Jacqueline J Tao, Saumya D Sisoudiya, Hanna Tukachinsky, Alexa Schrock, Smruthy Sivakumar, Ethan S Sokol, Neil Vasan
{"title":"乳腺癌中PIK3CA, AKT1和PTEN突变的临床基因组景观和功能。","authors":"Jacqueline J Tao, Saumya D Sisoudiya, Hanna Tukachinsky, Alexa Schrock, Smruthy Sivakumar, Ethan S Sokol, Neil Vasan","doi":"10.1101/2025.06.18.25329632","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>To comprehensively characterize the clinical and genomic landscapes of <i>PIK3CA, AKT1,</i> and <i>PTEN</i> alterations and examine their functional implications in AKT-driven breast cancer.</p><p><strong>Experimental design: </strong>Comprehensive genomic profiling of 51,767 breast tumors was performed with FoundationOne <sup>®</sup> CDx or FoundationOne <sup>®</sup> . We examined the genomic landscape of <i>PIK3CA</i> , <i>PTEN</i> , and <i>AKT1</i> alterations and their distribution across clinical variables of interest. Prior deep mutational scanning (DMS) data was used to functionally characterize clinical <i>PTEN</i> variants.</p><p><strong>Results: </strong>There were 29,157 total variants across <i>PIK3CA, AKT1,</i> and <i>PTEN</i> , including pathogenic variants and VUS. The most frequently altered gene was <i>PIK3CA</i> (37.4% of cases), followed by <i>PTEN</i> (13.5%), then <i>AKT1</i> (5.4%). The most common alterations in each gene were <i>PIK3CA</i> H1047R (35.6% of <i>PIK3CA</i> -altered cases), E545K (19.7%), and E542K (11.7%); <i>AKT1</i> E17K (69.7%); and <i>PTEN</i> homozygous copy number deletion (37.3%). <i>PIK3CA</i> alterations were less prevalent in patients of African genetic ancestry (27.1% vs 38.6% in European genetic ancestry), while <i>AKT1</i> and <i>PTEN</i> alterations were balanced across ancestries. <i>PIK3CA</i> , <i>AKT1</i> , and <i>PTEN</i> pathogenic alterations were all mutually exclusive to each other. Using available DMS data on missense <i>PTEN</i> mutations, we found that 32.5% showed discordant effects on protein stability and phosphatase activity, underscoring the need for functional validation beyond predicted loss-of-function.</p><p><strong>Conclusions: </strong>Here we present the landscape of <i>PIK3CA</i> , <i>AKT1</i> , and <i>PTEN</i> alterations in the largest clinical cohort examined to date. The functional implications of lesser-known variants in each gene warrant further investigation by tools such as deep mutational scanning.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204289/pdf/","citationCount":"0","resultStr":"{\"title\":\"Clinicogenomic landscape and function of <i>PIK3CA</i> , <i>AKT1</i> , and <i>PTEN</i> mutations in breast cancer.\",\"authors\":\"Jacqueline J Tao, Saumya D Sisoudiya, Hanna Tukachinsky, Alexa Schrock, Smruthy Sivakumar, Ethan S Sokol, Neil Vasan\",\"doi\":\"10.1101/2025.06.18.25329632\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>To comprehensively characterize the clinical and genomic landscapes of <i>PIK3CA, AKT1,</i> and <i>PTEN</i> alterations and examine their functional implications in AKT-driven breast cancer.</p><p><strong>Experimental design: </strong>Comprehensive genomic profiling of 51,767 breast tumors was performed with FoundationOne <sup>®</sup> CDx or FoundationOne <sup>®</sup> . We examined the genomic landscape of <i>PIK3CA</i> , <i>PTEN</i> , and <i>AKT1</i> alterations and their distribution across clinical variables of interest. Prior deep mutational scanning (DMS) data was used to functionally characterize clinical <i>PTEN</i> variants.