Tumor suppressors status in cancer cell line Encyclopedia

Abstract

Tumor suppressors play a major role in the etiology of human cancer, and typically achieve a tumor-promoting effect upon complete functional inactivation. Bi-allelic inactivation of tumor suppressors may occur through genetic mechanisms (such as loss of function mutation, copy number (CN) loss, or loss of heterozygosity (LOH)), epigenetic mechanisms (such as promoter methylation or histone modification), or a combination of the two. We report systematically derived status of 69 known or putative tumor suppressors, across 799 samples of the Cancer Cell Line Encyclopedia. In order to generate such resource we constructed a novel comprehensive computational framework for the assessment of tumor suppressor functional "status". This approach utilizes several orthogonal genomic data types, including mutation data, copy number, LOH and expression. Through correlation with additional data types (compound sensitivity and gene set activity) we show that this integrative method provides a more accurate assessment of tumor suppressor status than can be inferred by expression, copy number, or mutation alone. This approach has the potential for a more realistic assessment of tumor suppressor genes for both basic and translational oncology research.

Keywords: CCLE; Cancer cell line; DNA methylation; Epigenetics; Loss of function; Tumor suppressor.

Figure 1

Tumor suppressor inactivation categories. G – stands for genetic alteration, D – stands for deletion, M – stands for mutation, E – stands for absence of expression.

Figure 2

Simplified flow chart of category assignments.

Figure 3

Nutlin‐3 sensitivity across 491 CCLE cell lines in relation to TP53 status. Each dot represents cell line with TP53 inactivation status marked by color. All cell lines with TP53 inactivated by any mechanism are insensitive to Nutlin‐3. TP53 Wild Type status covers: WT‐E and WT categories. TP53 Genetic Inactivation status covers: G‐M and G‐D categories. TP53 Epigenetic Inactivation status covers E‐LOH category. TP53 Epigenetic/Genetic Inactivation status covers: E‐G‐M and E‐G‐D categories.