Novel candidates in early-onset familial colorectal cancer

被引:10
作者
Jansen, Anne M. L. [1 ]
Ghosh, Pradipta [2 ]
Dakal, Tikam C. [3 ]
Slavin, Thomas P. [4 ]
Boland, C. Richard [2 ]
Goel, Ajay [1 ,5 ]
机构
[1] Baylor Scott & White Res Inst, Ctr Gastrointestinal Res,Ctr Translat Gen, Sammons Canc Ctr,Oncology,Charles, Dallas, TX USA
[2] Univ Calif San Diego, Departments Med, Cellular, Mol Med, La Jolla, CA USA
[3] Mohanlal Sukhadia Univ, Dept Biotechnol, Udaipur 313001, Rajasthan, India
[4] Natl Med Ctr, Dept Med Oncology, Div Clin Canc Gen City Hope, Duarte, CA USA
[5] Beckman Res Inst City Hope Comprehens Canc Ctr, Mol Diagnost, Expt Therapeut, Duarte, CA 91016 USA
关键词
Familial colorectal cancer; POLD1; Candidate variants; POLYMERASE-EPSILON; LYNCH-SYNDROME; MUTATIONS; GERMLINE; GENE; PREDISPOSE; DISORDER; RAB25; TET2;
D O I
10.1007/s10689-019-00145-5
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
In 20-30% of patients suspected of a familial colorectal cancer (CRC) syndrome, no underlying genetic cause is detected. Recent advances in whole exome sequencing have generated evidence for new CRC-susceptibility genes including POLE, POLD1 and NTHL1, but many patients remain unexplained. Whole exome sequencing was performed on DNA from nine patients from five different families with familial clusters of CRC in which traditional genetic testing failed to yield a diagnosis. Variants were filtered by minor allele frequencies, followed by prioritization based on in silico prediction tools, and the presence in cancer susceptibility genes or genes in cancer-associated pathways. Effects of frameshift variants on protein structure were modeled using I-Tasser. One known pathogenic variant in POLD1 was detected (p.S478N), together with variants in 17 candidate genes not previously associated with CRC. Additional in silico analysis using SIFT, PROVEAN and PolyPhen on the 14 missense variants indicated a possible damaging effect in nine of 14 variants. Modeling of the insertions/deletions showed a damaging effect of two variants in NOTCH2 and CYP1B1. One family was explained by a mutation in a known familial CRC gene. In the remaining four families, the most promising candidates found are a frameshift NOTCH2 and a missense RAB25 variant. This study provides potential novel candidate variants in unexplained familial CRC patients, however, functional validation is imperative to confirm the role of these variants in CRC tumorigenesis. Additionally, while whole exome sequencing enables detection of variants throughout the exome, other causes explaining the familial phenotype such as multiple single nucleotide polymorphisms accumulating to a polygenic risk or epigenetic events, might be missed with this approach.
引用
收藏
页码:1 / 10
页数:10
相关论文
共 38 条
[1]   Rab25 Regulates Invasion and Metastasis in Head and Neck Cancer [J].
Amornphimoltham, Panomwat ;
Rechache, Kamil ;
Thompson, Jamie ;
Masedunskas, Andrius ;
Leelahavanichkul, Kantima ;
Patel, Vyomesh ;
Molinolo, Alfredo ;
Gutkind, J. Silvio ;
Weigert, Roberto .
CLINICAL CANCER RESEARCH, 2013, 19 (06) :1375-1388
[2]   ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids [J].
Ashkenazy, Haim ;
Erez, Elana ;
Martz, Eric ;
Pupko, Tal ;
Ben-Tal, Nir .
NUCLEIC ACIDS RESEARCH, 2010, 38 :W529-W533
[3]  
Boland CR, 2010, GASTROENTEROLOGY, V138, P2073, DOI [10.1053/j.gastro.2009.12.064, 10.1053/j.gastro.2010.04.024]
[4]   Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers [J].
Briggs, Sarah ;
Tomlinson, Ian .
JOURNAL OF PATHOLOGY, 2013, 230 (02) :148-153
[5]   Tumor suppressor function of Rab25 in triple-negative breast cancer [J].
Cheng, Ji-Ming ;
Volk, Lisa ;
Janaki, Deepak Kumar Mummidavarapu ;
Vyakaranam, Sudhir ;
Ran, Sophia ;
Rao, Krishna A. .
INTERNATIONAL JOURNAL OF CANCER, 2010, 126 (12) :2799-2812
[6]  
Choi YH, 2012, PLOS ONE, V7, DOI [10.1371/journal.pone.0039927, 10.1371/journal.pone.0046688]
[7]   Update on Hereditary Colorectal Cancer [J].
Da Silva, Felipe Carneiro ;
Wernhoff, Patrik ;
Dominguez-Barrera, Constantino ;
Dominguez-Valentin, Mev .
ANTICANCER RESEARCH, 2016, 36 (09) :4399-4405
[8]   Predicting the functional consequences of non-synonymous single nucleotide polymorphisms in IL8 gene [J].
Dakal, Tikam Chand ;
Kala, Deepak ;
Dhiman, Gourav ;
Yadav, Vinod ;
Krokhotin, Andrey ;
Dokholyan, Nikolay V. .
SCIENTIFIC REPORTS, 2017, 7
[9]   Structural modeling of human organic cation transporters [J].
Dakal, Tikam Chand ;
Kurnar, Rajender ;
Ramotar, Dindial .
COMPUTATIONAL BIOLOGY AND CHEMISTRY, 2017, 68 :153-163
[10]   Identification of Novel Variants in Colorectal Cancer Families by High-Throughput Exome Sequencing [J].
DeRycke, Melissa S. ;
Gunawardena, Shanaka R. ;
Middha, Sumit ;
Asmann, Yan W. ;
Schaid, Daniel J. ;
McDonnell, Shannon K. ;
Riska, Shaun M. ;
Eckloff, Bruce W. ;
Cunningham, Julie M. ;
Fridley, Brooke L. ;
Serie, Daniel J. ;
Bamlet, William R. ;
Cicek, Mine S. ;
Jenkins, Mark A. ;
Duggan, David J. ;
Buchanan, Daniel ;
Clendenning, Mark ;
Haile, Robert W. ;
Woods, Michael O. ;
Gallinger, Steven N. ;
Casey, Graham ;
Potter, John D. ;
Newcomb, Polly A. ;
Le Marchand, Loic ;
Lindor, Noralane M. ;
Thibodeau, Stephen N. ;
Goode, Ellen L. .
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 2013, 22 (07) :1239-1251