</p><p><strong>Results: </strong>There were 29,157 total variants across <i>PIK3CA, AKT1,</i> and <i>PTEN</i> , including pathogenic variants and VUS. The most frequently altered gene was <i>PIK3CA</i> (37.4% of cases), followed by <i>PTEN</i> (13.5%), then <i>AKT1</i> (5.4%). The most common alterations in each gene were <i>PIK3CA</i> H1047R (35.6% of <i>PIK3CA</i> -altered cases), E545K (19.7%), and E542K (11.7%); <i>AKT1</i> E17K (69.7%); and <i>PTEN</i> homozygous copy number deletion (37.3%). <i>PIK3CA</i> alterations were less prevalent in patients of African genetic ancestry (27.1% vs 38.6% in European genetic ancestry), while <i>AKT1</i> and <i>PTEN</i> alterations were balanced across ancestries. <i>PIK3CA</i> , <i>AKT1</i> , and <i>PTEN</i> pathogenic alterations were all mutually exclusive to each other. Using available DMS data on missense <i>PTEN</i> mutations, we found that 32.5% showed discordant effects on protein stability and phosphatase activity, underscoring the need for functional validation beyond predicted loss-of-function.</p><p><strong>Conclusions: </strong>Here we present the landscape of <i>PIK3CA</i> , <i>AKT1</i> , and <i>PTEN</i> alterations in the largest clinical cohort examined to date. 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引用次数: 0
摘要
目的:全面表征PIK3CA, AKT1和PTEN改变的临床和基因组景观,并研究它们在akt驱动的乳腺癌中的功能意义。实验设计:使用FoundationOne®CDx或FoundationOne®对51767例乳腺肿瘤进行全面的基因组分析。我们研究了PIK3CA、PTEN和AKT1基因改变的基因组图谱,以及它们在相关临床变量中的分布。先前的深度突变扫描(DMS)数据用于临床PTEN变异的功能表征。结果:PIK3CA、AKT1和PTEN共存在29157个变异,包括致病性变异和VUS。最常见的改变基因是PIK3CA(37.4%),其次是PTEN(13.5%),然后是AKT1(5.4%)。每个基因中最常见的改变是PIK3CA H1047R(占PIK3CA改变病例的35.6%)、E545K(19.7%)和E542K (11.7%);Akt1 e17k (69.7%);PTEN纯合拷贝数缺失(37.3%)。PIK3CA改变在非洲遗传血统患者中不太普遍(27.1% vs 38.6%的欧洲遗传血统),而AKT1和PTEN改变在不同祖先中是平衡的。PIK3CA、AKT1和PTEN的致病改变都是相互排斥的。利用现有的DMS数据,我们发现32.5%的错义PTEN突变在蛋白质稳定性和磷酸酶活性方面表现出不一致的影响,强调了功能验证的必要性,而不是预测的功能丧失。结论:在这里,我们展示了迄今为止最大的临床队列中PIK3CA、AKT1和PTEN改变的情况。每个基因中鲜为人知的变异的功能含义需要通过深度突变扫描等工具进一步研究。
Clinicogenomic landscape and function of PIK3CA , AKT1 , and PTEN mutations in breast cancer.
Purpose: To comprehensively characterize the clinical and genomic landscapes of PIK3CA, AKT1, and PTEN alterations and examine their functional implications in AKT-driven breast cancer.
Experimental design: Comprehensive genomic profiling of 51,767 breast tumors was performed with FoundationOne ® CDx or FoundationOne ® . We examined the genomic landscape of PIK3CA , PTEN , and AKT1 alterations and their distribution across clinical variables of interest. Prior deep mutational scanning (DMS) data was used to functionally characterize clinical PTEN variants.
Results: There were 29,157 total variants across PIK3CA, AKT1, and PTEN , including pathogenic variants and VUS. The most frequently altered gene was PIK3CA (37.4% of cases), followed by PTEN (13.5%), then AKT1 (5.4%). The most common alterations in each gene were PIK3CA H1047R (35.6% of PIK3CA -altered cases), E545K (19.7%), and E542K (11.7%); AKT1 E17K (69.7%); and PTEN homozygous copy number deletion (37.3%). PIK3CA alterations were less prevalent in patients of African genetic ancestry (27.1% vs 38.6% in European genetic ancestry), while AKT1 and PTEN alterations were balanced across ancestries. PIK3CA , AKT1 , and PTEN pathogenic alterations were all mutually exclusive to each other. Using available DMS data on missense PTEN mutations, we found that 32.5% showed discordant effects on protein stability and phosphatase activity, underscoring the need for functional validation beyond predicted loss-of-function.
Conclusions: Here we present the landscape of PIK3CA , AKT1 , and PTEN alterations in the largest clinical cohort examined to date. The functional implications of lesser-known variants in each gene warrant further investigation by tools such as deep mutational scanning.