{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"contact_person":["CLS DAC"],"full_dataset_link":["https://ega-archive.org/dacs/EGAC00001001041"],"host":["EGA"],"description":["EGA DAC EGAC00001001041"],"repository":["EGA"],"email":["clsfeedback@ucl.ac.uk"],"pubmed_abstract":["Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1-5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes.","Overgrowth syndromes comprise a group of heterogeneous disorders characterised by excessive growth parameters, often in association with intellectual disability. To identify new causes of human overgrowth, we have been undertaking trio-based exome sequencing studies in overgrowth patients and their unaffected parents. Prioritisation of functionally relevant genes with multiple unique de novo mutations revealed four mutations in protein phosphatase 2A (PP2A) regulatory subunit B family genes protein phosphatase 2, regulatory Subunit B', beta (PPP2R5B); protein phosphatase 2, regulatory Subunit B', gamma (PPP2R5C); and protein phosphatase 2, regulatory Subunit B', delta (PPP2R5D). This observation in 3 related genes in 111 individuals with a similar phenotype is greatly in excess of the expected number, as determined from gene-specific de novo mutation rates (P = 1.43 × 10(-10)). Analysis of exome-sequencing data from a follow-up series of overgrowth probands identified a further pathogenic mutation, bringing the total number of affected individuals to 5. Heterozygotes shared similar phenotypic features including increased height, increased head circumference and intellectual disability. The mutations clustered within a region of nine amino acid residues in the aligned protein sequences (P = 1.6 × 10(-5)). We mapped the mutations onto the crystal structure of the PP2A holoenzyme complex to predict their molecular and functional consequences. These studies suggest that the mutations may affect substrate binding, thus perturbing the ability of PP2A to dephosphorylate particular protein substrates. PP2A is a major negative regulator of v-akt murine thymoma viral oncogene homolog 1 (AKT). Thus, our data further expand the list of genes encoding components of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signalling cascade that are disrupted in human overgrowth conditions."],"pubmed_title":["Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth.","Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer."],"pubmed_authors":["Loveday Chey C, Tatton-Brown Katrina K, Clarke Matthew M, Westwood Isaac I, Renwick Anthony A, Ramsay Emma E, Nemeth Andrea A, Campbell Jennifer J, Joss Shelagh S, Gardner McKinlay M, Zachariou Anna A, Elliott Anna A, Ruark Elise E, van Montfort Rob R, Rahman Nazneen N","Chubb Daniel D, Broderick Peter P, Dobbins Sara E SE, Frampton Matthew M, Kinnersley Ben B, Penegar Steven S, Price Amy A, Ma Yussanne P YP, Sherborne Amy L AL, Palles Claire C, Timofeeva Maria N MN, Bishop D Timothy DT, Dunlop Malcolm G MG, Tomlinson Ian I, Houlston Richard S RS"],"additional_accession":[]},"is_claimable":false,"name":"METADAC","description":"Data Access Committee EGAC00001001041","dates":{"output":"2025-1-9"},"accession":"EGAC00001001041","cross_references":{"TAXONOMY":["9606"],"pubmed":["25972378","27329137"],"EGA":["EGAS00001000971","EGAS00001001667","EGAD00001001021","EGAD00001004396"]}}