Comprehensive germline genomic profiles of children, adolescents and young adults with solid tumors.
Adolescent
Case-Control Studies
Child
DNA Helicases
/ genetics
Female
Genetic Predisposition to Disease
/ genetics
Genomics
/ methods
Germ Cells
/ metabolism
Germ-Line Mutation
Humans
Male
Neoplasms
/ genetics
Smad7 Protein
/ genetics
Ubiquitin-Protein Ligases
/ genetics
Exome Sequencing
/ methods
Young Adult
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 05 2020
05 05 2020
Historique:
received:
18
10
2019
accepted:
08
04
2020
entrez:
7
5
2020
pubmed:
7
5
2020
medline:
4
8
2020
Statut:
epublish
Résumé
Compared to adult carcinomas, there is a paucity of targeted treatments for solid tumors in children, adolescents, and young adults (C-AYA). The impact of germline genomic signatures has implications for heritability, but its impact on targeted therapies has not been fully appreciated. Performing variant-prioritization analysis on germline DNA of 1,507 C-AYA patients with solid tumors, we show 12% of these patients carrying germline pathogenic and/or likely pathogenic variants (P/LP) in known cancer-predisposing genes (KCPG). An additional 61% have germline pathogenic variants in non-KCPG genes, including PRKN, SMARCAL1, SMAD7, which we refer to as candidate genes. Despite germline variants in a broad gene spectrum, pathway analysis leads to top networks centering around p53. Our drug-target analysis shows 1/3 of patients with germline P/LP variants have at least one druggable alteration, while more than half of them are from our candidate gene group, which would otherwise go unidentified in routine clinical care.
Identifiants
pubmed: 32371905
doi: 10.1038/s41467-020-16067-1
pii: 10.1038/s41467-020-16067-1
pmc: PMC7200683
doi:
Substances chimiques
SMAD7 protein, human
0
Smad7 Protein
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
parkin protein
EC 2.3.2.27
SMARCAL1 protein, human
EC 2.7.7.-
DNA Helicases
EC 3.6.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2206Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM088088
Pays : United States
Références
Grobner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018).
pubmed: 29489754
doi: 10.1038/nature25480
pmcid: 29489754
Zhang, J. et al. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373, 2336–2346 (2015).
pubmed: 26580448
pmcid: 4734119
doi: 10.1056/NEJMoa1508054
Parsons, D. W. et al. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol. 2, 616–624 (2016).
Mody, R. J. et al. Integrative clinical sequencing in the management of refractory or relapsed cancer in youth. JAMA 314, 913–925 (2015).
pubmed: 26325560
pmcid: 4758114
doi: 10.1001/jama.2015.10080
McGee, R. B. & Nichols, K. E. Introduction to cancer genetic susceptibility syndromes. Hematol. Am. Soc. Hematol. Educ. Program 2016, 293–301 (2016).
doi: 10.1182/asheducation-2016.1.293
Rahman, N. Realizing the promise of cancer predisposition genes. Nature 505, 302–308 (2014).
pubmed: 24429628
pmcid: 4975511
doi: 10.1038/nature12981
Knapke, S., Zelley, K., Nichols, K. E., Kohlmann, W. & Schiffman, J. D. Identification, management, and evaluation of children with cancer-predisposition syndromes. Am. Soc. Clin. Oncol. Educ. Book 576–584 (2012).
Wang, Z. et al. Genetic risk for subsequent neoplasms among long-term survivors of childhood cancer. J. Clin. Oncol. 36, 2078–2087 (2018).
pubmed: 29847298
pmcid: 6036620
doi: 10.1200/JCO.2018.77.8589
Thavaneswaran, S. et al. Therapeutic implications of germline genetic findings in cancer. Nat. Rev. Clin. Oncol. 16, 386–396 (2019).
pubmed: 30783251
doi: 10.1038/s41571-019-0179-3
pmcid: 30783251
Cheng, F. et al. Network-based approach to prediction and population-based validation of in silico drug repurposing. Nat. Commun. 9, 2691 (2018).
pubmed: 30002366
pmcid: 6043492
doi: 10.1038/s41467-018-05116-5
Cheng, F., Kovacs, I. A. & Barabasi, A. L. Publisher Correction: Network-based prediction of drug combinations. Nat. Commun. 10, 1806 (2019).
pubmed: 30988295
pmcid: 6465348
doi: 10.1038/s41467-019-09692-y
Chen, K. et al. Clinical actionability enhanced through deep targeted sequencing of solid tumors. Clin. Chem. 61, 544–553 (2015).
