Comprehensive molecular characterization of human colon and rectal cancer : Nature : Nature Research. Tumour and normal pairs were analysed by different platforms. The specific numbers of samples analysed by each platform are shown in Supplementary Table 1. Outils de recherche en ligne sur la m Exome- sequence analysis. To define the mutational spectrum, we performed exome capture DNA sequencing on 2. Supplementary Table 2). Sequencing achieved > 2. The somatic mutation rates varied considerably among the samples. Some had mutation rates of < 1 per 1. We separated cases (8. Fig. Note a clear separation of hypermutated and non- hypermutated samples. Red, MSI high, CIMP high or MLH1 silenced; light blue, MSI low, or CIMP low; black, rectum; white, colon; grey, no data. Inset, mutations in mismatch- repair genes and POLE among the hypermutated samples. The order of the samples is the same as in the main graph. Blue bars represent genes identified by the Mut. Sig algorithm and black bars represent genes identified by manual examination of sequence data. To assess the basis for the considerably different mutation rates, we evaluated MSI7 and mutations in the DNA mismatch- repair pathway. MLH1, MLH3, MSH2, MSH3, MSH6 and PMS2. Among the 3. 0 hypermutated tumours with a complete data set, 2. MSI (MSI- H). Included in this group were 1. MLH1 methylation, 1. CIMP. By comparison, the remaining seven hypermutated tumours, including the six with the highest mutation rates, lacked MSI- H, CIMP or MLH1 methylation but usually had somatic mutations in one or more mismatch- repair genes or POL. Gene mutations. Overall, we identified 3. Mut. Sig. 11 and manual curation) in the hypermutated and non- hypermutated cancers (Fig. After removal of non- expressed genes, there were 1. Fig. 1b; for a complete list see Supplementary Table 3). Among the non- hypermutated tumours, the eight most frequently mutated genes were APC, TP5. Comprehensive molecular characterization of human colon and rectal cancer. The Cancer Genome Atlas Network; Affiliations; Contributions; Corresponding author; Journal name: Nature Volume: 487, Pages: 330–337 Date published.KRAS, PIK3. CA, FBXW7, SMAD4, TCF7. L2 and NRAS. As expected, the mutated KRAS and NRAS genes usually had oncogenic codon 1. CTNNB1, SMAD2, FAM1. B (also known as WTX) and SOX9 were also mutated frequently. FAM1. 23. B is an X- linked negative regulator of WNT signalling. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) Autophagy: Vol. Search the Berkshire County MLS for country homes, historic homes, farms, land for sale, lakefront houses, mountain properties, commercial property, and real estate auctions. Tchatche : tchatche-france.com est le tchatche francophone gratuit pour discuter en direct avec plus de 15 000 d'inscrits. American Genealogy; Beginning Genealogy; DNA Genealogy; Family Genealogy; Free Genealogy; Free Genealogy Search; Genealogy Definitions; Genealogy Home Pages; Genealogy Relationships; Genealogy Research; Genealogy Researcher. Mutations in SOX9, a gene important for cell differentiation in the intestinal stem cell niche. CRCs were frameshift or nonsense mutations. Tumour- suppressor genes ATM and ARID1. A also had a disproportionately high number of frameshift or nonsense mutations. ARID1. A mutations have recently been reported in CRC and many other cancers. In the hypermutated tumours, ACVR2. A, APC, TGFBR2, MSH3, MSH6, SLC9. A9 and TCF7. L2 were frequent targets of mutation (Fig. BRAF(V6. 00. E) mutations. However, two genes that were frequently mutated in the non- hypermutated cancers were significantly less frequently mutated in hypermutated tumours: TP5. P < 0. 0. 00. 1) and APC (8. P = 0. 0. 02. 3; both Fisher’s exact test). Other genes, including TGFBR2, were mutated recurrently in the hypermutated cancers, but not in the non- hypermutated samples. These findings indicate that hypermutated and non- hypermutated tumours progress through different sequences of genetic events. As expected, hypermutated tumours with MLH1 silencing and MSI- H showed additional differences in the mutational profile. When we specifically examined 2. MLH1 silencing and 5. Supplementary Table 2). Mutation rate and methylation patterns. As mentioned above, patients with colon and rectal tumours are managed differently. An initial integrative analysis of MSI status, somatic copy- number alterations (SCNAs), CIMP status and gene- expression profiles of 1. Among the non- hypermutated tumours, however, the overall patterns of changes in copy number, CIMP, m. RNA and mi. RNA were indistinguishable between colon and rectal carcinomas (Fig. On the basis of this result, we merged the two for all subsequent analyses. Non- hypermutated tumours originating from different sites are virtually indistinguishable from each other on the basis of their copy- number alteration patterns, DNA methylation or gene- expression patterns. Copy- number changes of the 2. Unsupervised clustering of the promoter DNA methylation profiles of 2. Supplementary Fig. Supplementary Methods). Two of the clusters contained tumours with elevated rates of methylation and were classified as CIMP high and CIMP low, as previously described. The two non- CIMP clusters were predominantly from tumours that were non- hypermutated and derived from different anatomic locations. One significantly overlapped with CIMP- high tumours (P = 3 . Analysis of mi. RNA expression by unsupervised clustering (Supplementary Fig. Chromosomal and sub- chromosomal changes. In total, 2. 57 tumours were profiled for SCNAs with Affymetrix SNP 6. Of these tumours, 9. As expected, the hypermutated tumours had far fewer SCNAs (Fig. No difference was found between microsatellite- stable and - unstable hypermutated tumours (Supplementary Fig. We used the GISTIC algorithm. There were several previously well- defined arm- level changes, including gains of 1q, 7p and q, 8p and q, 1. Supplementary Table 4). Significantly deleted chromosome arms were 1. SMAD4) in 6. 