Loading
Applying the Lehmann subtypes to 550 triple-negative tumours from the two biggest breast cancer genome projects showed each subtype has its own mutations: BL1 is TP53-mutant and unstable, LAR carries PIK3CA in more than half, the immunomodulatory type does best and LAR worst.
Copy-number, somatic mutation and gene expression data from METABRIC (355) and TCGA (195) gave 550 TNBC samples classified with the TNBCtype tool; 485 were stably classified (BL1 25%, IM 25%, M 21%, LAR 16%, MSL 13%) and 447 had sequencing. TP53 (81%), MUC16 (21%) and PIK3CA (20%) were the most mutated genes. IM was associated with better prognosis (HR 0.68, 95% CI 0.46 to 0.99) and LAR with worse (HR 1.47, 1.0 to 2.14). BL1 was the most genomically unstable subtype with TP53 mutation in 92% and copy-number deletion of BRCA2, MDM2, PTEN, RB1 and TP53. LAR carried a higher mutational burden with PIK3CA (55%), KMT2C (19%), CDH1 (13%), NF1 (13%) and AKT1 (13%) mutations and was 75% HER2-enriched by PAM50. MYC (64%), PIK3CA (51%) and CDK6 (39%) were the most gained or amplified genes. IM showed high expression of PD1, PDL1 and CTLA4. By PAM50, 76% of TNBCs were basal-like, 15% HER2-enriched, 5% normal-like and 2% luminal.
This is the sourced bridge between expression subtype and mutation: it tells a clinician that a LAR tumour is the one to sequence for PIK3CA and AKT1, and that immunomodulatory biology is a favourable prognostic group before any immunotherapy.
Shares PTEN, PAM50 / intrinsic subtypes, RB1, MYC.
Shares AKT1 E17K mutation, PIK3CA mutation, PTEN, AKT.
Shares PAM50 / intrinsic subtypes, PIK3CA / PI3K-alpha, TP53, Triple-negative breast cancer (TNBC).
Shares PTEN, AKT, PIK3CA / PI3K-alpha, PI3K / AKT / mTOR.
Shares PTEN, AKT, PIK3CA / PI3K-alpha, PI3K / AKT / mTOR.
Shares PTEN, PIK3CA / PI3K-alpha, TP53, Triple-negative breast cancer (TNBC).
Shares PTEN, AKT, PIK3CA / PI3K-alpha, PI3K / AKT / mTOR.
Shares NF1 (neurofibromin), RB1, TP53, Triple-negative breast cancer (TNBC).