Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.
Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.
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DOI：
10.1371/journal.pgen.1009876
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发表时间：
2021-11
期刊：
影响因子：
4.5
通讯作者：
Vanhaesebroeck B
中科院分区：
文献类型：
--
作者：
Madsen RR;Erickson EC;Rueda OM;Robin X;Caldas C;Toker A;Semple RK;Vanhaesebroeck B
一种PI3Kα选择性抑制剂最近被批准用于编码p110α的基因PIK3CA突变的乳腺肿瘤。临床前研究表明，PI3K/AKT/mTOR信号通路影响干性，干性是一种与侵袭性癌症相关的去分化相关细胞表型。然而，到目前为止，还没有在人类肿瘤中证明这种相关性的直接证据。在两个独立的人类乳腺癌队列中，包括近3,000个肿瘤样本，基于转录足迹的分析发现，转录推断的PI3K/AKT/mTOR信号评分与干性评分之间存在正向线性关联。出乎意料的是，根据PIK3CA基因对肿瘤进行分层，发现突变的PIK3CA等位基因剂量与这些分数呈“双相”关系。与无PIK3CA突变的肿瘤样本相比，单拷贝热点PIK3CA变异的存在与较低的PI3K/AKT/mTOR信号和干性评分相关，而多拷贝PIK3CA热点突变的存在与较高的PI3K/AKT/mTOR信号和干性评分相关。这一观察结果在杂合和纯合子PIK3CAH1047R表达的人类细胞模型中得到了概括。总而言之，我们的分析(1)为人类乳腺癌中依赖信号强度的PI3K-干性关系提供了证据；(2)支持基于传统PI3K途径遗传信息和PI3K信号激活的转录转录指数相结合的患者分层的潜在益处的评估。乳腺癌通常具有所谓的PI3Kα酶的活性增强及其激活的途径，这通常归因于PI3CA基因的遗传变化，编码关键的PI3Kα成分。最近的细胞研究表明，PIK3CA突变的影响取决于存在多少拷贝。例如，强突变的两个副本，而不是一个副本，将细胞固定在“干性”状态，这是一种与肿瘤侵袭性和治疗失败相关的特性。为了确定乳腺癌中PI3K基因变异、PI3K活性和干性之间的关系，我们使用了涵盖近3,000个肿瘤的独立患者队列数据。使用PI3K信号或来自基因表达数据的干性评分，我们发现这些评分之间存在强烈的正相关：侵袭性肿瘤显示出最高的评分。相比之下，这些得分与PIK3CA突变状态的关系是意想不到的--具有一个PIK3CA突变拷贝的癌症显示这两个得分都下降，而在具有额外拷贝的癌症中这两个得分都上升。这在细胞模型中得到了证实。这表明，使用关于PIK3CA突变的二进制信息来定义试验的患者组可能会错过等位基因剂量的重要影响。我们建议将PIK3CA突变信息与PI3K通路激活的功能指标结合起来，可以改善分组。
A PI3Kα-selective inhibitor has recently been approved for use in breast tumors harboring mutations in PIK3CA, the gene encoding p110α. Preclinical studies have suggested that the PI3K/AKT/mTOR signaling pathway influences stemness, a dedifferentiation-related cellular phenotype associated with aggressive cancer. However, to date, no direct evidence for such a correlation has been demonstrated in human tumors. In two independent human breast cancer cohorts, encompassing nearly 3,000 tumor samples, transcriptional footprint-based analysis uncovered a positive linear association between transcriptionally-inferred PI3K/AKT/mTOR signaling scores and stemness scores. Unexpectedly, stratification of tumors according to PIK3CA genotype revealed a “biphasic” relationship of mutant PIK3CA allele dosage with these scores. Relative to tumor samples without PIK3CA mutations, the presence of a single copy of a hotspot PIK3CA variant was associated with lower PI3K/AKT/mTOR signaling and stemness scores, whereas the presence of multiple copies of PIK3CA hotspot mutations correlated with higher PI3K/AKT/mTOR signaling and stemness scores. This observation was recapitulated in a human cell model of heterozygous and homozygous PIK3CAH1047R expression. Collectively, our analysis (1) provides evidence for a signaling strength-dependent PI3K-stemness relationship in human breast cancer; (2) supports evaluation of the potential benefit of patient stratification based on a combination of conventional PI3K pathway genetic information with transcriptomic indices of PI3K signaling activation. Breast cancers often have increased activity of the so-called PI3Kα enzyme and the pathway it activates, usually attributed to genetic alterations in the PIK3CA gene, encoding a critical PI3Kα component. Recent cell studies have shown that effects of a PIK3CA mutation depend on how many copies are present. For example, two copies of a strong mutation, but not one, fix cells in a state of “stemness”, a property associated with tumor aggressiveness and therapy failure. To determine relationships among PI3K genetic variation, PI3K activity and stemness in breast cancers we used data from independent patient cohorts encompassing nearly 3,000 tumors. Using PI3K signaling or stemness scores derived from gene expression data, we found a strong, positive association between the scores: aggressive tumors show the highest scores. In contrast, the relationship of these scores with PIK3CA mutation status was unexpected–cancers with one PIK3CA mutant copy showed a decrease in both scores, while they increased in cancers with additional copies. This was confirmed in cellular models. This suggests that using binary information about a PIK3CA mutation to define patient groups for trials may miss important effects of allele dosage. We suggest that grouping may be improved by combining PIK3CA mutational information with functional indices of PI3K pathway activation.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
影响因子：
8
作者：
Du L;Chen X;Cao Y;Lu L;Zhang F;Bornstein S;Li Y;Owens P;Malkoski S;Said S;Jin F;Kulesz-Martin M;Gross N;Wang XJ;Lu SL
通讯作者：
Lu SL
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y