Proteogenomic Markers of Chemotherapy Resistance and Response in Triple-Negative Breast Cancer

Meenakshi Anurag, Eric J. Jaehnig, Karsten Krug, Jonathan T. Lei, Erik J. Bergstrom, Beom Jun Kim, Tanmayi D. Vashist, Anh Minh Tran Huynh, Yongchao Dou, Xuxu Gou, Chen Huang, Zhiao Shi, Bo Wen, Viktoriya Korchina, Richard A. Gibbs, Donna M. Muzny, Harshavardhan Doddapaneni, Lacey E. Dobrolecki, Henry Rodriguez, Ana I. RoblesTara Hiltke, Michael T. Lewis, Julie R. Nangia, Maryam Nemati Shafaee, Shunqiang Li, Ian S. Hagemann, Jeremy Hoog, Bora Lim, C. Kent Osborne, D. R. Mani, Michael A. Gillette, Bing Zhang, Gloria V. Echeverria, George Miles, Mothaffar F. Rimawi, Steven A. Carr, Foluso O. Ademuyiwa, Shankha Satpathy, Matthew J. Ellis

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin and docetaxel combination chemo therapy for triple-negative breast cancer (TNBC). Proteomic analyses of pretreatment patient biopsies uniquely revealed metabolic pathways, including oxidative phosphorylation, adipogenesis, and fatty acid metabolism, that were associated with resistance. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G2–M checkpoint, interferongamma signaling, and immune-checkpoint components. Proteogenomic analyses of somatic copy-number aberrations identified a resistance-associated 19q13.31–33 deletion where LIG1, POLD1, and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I) gene deletion and/or low mRNA expression levels were associated with lack of pathologic complete response, higher chromosomal instability index (CIN), and poor prognosis in TNBC, as well as carboplatin-selective resistance in TNBC preclinical models. Hemizygous loss of LIG1 was also associated with higher CIN and poor prognosis in other cancer types, demonstrating broader clinical implications. SIGNIFICANCE: Proteogenomic analysis of triple-negative breast tumors revealed a complex landscape of chemotherapy response associations, including a 19q13.31–33 somatic deletion encoding genes serving lagging-strand DNA synthesis (LIG1, POLD1, and XRCC1), that correlate with lack of pathologic response, carboplatin-selective resistance, and, in pan-cancer studies, poor prognosis and CIN.

Original languageEnglish
Pages (from-to)2586-2605
Number of pages20
JournalCancer discovery
Volume12
Issue number11
DOIs
StatePublished - Nov 1 2022

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