6% of the tumours and 1. TP5. 3) in 5. 6%. Other significantly deleted chromosome arms were 1p, 4q, 5q, 8p, 1. We identified 2. 8 recurrent deletion peaks (Supplementary Fig. Supplementary Table 4), including the genes FHIT, RBFOX1 and WWOX with large genomic footprints located in potentially fragile sites of the genome, in near- diploid hypermutated tumours. Other focal deletions involved tumour- suppressor genes such as SMAD4, APC, PTEN and SMAD3. A significant focal deletion of 1. TCF7. L2, which was also frequently mutated in our data set. A gene fusion between adjacent genes VTI1. A and TCF7. L2 through an interstitial deletion was found in 3% of CRCs and is required for survival of CRC cells bearing the translocation. There were 1. 7 regions of significant focal amplification (Supplementary Table 4). Some of these were superimposed on broad gains of chromosome arms, and included a peak at 1. USP1. 2 and at ~5. CRC candidate oncogene CDK8; an adjacent peak at 1. KLF5 at 1. 3q. 22. HNF4. A. Peaks on chromosome 8 included 8p. WHSC1. L1, adjacent to FGFR1) and 8q. MYC). An amplicon at 1. ERBB2. ERBB2 amplifications have been described in colon, breast and gastro–oesophageal tumours, and breast and gastric cancers bearing these amplifications have been treated effectively with the anti- ERBB2 antibody trastuzumab. One of the most common focal amplifications, found in 7% of the tumours, is the gain of a 1. It contains genes encoding insulin (INS), insulin- like growth factor 2 (IGF2) and tyrosine hydroxylase (TH), as well as mi. R- 4. 83, which is embedded within IGF2 (Fig. We found elevated expression of IGF2 and mi. R- 4. 83 but not of INS and TH (Fig. Immediately adjacent to the amplified region is ASCL2, a transcription factor active in specifying intestinal stem- cell fate. Although ASCL2 has been implicated as a target of amplification in CRC2. These observations suggest that IGF2 and mi. R- 4. 83 are candidate functional targets of 1. IGF2 overexpression through loss of imprinting has been implicated in the promotion of CRC2. Mi. R- 4. 83 may also have a role in CRC pathogenesis. Segmented DNA copy- number data from single- nucleotide polymorphism (SNP) arrays and low- pass whole- genome sequencing (WGS) are shown. Each row represents a patient; amplified regions are shown in red. The structure of the two genes, locations of the breakpoints leading to the translocation and circular representations of all rearrangements in tumours with a fusion are shown. Red line lines represent the NAV2–TCF7. L2 fusions and black lines represent other rearrangements. The inner ring represents copy- number changes (blue denotes loss, pink denotes gain). A subset of tumours without IGF2 amplification (1. IGF2 gene expression (as much as a 1. IGF2 promoter. To assess the context of IGF2 amplification/overexpression, we systematically searched for mutually exclusive genomic events using the MEMo method. We found a pattern of near exclusivity (corrected P < 0. IGF2 overexpression with genomic events known to activate the PI3. K pathway (mutations of PIK3. CA and PIK3. R1 or deletion/mutation of PTEN; Fig. Supplementary Table 5). The IRS2 gene, encoding a protein linking IGF1. R (the receptor for IGF2) with PI3. K, is on chromosome 1. CRC. The cases with the highest IRS2 expression were mutually exclusive of the cases with IGF2 overexpression (P = 0. PI3. K pathway (P = 0. Fig. These results strongly suggest that the IGF2–IGF1. R–IRS2 axis signals to PI3. K in CRC and imply that therapeutic targeting of the pathway could act to block PI3. K activity in this subset of patients. Translocations. To identify new chromosomal translocations, we performed low- pass, paired- end, whole- genome sequencing on 9. In each case we achieved sequence coverage of ~3–4- fold and a corresponding physical coverage of 7. Despite the low genome coverage, we detected 2. Among these events, 2. Supplementary Table 6). We found three separate cases in which the first two exons of the NAV2 gene on chromosome 1. TCF7. L1 encodes TCF3, a member of the TCF/LEF class of transcription factors that heterodimerize with nuclear . Intriguingly, in all three cases, the predicted structure of the NAV2–TCF7. L1 fusion protein lacks the TCF3 . This translocation is similar to another recurrent translocation identified in CRC, a fusion in which the amino terminus of VTI1. A is joined to TCF4, which is encoded by TCF7. L2, a homologue of TCF7. L1 that is deleted or mutated in 1. We also observed 2. TTC2. 8 located on chromosome 2. Supplementary Table 6). In all cases the fusions predict inactivation of TTC2. P5. 3 and an inhibitor of tumour cell growth. Eleven of the 1. 9 (5. PCR products or, in some cases, sequencing the junction fragments (Supplementary Fig. Altered pathways in CRCIntegrated analysis of mutations, copy number and m. RNA expression changes in 1. Chinese Medicine Chronology. TCM Chronology Traditional Chinese medicine (TCM) has undergone a long course of development; it encompasses a complete array of medical theories, practical experiences and unique therapeutic techniques. Its original foundation was established over two thousand years ago, but was shaped by accumulative and consolidated knowledge gathered from accomplished medical practitioners of different medical approaches who had the foresight to document their findings in medical literature. Additionally, the developmental process of TCM was also influenced by various medical and cultural practices of different geographic locations and medical philosophies, which sometimes did not agree with one another.
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