapeutic agents. The implications for MSI-L are not yet clear. (d) MSI can be measured in fresh or fixed tumor specimens equally well; microdissection of pathological specimens is recommended to enrich for neoplastic tissue; and normal tissue is required to document the presence of MSI. (e) The "Bethesda guidelines," which were developed in 1996 to assist in the selection of tumors for microsatellite analysis, are endorsed. (f) The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms. (g) A research agenda was recommended.
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                Author and article information

                Contributors
                Journal
                Gastroenterol Res Pract
                Gastroenterol Res Pract
                GRP
                Gastroenterology Research and Practice
                Hindawi
                1687-6121
                1687-630X
                2018
                13 June 2018
                : 2018
                : 2397863
                Affiliations
                1Unit of General Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
                2Colorectal Surgery Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain
                3Department of Medical and Surgical Sciences, OU of General Surgery, University of Catanzaro, Catanzaro, Italy
                4Department of Colorectal Surgery, Clinic S. Rita, Vercelli, Italy
                5Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), Via S. Pansini 5, Naples, Italy
                6Department of Medicine and Health Sciences, University of Molise, Via Francesco de Sanctis 1, 86100 Campobasso, Italy
                7Department of Abdominal Oncology, Division of Abdominal Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione G. Pascale, ” IRCCS, Naples, Italy
                81st Surgical Clinic, Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy
                9Dipartimento di Sanità Pubblica, Università degli Studi di Napoli Federico II, Naples, Italy
                10Department of Colorectal Surgery, Royal Marsden Hospital, London, UK
                11Department of Internal and Experimental Medicine, Magrassi-Lanzara, Institute of Radiology, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
                12Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy
                13Department of Surgery and Cancer, Chelsea and Westminster Hospital Campus, Imperial College London, London, UK
                Author notes

                Academic Editor: Alessandro Passardi

                Author information
                http://orcid.org/0000-0002-8322-6421
                http://orcid.org/0000-0003-1066-4671
                http://orcid.org/0000-0001-7319-684X
                http://orcid.org/0000-0002-6033-8463
                http://orcid.org/0000-0003-2107-1177
                http://orcid.org/0000-0003-3211-9957
                http://orcid.org/0000-0001-6450-6463
                http://orcid.org/0000-0002-1828-1395
                http://orcid.org/0000-0002-3219-3797
                Article
                10.1155/2018/2397863
                6020538
                30008744
                4b28ba9e-d505-43e4-a6ce-14a5c68c38da
                Copyright © 2018 Gianluca Pellino et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 October 2017
                : 3 April 2018
                : 15 April 2018
                Categories
                Review Article

                Gastroenterology & Hepatology
                Gastroenterology & Hepatology

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