Abstract 1738: Characterization of structural variants within MACROD2 in the pathogenesis of colorectal cancer
Authors: Fijneman Remond J A , Mekkes Nienke , Broek Evert van den , Stringer Bas , Glas Roel A. , Komor Malgorzata A. , Rausch Christian , Lieshout Stef van , Cuppen Edwin , Smith Melissa L. , Sebra Robert P. , Rowell William J. , Ashby Meredith , Carvalho Beatriz , Heringa Jaap , Meijer Gerrit A. , Abeln Sanne 
Published: August 2019

Abstract
Background: Cancer is caused by somatic DNA alterations, which comprise small nucleotide variants (SNVs), chromosome somatic copy number alterations (SCNAs) and chromosomal breakpoint structural variants (SVs). Previously, we investigated SCNA-associated SVs in colorectal cancer (CRC) and demonstrated that SVs within the MACROD2 gene are highly prevalent. This raises the question whether SVs in MACROD2 may already be present in CRC precursor lesions, i.e. in colorectal adenomas. We have also demonstrated that loss of MACROD2 protein expression is associated with poor response to treatment with 5-fluorouracil-based adjuvant chemotherapy, indicating that MACROD2 function is clinically relevant. The aim of this study is to characterize SVs within MACROD2 in more detail in the pathogenesis of colorectal cancer.
Methods: The frequencies of SCNA-associated SVs in 466 CRCs were compared to those in 118 colorectal adenomas, using array-comparative genomic hybridization. Targeted PacBio long-read sequencing was applied to detect and characterize SVs at nucleotide resolution within MACROD2, in tens of primary CRCs. Illumina whole genome sequencing data of &gt; 450 CRC metastatic lesions, generated by the Hartwig Medical Foundation (HMF; www.hartwigmedicalfoundation.nl), were used for validation purposes.
Results: MACROD2 SCNA-associated SVs were rarely detected among 118 colorectal adenomas (&lt;2%) while being highly prevalent among 466 CRCs (40%). SVs in MACROD2 are currently being characterized at nucleotide resolution by analysis of targeted PacBio long-read sequencing data, the results of which will be presented during the AACR annual meeting. Preliminary analysis of HMF whole genome sequencing data confirms that at least 40% of CRC metastatic lesions are affected by SVs within the MACROD2 gene, most commonly by focal deletions.
Discussion: The current observation that SVs in MACROD2 are nearly absent in adenomas while being highly prevalent in CRCs indicates that MACROD2 is affected at a late stage of colorectal adenoma-to-carcinoma progression. A recent publication by Sakthianandeswaren et al (Cancer Discovery 2018) indicated that loss of MACROD2 promotes chromosomal instability. Taken together, these data support a model in which adenoma-to-carcinoma progression is driven, at least in part, by genomic instability caused by loss of function of the MACROD2 tumor suppressor gene.
Citation Format: Remond J A Fijneman, Nienke Mekkes, Evert van den Broek, Bas Stringer, Roel A. Glas, Malgorzata A. Komor, Christian Rausch, Stef van Lieshout, Edwin Cuppen, Melissa L. Smith, Robert P. Sebra, William J. Rowell, Meredith Ashby, Beatriz Carvalho, Jaap Heringa, Gerrit A. Meijer, Sanne Abeln. Characterization of structural variants within MACROD2 in the pathogenesis of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1738.