Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers

• Published in: Nature communications Vol. 13; no. 1; p. 1618
• Main Authors: Serebriiskii, Ilya G., Pavlov, Valery, Tricarico, Rossella, Andrianov, Grigorii, Nicolas, Emmanuelle, Parker, Mitchell I., Newberg, Justin, Frampton, Garrett, Meyer, Joshua E., Golemis, Erica A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.03.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/1244; 631/67/69; 692/4028/67/1504/1885; 692/4028/67/68; Adenomatous polyposis coli; AKT protein; Cancer; Class I Phosphatidylinositol 3-Kinases - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - pathology; Data analysis; DNA Mutational Analysis; Humanities and Social Sciences; Humans; Intracellular levels; Intracellular signalling; Microsatellite Instability; multidisciplinary; Mutation; Nucleotides; p53 Protein; Pathogenesis; Patients; Phosphatidylinositol; Phosphatidylinositol 3,4,5-triphosphate; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Proteins; PTEN Phosphohydrolase - genetics; PTEN protein; Science; Science (multidisciplinary); Sequences; Signal transduction; Signaling; Tumor suppressor genes; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29227-2

Loss of expression or activity of the tumor suppressor PTEN acts similarly to an activating mutation in the oncogene PIK3CA in elevating intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), inducing signaling by AKT and other pro-tumorigenic signaling proteins. Here, we analyze sequence data for 34,129 colorectal cancer (CRC) patients, capturing 3,434 PTEN mutations. We identify specific patterns of PTEN mutation associated with microsatellite stability/instability (MSS/MSI), tumor mutational burden (TMB), patient age, and tumor location. Within groups separated by MSS/MSI status, this identifies distinct profiles of nucleotide hotspots, and suggests differing profiles of protein-damaging effects of mutations. Moreover, discrete categories of PTEN mutations display non-identical patterns of co-occurrence with mutations in other genes important in CRC pathogenesis, including KRAS , APC , TP53 , and PIK3CA . These data provide context for clinical targeting of proteins upstream and downstream of PTEN in distinct CRC cohorts. Loss of the tumour suppressor gene PTEN leads to the activation of pro-tumourigenic signalling pathways. Here, the authors analyse sequencing data from a large cohort of colorectal cancer patients harbouring PTEN mutations and identify distinct patterns of associations with genomic and clinical features.