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. 2020 Dec 9;588(7837):331–336. doi: 10.1038/s41586-020-2969-2

Extended Data Fig. 6. Association of chr 8p gene copy number status and PI3K-response signatures with brain metastasis in clinical breast cancer specimens.

Extended Data Fig. 6

a, Heat maps showing coordinated expression of chr 8p genes mirrored their copy number status in the two large breast cancer datasets, METABRIC and TCGA. The 8plow cluster is defined by CNA data. The right panel shows distribution of 8plow cluster in different breast cancer subtypes and its association with disease specific survival. P values calculated using two-sided, log-rank tests. CNA, Copy Number Alteration. Exp, RNA-Seq Expression. b, Hierarchical clustering of primary breast tumours by 8p gene expression in the EMC-MSK dataset. The 8plow cluster is enriched in tumours that developed brain metastasis, but not lung or bone metastasis. The right panel shows organ-specific metastasis free survival curves stratified by 8plow status. The 8plow cluster displays poorer brain metastasis compared to the 8pWT cluster. Brain metastasis free survival curves stratified by 8plow status in different subtypes is also presented. P values calculated using two-sided, log-rank tests. c, Hierarchical clustering of breast cancer metastases by 8p gene expression, with the 8plow cluster being enriched in brain metastases. d, Chr 8p CNA status determined by Targeted Seq in the MSK metastatic breast cancer dataset. Brain metastases are enriched in chr 8p deletion compared to primary tumour, local recurrence and metastases at other sites. The 8plow cluster predicts poor brain metastasis free survival. P values calculated using two-sided, log-rank tests. LN, lymph node. e, Heat maps showing co-regulated patterns of two independent PI3K-response signatures in METABRIC and TCGA breast cancer datasets. PI3Ksig.1 was generated by overexpression of PIK3CAmut in breast epithelial cells. PI3Ksig.2 was generated by PI3K inhibitor treatment in the CMap database. The right panel shows distribution of PI3Ksighigh cluster in different breast cancer subtypes and its association with disease specific survival. P values calculated using two-sided, log-rank tests. f, Hierarchical clustering of primary breast tumours by PI3K signatures in the EMC-MSK dataset. The PI3Ksighigh cluster is enriched in tumours that developed brain metastasis. The right panel shows organ-specific metastasis free survival curves stratified by PI3K signatures. The PI3Ksighigh cluster displayed poorer brain metastasis. Brain metastasis free survival curves stratified by PI3K signatures in different subtypes is also presented. P values calculated using two-sided, log-rank tests. g, Hierarchical clustering of breast cancer metastases by PI3K signatures, with the PI3Ksighigh cluster being enriched in brain metastases. h, Heat maps showing significant yet non-complete overlap between 8plow and PI3Ksighigh clusters in the EMC-MSK dataset. 8plow and PI3Ksighigh clusters co-capture a subset of patients with the worst brain metastasis prognosis. P values calculated using two-sided, log-rank tests. The lower panel presents a Cox proportional-hazards model of brain metastasis free survival using multi variates – 8p, PI3Ksig, and breast cancer subtype. The 8plow/PI3Ksighigh cluster is the most associated with brain metastasis. i. 8plow and PI3Ksighigh clusters co-capture the majority of brain metastasis samples.

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