Abstract 449: Exome sequencing reveals Bcl6 co-repressor (Bcor) as a frequently mutated tumor suppressor gene in Eμ-Myc lymphoma
Authors: Lefebure Marcus P. , Tothill Richard , Li Jason , Matthews Geoff , Shortt Jake , Hawkins Edwin , Kruse Elizabeth , Doyle Maria , Poortinga Gretchen , Hannan Ross , Bardwell Vivian , Gearhart Micah , Johnstone Ricky W. 
Published: May 2015

Genetically-engineered mouse models offer controlled and reproducible systems in which to study the genetics of cancer development. We have used massively-parallel sequencing to provide a comprehensive analysis of the step-wise progression of cancer in the highly tractable Eμ-Myc mouse model. The Eμ-Myc mouse has been engineered to harbor a t(8;14) translocation juxtaposing the IgH enhancer to the proto-oncogene Myc, a lesion frequently observed in mature B-cell malignancies. Eμ-Myc mice develop spontaneous Burkitt-like B-cell leukemia/lymphoma with 100% penetrance through predicable premalignant to malignant progression phases. Malignant progression ostensibly occurs as a result of secondary somatic mutations that co-operate with Myc. Despite common perception that the majority of tumors can be explained by disruption of the archetypal Cdkn2a and Trp53 tumor suppressor axis, in more than half of spontaneous Eμ-Myc tumors harbor secondary mutations that remain unknown. We hypothesize that the identification of genes that cooperate with Myc could therefore yield not only new biological insight into oncogenic pathways involved in B-cell lymphomagenesis but also improve therapy for patients in the future.

We applied exome-sequencing to a cohort of 18 spontaneous murine Eμ-Myc lymphomas to determine novel somatic driver mutations capable of cooperating with Myc. In addition to exome-sequencing, we harvested blood samples at 2-week intervals throughout the premalignant to malignant phases to allow a temporal analysis of mutations that were detected at end-stage. End-stage tumors were found to be heterogeneous in nature, ranging from 11 to 36 single-base mutations, deletions or insertions. The screen identified genes previously described to be mutated in Eμ-Myc lymphoma (Trp53, Cdkn2a, Kras and Nras). Interestingly, concurrent mutations in known cancer genes were evident in clonal tumors from the sequenced cohort with, for example, a Cdkn2a deletion co-occurring with an activating Kras mutation. In addition to these mutations, we identified novel protein-truncating mutations in Bcl6 co-repressor (Bcor), which has not previously been described in Eμ-Myc lymphoma. Bcor truncating mutations were present at a high frequency, occurring in 3 out of 18 samples. RNAi mediated knockdown of Bcor in Eμ-Myc fetal liver hematopoietic stem cells reconstituted into lethally irradiated congenic recipient mice accelerated lymphomagenesis, validating Bcor as a tumor suppressor gene in this model.

BCOR loss-of-function mutations have recently been identified in human cancers suggesting that BCOR acts as a tumor-suppressor in a wide range of malignancies. Given that Bcor mutations frequently occur in the Eμ-Myc lymphoma, we hypothesize that Bcor is critically important for B-cell development and that its disruption can induce malignancy in co-operation with other potent oncogenes such as Myc.

Citation Format: Marcus P. Lefebure, Richard Tothill, Jason Li, Geoff Matthews, Jake Shortt, Edwin Hawkins, Elizabeth Kruse, Maria Doyle, Gretchen Poortinga, Ross Hannan, Vivian Bardwell, Micah Gearhart, Ricky W. Johnstone. Exome sequencing reveals Bcl6 co-repressor (Bcor) as a frequently mutated tumor suppressor gene in Eμ-Myc lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 449. doi:10.1158/1538-7445.AM2014-449