Oral presentation | Open | Published:
Clinico-pathological and transcriptomic determinants of SLFN11 expression in invasive breast carcinoma
Journal for ImmunoTherapy of Cancervolume 3, Article number: O3 (2015)
SLFN11 is a putative DNA/RNA helicase we discovered as causally associated with sensitivity to DNA damaging agents, such as platinum salts, topoisomerase I and II inhibitors, and other alkylators in the NCI-60 panel of cancer cell lines . Later, SLFN11 was identified as an early interferon response gene, in association with HIV infection . Here we assessed SLFN11 determinants in a gene expression meta-set of 5,061 breast cancer patients annotated with clinical data and multigene signatures obtained with the package genefu . By correlation analysis, we found 537 transcripts above the 95th percentile of Pearson’s coefficients with SLFN11, identifying “immune response”, “lymphocyte activation”, and “T cell activation” as top Gene Ontology enriched processes . Through multiple correspondence analysis, we discovered a subgroup of patients characterized by high SLFN11 levels, ER negativity, basal phenotype, elevated CD3D, STAT1 signature , and young age. Fitting a penalized maximum likelihood lasso regression model , we found a strong multivariable association of SLN11 with the stroma 1 and stroma 2 signatures [7, 8], associated with basal cancer and response to chemotherapy in ER- tumors. Finally, using Cox proportional hazard regression, ER-, high proliferation, high SLFN11 patients undergoing chemotherapy treatment showed a significantly longer disease-free interval than other patient categories included in our model.
Zoppoli G, Regairaz M, Leo E, Reinhold WC, Varma S, Ballestrero A, Doroshow JH, Pommier Y: Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents. Proc Natl Acad Sci U S A. 2012, 109 (37): 15030-5. 10.1073/pnas.1205943109.
Li M, Kao E, Gao X, Sandig H, Limmer K, Pavon-Eternod M, Jones TE, Landry S, Pan T, Weitzman MD, David M: Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11. Nature. 2012, 491 (7422): 125-8. 10.1038/nature11433.
Haibe-Kains B, Schroeder M, Bontempi G, Sotiriou C, Quackenbush J: genefu: Relevant Functions for Gene Expression Analysis, Especially in Breast Cancer. 2014, R package version 1.16.0
Huang da W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009, 4 (1): 44-57.
Desmedt C, Haibe-Kains B, Wirapati P, Buyse M, Larsimont D, Bontempi G, Delorenzi M, Piccart M, Sotiriou C: Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res. 2008, 14 (16): 5158-65. 10.1158/1078-0432.CCR-07-4756.
Friedman J, Hastie T, Tibshirani R: Regularization Paths for Generalized Linear Models via Coordinate Descent. J Stat Softw. 2010, 33 (1): 1-22.
Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V, AndrÃ© S, Piccart M, Campone M, Brain E, Macgrogan G, Petit T, Jassem J, Bibeau F, Blot E, Bogaerts J, Aguet M, Bergh J, Iggo R, Delorenzi M: A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med. 2009, 15 (1): 68-74. 10.1038/nm.1908.
Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, Hallett M, Park M: Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 2008, 14 (5): 518-27. 10.1038/nm1764.