Abstract
Carcinomas originate from epithelial tissues, which have apical (luminal) and basal orientations. The degree of luminal versus basal differentiation in cancer has been shown to be biologically important in some carcinomas and impacts treatment response. Although prior studies have focused on individual cancer types, we used a modified clinical-grade classifier (PAM50) to subtype 8,764 tumors across 22 different carcinomas into luminal A, luminal B, and basal-like tumors. We found that all epithelial tumors demonstrated similar gene expression-based luminal/basal subtypes. As expected, basal-like tumors were associated with increased expression of the basal markers KRT5/6 and KRT14, and luminal-like tumors were associated with increased expression of the luminal markers KRT20. Luminal A tumors consistently had improved outcomes compared with basal across many tumor types, with luminal B tumors falling between the two. Basal tumors had the highest rates of TP53 and RB1 mutations and copy number loss. Luminal breast, cervical, ovarian, and endometrial tumors had increased ESR1 expression, and luminal prostate, breast, cervical, and bladder tumors had increased androgen receptor (AR) expression. Furthermore, luminal B tumors had the highest rates of AR and ESR1 mutations and had increased sensitivity in vitro to bicalutamide and tamoxifen. Luminal B tumors were more sensitive to gemcitabine, and basal tumors were more sensitive to docetaxel. This first pan-carcinoma luminal/basal subtyping across epithelial tumors reveals global similarities across carcinomas in the transcriptome, genome, clinical outcomes, and drug sensitivity, emphasizing the biological and translational importance of these luminal versus basal subtypes.
Highlights
By definition, epithelial tissues all have apical and basal orientations [1]
We present the first pan-carcinoma luminal/basal subtyping across 8,764 samples from 22 epithelial tumors from the The Cancer Genome Atlas (TCGA), revealing global similarities in the transcriptome, genome, clinical outcomes, and drug sensitivity, which emphasize the biological and translational importance of these subtypes
gene set enrichment analysis (GSEA) revealed that the Hallmark epithelial–mesenchymal transition (EMT) gene signature was most correlated with Basal-ness [normalized enrichment score (NES) 1⁄4 1.87 for Basal vs. 1.45 for Luminal A (LumA) and À2.67 for Luminal B (LumB)] consistent with the literature in breast [23] and prostate [24] cancer (Supplementary Fig. S2)
Summary
We first subtyped 8764 TCGA pan-cancer tumor samples across 22 carcinoma types into LumA, LumB, and basal-like subtypes using the PAM50 clustering algorithm (Fig. 1A; Supplementary Table S2, Supplementary Fig. S1). TP53 mutation frequency was highest in the basal-like subtype overall (49.5% in basal, 25.0% in LumA, 36.0% in LumB, FDR q < 0.0001), as well as in 15 of 22 individual tumor types (Fig. 2J). In the GDSC cell line drug response data, we grouped 421 carcinoma cell lines into the same luminal and basal subtypes (Fig. 1A; Supplementary Table S6) and compared the response across subtypes in four hormone-driven tumors commonly treated with antihormonal therapies (breast, prostate, ovarian, and endometrial cancer). Sensitivity to gemcitabine, whereas basal cell lines showed increased sensitivity to docetaxel (Fig. 4) These results suggest that the biological differences between subtypes may have clinical implications and provide preliminary evidence that these subtypes may be important in selecting therapies in patients with cancer
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