pubmed: 25626406
pmcid: 4511273
doi: 10.1373/clinchem.2014.231100
Homeida, L., Wiley, R. T. & Fatahzadeh, M. Oral squamous cell carcinoma in a patient with keratitis-ichthyosis-deafness syndrome: a rare case. Oral. Surg. Oral. Med Oral. Pathol. Oral. Radiol. 119, e226–e232 (2015).
pubmed: 25758847
doi: 10.1016/j.oooo.2015.01.005
pmcid: 25758847
Shi, J. H. & Hao, Y. J. DDX10 overexpression predicts worse prognosis in osteosarcoma and its deletion prohibits cell activities modulated by MAPK pathway. Biochem. Biophys. Res. Commun. 510, 525–529 (2019).
pubmed: 30738579
doi: 10.1016/j.bbrc.2019.01.114
pmcid: 30738579
Wang, Z. et al. Association of germline BRCA2 mutations with the risk of pediatric or adolescent non-hodgkin lymphoma. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2019.2203 (2019).
Luo, P. et al. Dysregulation of TMPRSS3 and TNFRSF11B correlates with tumorigenesis and poor prognosis in patients with breast cancer. Oncol. Rep. 37, 2057–2062 (2017).
pubmed: 28260080
doi: 10.3892/or.2017.5449
pmcid: 28260080
Sawasaki, T., Shigemasa, K., Gu, L., Beard, J. B. & O’Brien, T. J. The transmembrane protease serine (TMPRSS3/TADG-12) D variant: a potential candidate for diagnosis and therapeutic intervention in ovarian cancer. Tumour Biol. 25, 141–148 (2004).
pubmed: 15361711
doi: 10.1159/000079146
pmcid: 15361711
Wallrapp, C. et al. A novel transmembrane serine protease (TMPRSS3) overexpressed in pancreatic cancer. Cancer Res. 60, 2602–2606 (2000).
pubmed: 10825129
pmcid: 10825129
Li, S. L. et al. Knockdown of TMPRSS3 inhibits gastric cancer cell proliferation, invasion and EMT via regulation of the ERK1/2 and PI3K/Akt pathways. Biomed. Pharmacother. 107, 841–848 (2018).
pubmed: 30142546
doi: 10.1016/j.biopha.2018.08.023
pmcid: 30142546
Cesari, R. et al. Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc. Natl. Acad. Sci. USA 100, 5956–5961 (2003).
pubmed: 12719539
doi: 10.1073/pnas.0931262100
pmcid: 12719539
Denison, S. R., Callahan, G., Becker, N. A., Phillips, L. A. & Smith, D. I. Characterization of FRA6E and its potential role in autosomal recessive juvenile parkinsonism and ovarian cancer. Genes Chromosomes Cancer 38, 40–52 (2003).
pubmed: 12874785
doi: 10.1002/gcc.10236
pmcid: 12874785
Wahabi, K., Perwez, A. & Rizvi, M. A. Parkin in Parkinson’s disease and cancer: a double-edged sword. Mol. Neurobiol. 55, 6788–6800 (2018).
pubmed: 29349575
doi: 10.1007/s12035-018-0879-1
pmcid: 29349575
Picchio, M. C. et al. Alterations of the tumor suppressor gene Parkin in non-small cell lung cancer. Clin. Cancer Res. 10, 2720–2724 (2004).
pubmed: 15102676
doi: 10.1158/1078-0432.CCR-03-0086
pmcid: 15102676
Gupta, A., Anjomani-Virmouni, S., Koundouros, N. & Poulogiannis, G. PARK2 loss promotes cancer progression via redox-mediated inactivation of PTEN. Mol. Cell Oncol. 4, e1329692 (2017).
pubmed: 29209642
pmcid: 5706935
doi: 10.1080/23723556.2017.1329692
Tang, Z. et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45, W98–W102 (2017).
pubmed: 28407145
pmcid: 5570223
doi: 10.1093/nar/gkx247
Mandalenakis, Z. et al. Risk of cancer among children and young adults with congenital heart disease compared with healthy controls. JAMA Netw. Open 2, e196762 (2019).
pubmed: 31276179
doi: 10.1001/jamanetworkopen.2019.6762
pmcid: 31276179
Gutmann, D. H. et al. Neurofibromatosis type 1. Nat. Rev. Dis. Primers 3, 17004 (2017).
pubmed: 28230061
doi: 10.1038/nrdp.2017.4
pmcid: 28230061
Neiman, H. L., Mena, E., Holt, J. F., Stern, A. M. & Perry, B. L. Neurofibromatosis and congenital heart disease. Am. J. Roentgenol. Radium Ther. Nucl. Med. 122, 146–149 (1974).
