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Clin Cancer Res. 2018 Dec 20. pii: clincanres.3121.2018. doi: 10.1158/1078-0432.CCR-18-3121. [Epub ahead of print]

Clinical and Genomic Implications of Luminal and Basal Subtypes Across Carcinomas.

Author information

1
University of Michigan-Ann Arbor shgzhao1@gmail.com.
2
Yale School of Medicine, Yale University.
3
Radiation Oncology, UCSF Helen Diller Family Comprehensive Cancer Center.
4
Radiation Oncology, University of California, San Francisco.
5
Department of Pathology, Department of Urology, Michigan Center for Translational Pathology, Comprehensive Cancer Center, University of Michigan-Ann Arbor.
6
Medicine, University of California, San Francisco.
7
Epidemiology and Biostatistics, University of California, San Francisco.
8
Department of Medicine, Washington University School of Medicine.
9
Radiation Oncology, Dana-Farber Cancer Institute.
10
R&D, GenomeDx Biosciences.
11
Clinical Laboratory, GenomeDx Biosciences Inc.
12
Obstetrics and Gynecology, University of Virginia School of Medicine.
13
Urologic Oncology Program & Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center.
14
Radiation Oncology, University of Michigan-Ann Arbor.
15
Department of Radiation Oncology, University of Michigan-Ann Arbor.
16
Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital.
17
Oncology Division, Washington University School of Medicine.
18
Medical Oncology, University of California, San Francisco.
19
Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco.

Abstract

BACKGROUND:

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.

EXPERIMENTAL DESIGN:

While prior studies have focused on individual cancer types, we used a modified clinical-grade classifier (PAM50) to subtype 8764 tumors across 22 different carcinomas into luminal A, luminal B, and basal-like tumors.

RESULTS:

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 to 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 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.

CONCLUSIONS:

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 vs. basal subtypes.

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