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Analysis of 9,924 tumors across 33 TCGA cancer types shows common co-occurring alterations linked to activation of the PI3K–AKT pathway, with higher progression and mortality versus tumors with neither alteration. The effect is further amplified by additional TP53 alterations, and breast cancer triple-negative risk increases substantially. Mouse models with combined Rasal1 and Pten loss show robust PI3K signaling and metastasizing malignancies, supporting a key role in suppressing the pathway.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/the-genetic-duet-of-concurrent-rasal1-and-pten-alterations-promotes-cancer-aggressiveness-by-cooperatively-activating-the-pi3k-akt-pathway/331696/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/the-genetic-duet-of-concurrent-rasal1-and-pten-alterations-promotes-cancer-aggressiveness-by-cooperatively-activating-the-pi3k-akt-pathway/331696.png","ImageObject",300,407,{"name":92,"@type":93},"Aurelia","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-06","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What genes are studied for their concurrent alterations in cancer aggressiveness?","Question",{"text":112,"@type":113},"The study focuses on RASAL1 and PTEN alterations, and also evaluates how additional TP53 alterations further affect outcomes.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How are RASAL1 and PTEN alterations linked to signaling activity?",{"text":117,"@type":113},"Concurrent RASAL1 and PTEN alterations cooperatively activate the PI3K–AKT pathway.",{"name":119,"@type":110,"acceptedAnswer":120},"What do the mouse knockout results suggest about RASAL1 and PTEN function?",{"text":121,"@type":113},"Double knockouts of Rasal1 and Pten produce robust PI3K pathway activation and metastasizing malignancies, while single-gene knockouts result in only benign neoplasms.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},331696,1790196490,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":41,"preview_page_count":4},1099514068365,"https://ap-avatar.wpscdn.com/avatar/10000253d8d9f28188e?x-image-process=image/resize,m_fixed,w_180,h_180&k=1794309523707217728","The genetic duet of concurrent RASAL1 and PTEN alterations promotes cancer aggressiveness by cooperatively activating the PI3K–AKT pathway  \nXiaopei Shen 1, Jie Tan 1, Rengyun Liu 1, Guangwu Zhu 1, Lisa Rooper2 and Mingzhao Xing 1   \n1 Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA  \n2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA  \nKeywords  \ncancer aggressiveness; PI3K pathway; PTEN; RASAL1; tumor suppressor gene  \nCorrespondence  \nM. Xing, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, MD 21287, USA  \nFax: +1 410 955 8172  \nTel: +1 410 955 3663  \n[E-mail:](E-mail: mxing1@jhmi.edu)[ mxing1@jhmi.edu](E-mail: mxing1@jhmi.edu)  \nXiaopei Shen and Jie Tan contributed equally to this article  \n(Received 17 April 2023, revised 12 May 2024, accepted 8 July 2024, available online 20 July 2024)  \ndoi:10 . 1002/1878-0261 .13701  \nThe significance of the prominent tumor suppressor gene for RAS protein activator-like 1 (RASAL1) could be better understood by combined genetic, clinical, and functional studies. Here, we investigated the oncogenic and clinical impacts of genetic alterations of RASAL1, particularly when coexisting with genetic alterations of the gene for phosphatase and tensin homolog (PTEN), in 9924 cancers of 33 types in the TCGA database. We found common concurrent genetic alterations of the two genes, which were cooperatively associated with activation of the phosphatidylinositol 3-kinase (PI3K)–AKT pathway, with cancer progression and mortality rates being 46.36% and 31.72% with concurrent gene alterations, versus 29.80% and 16.93% with neither gene alteration (HR 1.64, 95% CI 1 .46–1.84 and 1 .77, 95% CI 1 .53–2.05), respectively. This was enhanced by additional tumor protein p53 (TP53) gene alterations, with cancer progression and mortality rates being 47.65% and 34.46% with coexisting RASAL1, PTEN, and TP53 alterations versus 25 .30% and 13 . 11% with no alteration (HR 2 .21, 95% CI 1 .92–2.56 and 2 .76, 95% CI 2 .31–3.30), respectively. In the case of breast cancer, this genetic trio was associated with a triple-negative risk of 68.75% versus 3.83% with no genetic alteration (RR 17.94, 95% CI 9.60– 33.51), consistent with the aggressive nature of triple-negative breast cancer. Mice with double knockouts ofRasal1 and Pten displayed robust Pi3k pathway activation, with the development of metastasizing malignancies, while single gene knockout resulted in only benign neoplasma. These results suggest that RASAL1, like PTEN, is a critical player in negatively regulating the PI3K–AKT pathway; defect in RASAL1 causes RAS activation, thus initiating the PI3K–  \nAbbreviations  \nACC, adrenocortical carcinoma; AML, acute myeloid leukemia; ATC, anaplastic thyroid cancer; BLCA, bladder urothelial cancer; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CGC, cancer gene census; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; CRISPR-CAS 9, clustered regularly interspaced palindromic repeats-associated protein 9; DLBC, diffuse large B-cell lymphoma; DSS, disease-specific survival; ER, estrogen receptor; ERK, extracellular signal-regulated kinase; ESCA, esophageal carcinoma; FTC, follicular thyroid cancer; GBM, glioblastoma multiforme; GDP, guanosine diphosphate; GISTIC, genomic identification of significant targets in cancer; GTP, guanosine triphosphate; HER2, human epidermal growth factor receptor 2; HNSC, head and neck squamous cell carcinoma; HR, hazard ratio; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; KO, knockout; LGG, low-grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lungsquamous cell carcinoma; MAPK, the mitog","cbCaisRQvmc20jwz","https://ap.wps.com/l/cbCaisRQvmc20jwz","pdf",3768118,12,"English","# Introduction\n## Study design and patient cohort\n## Cooperative genetic alterations and outcomes\n## Enhancement by TP53 alterations\n## Breast cancer risk association\n## Mouse knockout models\n## Mechanistic interpretation","[{\"question\":\"What genes are studied for their concurrent alterations in cancer aggressiveness?\",\"answer\":\"The study focuses on RASAL1 and PTEN alterations, and also evaluates how additional TP53 alterations further affect outcomes.\"},{\"question\":\"How are RASAL1 and PTEN alterations linked to signaling activity?\",\"answer\":\"Concurrent RASAL1 and PTEN alterations cooperatively activate the PI3K–AKT pathway.\"},{\"question\":\"What do the mouse knockout results suggest about RASAL1 and PTEN function?\",\"answer\":\"Double knockouts of Rasal1 and Pten produce robust PI3K pathway activation and metastasizing malignancies, while single-gene knockouts result in only benign neoplasms.\"}]","The genetic duet of concurrent RASAL1 and PTEN alterations promotes cancer aggressiveness by cooperatively activating the PI3K-AKT pathway | PDF",1789994712]