Susceptibility Loci Associated with Specific and Shared Subtypes of Lymphoid Malignancies
The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (PLYM = 3.89×10−8, OR = 1.29) and rs948562 (PLYM = 5.85×10−7, OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, PNHL = 5.72×10−7) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (PFL = 2.69×10−12, OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.
Vyšlo v časopise:
Susceptibility Loci Associated with Specific and Shared Subtypes of Lymphoid Malignancies. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003220
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1003220
Souhrn
The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (PLYM = 3.89×10−8, OR = 1.29) and rs948562 (PLYM = 5.85×10−7, OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, PNHL = 5.72×10−7) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (PFL = 2.69×10−12, OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.
Zdroje
1. PileriSA, MilaniM, Fraternali-OrcioniG, SabattiniE (1998) From the REAL classification to the upcoming WHO scheme: A step toward universal categorization of lymphoma entities? Ann Oncol 9: 607–612.
2. ZintzarasE, VoulgarelisM, MoutsopoulosHM (2005) The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med 165: 2337–2344.
3. SiddiquiR, OnelK, FacioF, OffitK (2004) The genetics of familial lymphomas. Curr Oncol Rep 6: 380–387.
4. CondeL, HalperinE, AkersNK, BrownKM, SmedbyKE, et al. (2010) Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32. Nat Genet 42: 661–664.
5. SkibolaCF, BracciPM, HalperinE, CondeL, CraigDW, et al. (2009) Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma. Nat Genet 41: 873–875.
6. SmedbyKE, FooJN, SkibolaCF, DarabiH, CondeL, et al. (2011) GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma. PLoS Genet 7: e1001378 doi:10.1371/journal.pgen.1001378.
7. Enciso-MoraV, BroderickP, MaY, JarrettRF, HjalgrimH, et al. (2010) A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat Genet 42: 1126–1130.
8. MoutsianasL, Enciso-MoraV, MaYP, LeslieS, DiltheyA, et al. (2011) Multiple Hodgkin lymphoma-associated loci within the HLA region at chromosome 6p21.3. Blood 118: 670–674.
9. KumarV, MatsuoK, TakahashiA, HosonoN, TsunodaT, et al. (2011) Common variants on 14q32 and 13q12 are associated with DLBCL susceptibility. J Hum Genet 56: 436–439.
10. MukherjeeS, SimonJ, BayugaS, LudwigE, YooS, et al. (2011) Including additional controls from public databases improves the power of a genome-wide association study. Hum Hered 72: 21–34.
11. MenasheI, RosenbergPS, ChenBE (2008) PGA: power calculator for case-control genetic association analyses. BMC Genet 9: 36.
12. DimasAS, DeutschS, StrangerBE, MontgomerySB, BorelC, et al. (2009) Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325: 1246–1250.
13. YangTP, BeazleyC, MontgomerySB, DimasAS, Gutierrez-ArcelusM, et al. (2010) Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies. Bioinformatics 26: 2474–2476.
14. DoresGM, MetayerC, CurtisRE, LynchCF, ClarkeEA, et al. (2002) Second malignant neoplasms among long-term survivors of Hodgkin's disease: a population-based evaluation over 25 years. J Clin Oncol 20: 3484–3494.
15. TravisLB, CurtisRE, GlimeliusB, HolowatyE, Van LeeuwenFE, et al. (1993) Second cancers among long-term survivors of non-Hodgkin's lymphoma. J Natl Cancer Inst 85: 1932–1937.
16. MorinRD, Mendez-LagoM, MungallAJ, GoyaR, MungallKL, et al. (2011) Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476: 298–303.
17. PasqualucciL, TrifonovV, FabbriG, MaJ, RossiD, et al. (2011) Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 43: 830–837.
18. AndersonCA, BoucherG, LeesCW, FrankeA, D'AmatoM, et al. (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43: 246–252.
19. EleftherohorinouH, HoggartCJ, WrightVJ, LevinM, CoinLJ (2011) Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways. Hum Mol Genet 20: 3494–3506.
20. ShenX, KimW, FujiwaraY, SimonMD, LiuY, et al. (2009) Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells. Cell 139: 1303–1314.
21. BolisettyMT, DyG, TamW, BeemonKL (2009) Reticuloendotheliosis virus strain T induces miR-155, which targets JARID2 and promotes cell survival. J Virol 83: 12009–12017.
22. TakeuchiT, WatanabeY, Takano-ShimizuT, KondoS (2006) Roles of jumonji and jumonji family genes in chromatin regulation and development. Dev Dyn 235: 2449–2459.
23. CaoW, LeeSH, LuJ (2005) CD83 is preformed inside monocytes, macrophages and dendritic cells, but it is only stably expressed on activated dendritic cells. Biochem J 385: 85–93.
24. LiuS, ThomasSM, WoodsideDG, RoseDM, KiossesWB, et al. (1999) Binding of paxillin to alpha4 integrins modifies integrin-dependent biological responses. Nature 402: 676–681.
25. DaiHP, XueYQ, ZhouJW, LiAP, WuYF, et al. (2009) LPXN, a member of the paxillin superfamily, is fused to RUNX1 in an acute myeloid leukemia patient with a t(11;21)(q12;q22) translocation. Genes Chromosomes Cancer 48: 1027–1036.
26. ChewV, LamKP (2007) Leupaxin negatively regulates B cell receptor signaling. J Biol Chem 282: 27181–27191.
27. ZhangJ, DingL, HolmfeldtL, WuG, HeatleySL, et al. (2012) The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481: 157–163.
28. StadlerZK, ThomP, RobsonME, WeitzelJN, KauffND, et al. (2010) Genome-wide association studies of cancer. J Clin Oncol 28: 4255–4267.
29. KornJM, KuruvillaFG, McCarrollSA, WysokerA, NemeshJ, et al. (2008) Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet 40: 1253–1260.
30. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.
31. LaurieCC, DohenyKF, MirelDB, PughEW, BierutLJ, et al. (2010) Quality control and quality assurance in genotypic data for genome-wide association studies. Genet Epidemiol 34: 591–602.
32. PriceAL, PattersonNJ, PlengeRM, WeinblattME, ShadickNA, et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38: 904–909.
33. MitchellMK, GregersenPK, JohnsonS, ParsonsR, VlahovD (2004) The New York Cancer Project: rationale, organization, design, and baseline characteristics. J Urban Health 81: 301–310.
34. JurinkeC, van den BoomD, CantorCR, KosterH (2002) The use of MassARRAY technology for high throughput genotyping. Adv Biochem Eng Biotechnol 77: 57–74.
35. FreemanC, MarchiniJ (2007) GTOOL.
36. HowieBN, DonnellyP, MarchiniJ (2009) A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5: e1000529 doi:10.1371/journal.pgen.1000529.
37. de BakkerPI, FerreiraMA, JiaX, NealeBM, RaychaudhuriS, et al. (2008) Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum Mol Genet 17: R122–128.
38. PruimRJ, WelchRP, SannaS, TeslovichTM, ChinesPS, et al. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26: 2336–2337.
39. BarrettJC, FryB, MallerJ, DalyMJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263–265.
40. LiuJZ, McRaeAF, NyholtDR, MedlandSE, WrayNR, et al. (2010) A versatile gene-based test for genome-wide association studies. Am J Hum Genet 87: 139–145.
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Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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