pubmed: 4214176
doi: 10.2214/ajr.122.1.146
pmcid: 4214176
Burger, N. B., Bekker, M. N., de Groot, C. J., Christoffels, V. M. & Haak, M. C. Why increased nuchal translucency is associated with congenital heart disease: a systematic review on genetic mechanisms. Prenat. Diagn. 35, 517–528 (2015).
pubmed: 25728762
doi: 10.1002/pd.4586
pmcid: 25728762
Lakkis, M. M. & Tennekoon, G. I. Neurofibromatosis type 1: II. Answers from animal models. J. Neurosci. Res. 65, 191–194 (2001).
pubmed: 11494353
doi: 10.1002/jnr.1142
pmcid: 11494353
Aster, J. C., Pear, W. S. & Blacklow, S. C. The varied roles of notch in cancer. Annu. Rev. Pathol. 12, 245–275 (2017).
pubmed: 27959635
doi: 10.1146/annurev-pathol-052016-100127
pmcid: 27959635
Zaidi, S. & Brueckner, M. Genetics and genomics of congenital heart disease. Circ. Res. 120, 923–940 (2017).
pubmed: 28302740
pmcid: 5557504
doi: 10.1161/CIRCRESAHA.116.309140
Lin, C. J., Lin, C. Y., Chen, C. H., Zhou, B. & Chang, C. P. Partitioning the heart: mechanisms of cardiac septation and valve development. Development 139, 3277–3299 (2012).
pubmed: 22912411
pmcid: 3424040
doi: 10.1242/dev.063495
Huang, K. L. et al. Pathogenic germline variants in 10,389 adult cancers. Cell 173, 355–370 e314 (2018).
pubmed: 29625052
pmcid: 5949147
doi: 10.1016/j.cell.2018.03.039
Banks, P., Xu, W., Murphy, D., James, P. & Sandhu, S. Relevance of DNA damage repair in the management of prostate cancer. Curr. Probl. Cancer 41, 287–301 (2017).
pubmed: 28712484
doi: 10.1016/j.currproblcancer.2017.06.001
Faraoni, I. & Graziani, G. Role of BRCA mutations in cancer treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. Cancers 10, E487 (2018).
pubmed: 30518089
doi: 10.3390/cancers10120487
Minchom, A., Aversa, C. & Lopez, J. Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies. Ther. Adv. Med Oncol. 10, 1758835918786658 (2018).
pubmed: 30023007
pmcid: 6047242
doi: 10.1177/1758835918786658
Downing, J. R. et al. The Pediatric Cancer Genome Project. Nat. Genet 44, 619–622 (2012).
pubmed: 22641210
pmcid: 3619412
doi: 10.1038/ng.2287
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
pubmed: 2705234
pmcid: 2705234
doi: 10.1093/bioinformatics/btp324
McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).
pubmed: 20644199
pmcid: 2928508
doi: 10.1101/gr.107524.110
Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).
pubmed: 2723002
pmcid: 2723002
Yeo, G. & Burge, C. B. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J. Comput. Biol. 11, 377–394 (2004).
pubmed: 15285897
doi: 10.1089/1066527041410418
pmcid: 15285897
Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J. & Kircher, M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 47, D886–D894 (2019).
pubmed: 30371827
doi: 10.1093/nar/gky1016
pmcid: 30371827
Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).
pubmed: 21221095
pmcid: 3346182
doi: 10.1038/nbt.1754
Ripperger, T. et al. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am. J. Med. Genet. A 173, 1017–1037 (2017).
pubmed: 28168833
doi: 10.1002/ajmg.a.38142
pmcid: 28168833
Rahman, N. Mainstreaming genetic testing of cancer predisposition genes. Clin. Med. (Lond.) 14, 436–439 (2014).
doi: 10.7861/clinmedicine.14-4-436
Fromer, M. & Purcell, S. M. Using XHMM software to detect copy number variation in whole-exome sequencing data. Curr. Protoc. Hum. Genet. 81, 7 23 21–21 (2014).
