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      NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis

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          Abstract

          Cutaneous SCC (cSCC) is the most frequent skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here we use massively parallel exome and targeted level sequencing 132 sporadic cSCC, 39 squamoproliferative lesions and cSCC arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples to identify significant NOTCH1 mutation as an early event in squamous cell carcinogenesis. Bisected vemurafenib induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC suggesting polyclonal origin.

          Immunohistochemical analysis using an antibody specific to nuclear NOTCH1 correlates with mutation status in sporadic cSCC and regions of NOTCH1 loss or down-regulation are frequently observed in normal looking skin. Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC.

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          Most cited references 33

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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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            APC mutations occur early during colorectal tumorigenesis.

            Human tumorigenesis is associated with the accumulation of mutations both in oncogenes and in tumour suppressor genes. But in no common adult cancer have the mutations that are critical in the early stages of the tumorigenic process been defined. We have attempted to determine if mutations of the APC gene play such a role in human colorectal tumours, which evolve from small benign tumours (adenomas) to larger malignant tumours (carcinomas) over the course of several decades. Here we report that sequence analysis of 41 colorectal tumours revealed that the majority of colorectal carcinomas (60%) and adenomas (63%) contained a mutated APC gene. Furthermore, the APC gene met two criteria of importance for tumour initiation. First, mutations of this gene were found in the earliest tumours that could be analysed, including adenomas as small as 0.5 cm in diameter. Second, the frequency of such mutations remained constant as tumours progressed from benign to malignant stages. These data provide strong evidence that mutations of the APC gene play a major role in the early development of colorectal neoplasms.
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              Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer.

              Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers. It occurs through mutations mainly of APC and less often of CTNNB1 (encoding beta-catenin) or AXIN2 (encoding axin-2, also known as conductin). These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free beta-catenin in the nucleus. We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer. SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development. Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer.
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                Author and article information

                Journal
                0426720
                4839
                J Invest Dermatol
                J. Invest. Dermatol.
                The Journal of investigative dermatology
                0022-202X
                1523-1747
                12 August 2014
                24 March 2014
                October 2014
                15 February 2016
                : 134
                : 10
                : 2630-2638
                Affiliations
                [1 ]Division of Cancer Research, University of Dundee, Dundee, UK
                [2 ]Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
                [3 ]Eastern Sequence and Informatics Hub (EASIH), University of Cambridge, Laboratory Block Addenbrooke’s Hospital, Cambridge, UK
                [4 ]Department of Dermatology, University of California, San Francisco, CA, USA
                [5 ]Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
                [6 ]Department of Cellular Pathology, Barts Health NHS Trust, London, UK
                Author notes
                [* ]Correspondence: Andrew P South, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, DD1 9SY

                Author Contributions A.P.S., I.M.L., C.A.H., C.M.P., and K.J.P. designed the research and obtained funding. C.A.H., C.M.P. and H.R. collected samples. A.P.S., K.J.P., S.A.W., A.M., D.X., K.S.R and J.H.D. performed the experiments. A.P.S., S.H., N.d.B., M.D., M.J.K, J.C.A. and S.T.A. analyzed the data. A.P.S., K.J.P., C.M.P., C.A.H. and I.M.L. wrote the paper.

                Article
                EMS57574
                10.1038/jid.2014.154
                4753672
                24662767

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                Dermatology

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