TY - JOUR
T1 - LobSig is a multigene predictor of outcome in invasive lobular carcinoma
AU - McCart Reed, Amy E.
AU - Lal, Samir
AU - Kutasovic, Jamie R.
AU - Wockner, Leesa
AU - Robertson, Alan
AU - de Luca, Xavier M.
AU - Kalita-de Croft, Priyakshi
AU - Dalley, Andrew J.
AU - Coorey, Craig P.
AU - Kuo, Luyu
AU - Ferguson, Kaltin
AU - Niland, Colleen
AU - Miller, Gregory
AU - Johnson, Julie
AU - Reid, Lynne E.
AU - Males, Renique
AU - Saunus, Jodi M.
AU - Chenevix-Trench, Georgia
AU - Coin, Lachlan
AU - Lakhani, Sunil R.
AU - Simpson, Peter T.
PY - 2019
Y1 - 2019
N2 - Invasive lobular carcinoma (ILC) is the most common special type of breast cancer, and is characterized by functional loss of E-cadherin, resulting in cellular adhesion defects. ILC typically present as estrogen receptor positive, grade 2 breast cancers, with a good short-term prognosis. Several large-scale molecular profiling studies have now dissected the unique genomics of ILC. We have undertaken an integrative analysis of gene expression and DNA copy number to identify novel drivers and prognostic biomarkers, using in-house (n = 25), METABRIC (n = 125) and TCGA (n = 146) samples. Using in silico integrative analyses, a 194-gene set was derived that is highly prognostic in ILC (P = 1.20 x 10(-5))-we named this metagene 'LobSig'. Assessing a 10-year follow-up period, LobSig outperformed the Nottingham Prognostic Index, PAM50 risk-of-recurrence (Prosigna), OncotypeDx, and Genomic Grade Index (MapQuantDx) in a stepwise, multivariate Cox proportional hazards model, particularly in grade 2 ILC cases (chi(2), P = 9.0 x 10(-6)), which are difficult to prognosticate clinically. Importantly, LobSig status predicted outcome with 94.6% accuracy amongst cases classified as 'moderate-risk' according to Nottingham Prognostic Index in the METABRIC cohort. Network analysis identified few candidate pathways, though genesets related to proliferation were identified, and a LobSig-high phenotype was associated with the TCGA proliferative subtype (chi(2), P < 8.86 x 10(-4)). ILC with a poor outcome as predicted by LobSig were enriched with mutations in ERBB2, ERBB3, TP53, AKT1 and ROS1. LobSig has the potential to be a clinically relevant prognostic signature and warrants further development.
AB - Invasive lobular carcinoma (ILC) is the most common special type of breast cancer, and is characterized by functional loss of E-cadherin, resulting in cellular adhesion defects. ILC typically present as estrogen receptor positive, grade 2 breast cancers, with a good short-term prognosis. Several large-scale molecular profiling studies have now dissected the unique genomics of ILC. We have undertaken an integrative analysis of gene expression and DNA copy number to identify novel drivers and prognostic biomarkers, using in-house (n = 25), METABRIC (n = 125) and TCGA (n = 146) samples. Using in silico integrative analyses, a 194-gene set was derived that is highly prognostic in ILC (P = 1.20 x 10(-5))-we named this metagene 'LobSig'. Assessing a 10-year follow-up period, LobSig outperformed the Nottingham Prognostic Index, PAM50 risk-of-recurrence (Prosigna), OncotypeDx, and Genomic Grade Index (MapQuantDx) in a stepwise, multivariate Cox proportional hazards model, particularly in grade 2 ILC cases (chi(2), P = 9.0 x 10(-6)), which are difficult to prognosticate clinically. Importantly, LobSig status predicted outcome with 94.6% accuracy amongst cases classified as 'moderate-risk' according to Nottingham Prognostic Index in the METABRIC cohort. Network analysis identified few candidate pathways, though genesets related to proliferation were identified, and a LobSig-high phenotype was associated with the TCGA proliferative subtype (chi(2), P < 8.86 x 10(-4)). ILC with a poor outcome as predicted by LobSig were enriched with mutations in ERBB2, ERBB3, TP53, AKT1 and ROS1. LobSig has the potential to be a clinically relevant prognostic signature and warrants further development.
UR - https://hdl.handle.net/1959.7/uws:67515
U2 - 10.1038/s41523-019-0113-y
DO - 10.1038/s41523-019-0113-y
M3 - Article
SN - 2374-4677
VL - 5
JO - npj Breast Cancer
JF - npj Breast Cancer
IS - 1
M1 - 18
ER -