Mayakonda, A., Lin, D. C., Assenov, Y., Plass, C. & Koeffler, H. P. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 28, 1747–1756 (2018).
pubmed: 30341162
pmcid: 6211645
doi: 10.1101/gr.239244.118
Kramer, A., Green, J., Pollard, J. Jr & Tugendreich, S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics 30, 523–530 (2014).
doi: 10.1093/bioinformatics/btt703
Law, V. et al. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res. 42, D1091–D1097 (2014).
pubmed: 24203711
doi: 10.1093/nar/gkt1068
pmcid: 24203711
Li, Y. H. et al. Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics. Nucleic Acids Res. 46, D1121–D1127 (2018).
pubmed: 29140520
doi: 10.1093/nar/gkx1076
pmcid: 29140520
Hernandez-Boussard, T. et al. The pharmacogenetics and pharmacogenomics knowledge base: accentuating the knowledge. Nucleic Acids Res. 36, D913–D918 (2008).
pubmed: 18032438
doi: 10.1093/nar/gkm1009
pmcid: 18032438
Ursu, O. et al. DrugCentral: online drug compendium. Nucleic Acids Res. 45, D932–D939 (2017).
pubmed: 27789690
doi: 10.1093/nar/gkw993
pmcid: 27789690
Gaulton, A. et al. ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Res. 40, D1100–D1107 (2012).
pubmed: 21948594
doi: 10.1093/nar/gkr777
pmcid: 21948594
Liu, T., Lin, Y., Wen, X., Jorissen, R. N. & Gilson, M. K. BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 35, D198–D201 (2007).
pubmed: 17145705
doi: 10.1093/nar/gkl999
pmcid: 17145705
Pawson, A. J. et al. The IUPHAR/BPS guide to pharmacology: an expert-driven knowledgebase of drug targets and their ligands. Nucleic Acids Res. 42, D1098–D1106 (2014).
pubmed: 24234439
doi: 10.1093/nar/gkt1143
pmcid: 24234439
Apweiler, R. et al. UniProt: the Universal Protein knowledgebase. Nucleic Acids Res. 32, D115–D119 (2004).
pubmed: 14681372
pmcid: 308865
doi: 10.1093/nar/gkh131
Stolfi, C., Marafini, I., De Simone, V., Pallone, F. & Monteleone, G. The dual role of Smad7 in the control of cancer growth and metastasis. Int J. Mol. Sci. 14, 23774–23790 (2013).
pubmed: 24317436
pmcid: 3876077
doi: 10.3390/ijms141223774
Gudbjartsson, D. F. et al. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat. Genet. 40, 886–891 (2008).
pubmed: 18488027
doi: 10.1038/ng.161
pmcid: 18488027
Perry, J. K., Liu, D. X., Wu, Z. S., Zhu, T. & Lobie, P. E. Growth hormone and cancer: an update on progress. Curr. Opin. Endocrinol. Diabetes Obes. 20, 307–313 (2013).
pubmed: 23807602
doi: 10.1097/MED.0b013e328363183a
pmcid: 23807602
Davidsson, J. et al. SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies. Leukemia 32, 1106–1115 (2018).
pubmed: 29535429
pmcid: 5940635
doi: 10.1038/s41375-018-0074-4
Schwartz, J. R. et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat. Commun. 8, 1557 (2017).
pubmed: 29146900
pmcid: 5691144
doi: 10.1038/s41467-017-01590-5
Poole, L. A. & Cortez, D. SMARCAL1 and telomeres: replicating the troublesome ends. Nucleus 7, 270–274 (2016).
pubmed: 27355316
pmcid: 4991236
doi: 10.1080/19491034.2016.1179413
Taglialatela, A. et al. Restoration of replication fork stability in BRCA1- and BRCA2-deficient cells by inactivation of SNF2-family fork remodelers. Mol. Cell 68, 414–430 e418 (2017).
pubmed: 29053959
pmcid: 5720682
doi: 10.1016/j.molcel.2017.09.036
Kiehl, S. et al. ABCB4 is frequently epigenetically silenced in human cancers and inhibits tumor growth. Sci. Rep. 4, 6899 (2014).
pubmed: 25367630
pmcid: 4219162
doi: 10.1038/srep06899
Tougeron, D., Fotsing, G., Barbu, V. & Beauchant, M. ABCB4/MDR3 gene mutations and cholangiocarcinomas. J. Hepatol. 57, 467–468 (2012).
pubmed: 22387667
doi: 10.1016/j.jhep.2012.01.025
pmcid: 22387667
Alsiary, R. et al. Expression analysis of the MCPH1/BRIT1 and BRCA1 tumor suppressor genes and telomerase splice variants in epithelial ovarian cancer. Gene 672, 34–44 (2018).
pubmed: 29860064
doi: 10.1016/j.gene.2018.05.113
pmcid: 29860064
Trimborn, M. et al. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am. J. Hum. Genet. 75, 261–266 (2004).
pubmed: 15199523
pmcid: 1216060
doi: 10.1086/422855
Cummings, C. T., Deryckere, D., Earp, H. S. & Graham, D. K. Molecular pathways: MERTK signaling in cancer. Clin. Cancer Res. 19, 5275–5280 (2013).
pubmed: 23833304
doi: 10.1158/1078-0432.CCR-12-1451
pmcid: 23833304