Structural variants within MACROD2, found through long-read sequencing technology from PacBio and validated via whole-genome sequencing data of more than 450 metastatic colorectal cancers (CRCs) using Illumina machines, were found in 40% of patients with CRC but fewer than 2% of patients with colorectal adenomas. The research, presented at the American Association for Cancer Research (AACR) Annual Meeting 2019, suggests that the changes to MACROD2 occur at a late stage of colorectal adenoma-to-carcinoma progression.1

Previous research on MACROD2 in mice has shown that the loss of the function of this tumor suppressor gene stimulates further chromosomal instability.2 Loss of MACROD2 protein expression is believed to impair DNA repair functions through the stunting of PARP1 activity. Deletion of this gene is also associated with poor response to treatment with 5-fluorouracil-based adjuvant chemotherapy.1

Related Articles

Because almost no structural variants within this gene were found in patients with colorectal adenomas (118 individuals), but were highly prevalent among patients with colorectal carcinomas (466 individuals), the researchers concluded the appearance of the structural variants may be a hallmark of CRC pathogenesis. Colorectal adenomas are considered CRC precursor lesions.

Based on what is known about chromosomal instability in CRC and the results of this study, the authors concluded that the function of MACROD2 is clinically relevant, and “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.” And, according to the authors, because the function of MACROD2 has clinical utility, it could have the potential to inform care decisions.

Disclosure: Some authors of the research presented at the AACR Annual Meeting 2019 disclosed financial ties to Pacific Biosciences (PacBio). For a full list of disclosures, please see the original abstract.


Read more of Cancer Therapy Advisor‘s coverage of the AACR Annual Meeting 2019 by visiting the conference page.

References

  1. Fijneman RJ, Mekkes N, van den Broek E, et al. Characterization of structural variants within MACROD2 in the pathogenesis of colorectal cancer. Presented at: American Association for Cancer Research (AACR) Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. Abstract 1738/3.
  2. Sakthianandeswaren A, Parsons MJ, Mouradov D, et al. MACROD2 haploinsufficiency impairs catalytic activity of PARP1 and promotes chromosome instability and growth of intestinal tumors. Cancer Discov. 2018;8(8):988-1005.