Abstract 1436: Identification of novel tumor suppressor candidates in familial cholangiocarcinoma using sequencing-based Megabase-scale haplotypes from germline and cancer genomes
| Autor: | Hanlee P. Ji, John Bell, Erik S. Hopmans, Billy T. Lau, Lincoln Nadauld, Laura Miotke, David A. Jones, Stephanie Greer, Christina Wood |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Cancer Research. 77:1436-1436 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2017-1436 |
| Popis: | Cholangiocarcinoma (bile duct cancer) is a rare epithelial malignancy with an extremely poor prognosis characterized by a 5-year survival of less than 10%. While this tumor type can be amenable to specific combination chemotherapy regimens, it is typically diagnosed at an advanced stage and inevitably progresses towards distant metastasis. We identified a family with a predisposition to cholangiocarcinoma, having multiple affected family members, and sought to identify the underlying germline mutation(s). We employed linked-read sequencing, a microfluidic technology where high-molecular weight DNA molecules (>20 kb) are partitioned into droplets and labeled with unique barcodes, enabling computational reconstruction of the original large molecules following traditional short-read sequencing, to identify entire megabase-scale regions of the genome that segregate with the disease. We applied this technology to an entire generation of a family predisposed to cholangiocarcinoma, including a mix of 8 affected and unaffected siblings. We additionally utilized each affected individual’s cancer genome to search for a common second hit that would serve as further confirmation. Our analysis yielded a small set of four candidate pathogenic variants. Functional validation of the candidate genes in a zebrafish model, using morpholino-based gene silencing, identified one candidate whose silencing led to a reproducible phenotype consistent with known aspects of the candidate gene’s function. The candidate variant occurs in a TGF family-interacting domain, and has not been extensively characterized in other cancers. Cross-validation with TCGA datasets showed the gene was altered in 5% of cholangiocarcinomas, all of which displayed homozygous deletions. This identification of a germline allele associated with familial cholangiocarcinoma represents a unique discovery with clinical implications for the described family and warrants further investigation in other patients who display features of an inherited cholagniocarcinoma. This finding also raises the possibility of TGF pathway targeting as a therapeutic strategy in select cholangiocarcinomas, and highlights the power of whole-genome phasing to discover novel inherited tumor suppressor variants. Citation Format: Stephanie Greer, Lincoln Nadauld, Billy Lau, Laura Miotke, Erik Hopmans, Christina M. Wood, John M. Bell, David A. Jones, Hanlee P. Ji. Identification of novel tumor suppressor candidates in familial cholangiocarcinoma using sequencing-based Megabase-scale haplotypes from germline and cancer genomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1436. doi:10.1158/1538-7445.AM2017-1436 |
| Databáze: | OpenAIRE |
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