Non-del(5q) myelodysplastic syndromes–associated loci detected by SNP-array genome-wide association meta-analysis

Kathy L. McGraw; Chia Ho Cheng; Y. Ann Chen; Hsin An Hou; Björn Nilsson; Giulio Genovese; Thomas Cluzeau; Andrea Pellagatti; Bartlomiej P. Przychodzen; Mar Mallo; Leonor Arenillas; Azim Mohamedali; Lionel Adès; David A. Sallman; Eric Padron; Lubomir Sokol; Chimene Moreilhon; Sophie Raynaud; Hwei Fang Tien; Jacqueline Boultwood; Benjamin L. Ebert; Francesc Sole; Pierre Fenaux; Ghulam J. Mufti; Jaroslaw P. Maciejewski; Peter A. Kanetsky; Alan F. List

doi:10.1182/bloodadvances.2019000922

Non-del(5q) myelodysplastic syndromes–associated loci detected by SNP-array genome-wide association meta-analysis

Kathy L. McGraw^*, Chia Ho Cheng, Y. Ann Chen, Hsin An Hou, Björn Nilsson, Giulio Genovese, Thomas Cluzeau, Andrea Pellagatti, Bartlomiej P. Przychodzen, Mar Mallo, Leonor Arenillas, Azim Mohamedali, Lionel Adès, David A. Sallman, Eric Padron, Lubomir Sokol, Chimene Moreilhon, Sophie Raynaud, Hwei Fang Tien, Jacqueline BoultwoodBenjamin L. Ebert, Francesc Sole, Pierre Fenaux, Ghulam J. Mufti, Jaroslaw P. Maciejewski, Peter A. Kanetsky, Alan F. List

^*Corresponding author for this work

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.

Original language	English
Pages (from-to)	3579-3589
Number of pages	11
Journal	Blood Advances
Volume	3
Issue number	22
DOIs	https://doi.org/10.1182/bloodadvances.2019000922
Publication status	Published - 1 Jan 2019

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McGraw, K. L., Cheng, C. H., Chen, Y. A., Hou, H. A., Nilsson, B., Genovese, G., Cluzeau, T., Pellagatti, A., Przychodzen, B. P., Mallo, M., Arenillas, L., Mohamedali, A., Adès, L., Sallman, D. A., Padron, E., Sokol, L., Moreilhon, C., Raynaud, S., Tien, H. F., ... List, A. F. (2019). Non-del(5q) myelodysplastic syndromes–associated loci detected by SNP-array genome-wide association meta-analysis. Blood Advances, 3(22), 3579-3589. https://doi.org/10.1182/bloodadvances.2019000922

@article{1b904dbbb1b94893b325dbe44e257d4e,

title = "Non-del(5q) myelodysplastic syndromes–associated loci detected by SNP-array genome-wide association meta-analysis",

abstract = "Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.",

author = "McGraw, {Kathy L.} and Cheng, {Chia Ho} and Chen, {Y. Ann} and Hou, {Hsin An} and Bj{\"o}rn Nilsson and Giulio Genovese and Thomas Cluzeau and Andrea Pellagatti and Przychodzen, {Bartlomiej P.} and Mar Mallo and Leonor Arenillas and Azim Mohamedali and Lionel Ad{\`e}s and Sallman, {David A.} and Eric Padron and Lubomir Sokol and Chimene Moreilhon and Sophie Raynaud and Tien, {Hwei Fang} and Jacqueline Boultwood and Ebert, {Benjamin L.} and Francesc Sole and Pierre Fenaux and Mufti, {Ghulam J.} and Maciejewski, {Jaroslaw P.} and Kanetsky, {Peter A.} and List, {Alan F.}",

year = "2019",

month = jan,

day = "1",

doi = "10.1182/bloodadvances.2019000922",

language = "English",

volume = "3",

pages = "3579--3589",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

number = "22",

}

McGraw, KL, Cheng, CH, Chen, YA, Hou, HA, Nilsson, B, Genovese, G, Cluzeau, T, Pellagatti, A, Przychodzen, BP, Mallo, M, Arenillas, L, Mohamedali, A, Adès, L, Sallman, DA, Padron, E, Sokol, L, Moreilhon, C, Raynaud, S, Tien, HF, Boultwood, J, Ebert, BL, Sole, F, Fenaux, P, Mufti, GJ, Maciejewski, JP, Kanetsky, PA & List, AF 2019, 'Non-del(5q) myelodysplastic syndromes–associated loci detected by SNP-array genome-wide association meta-analysis', Blood Advances, vol. 3, no. 22, pp. 3579-3589. https://doi.org/10.1182/bloodadvances.2019000922

TY - JOUR

T1 - Non-del(5q) myelodysplastic syndromes–associated loci detected by SNP-array genome-wide association meta-analysis

AU - McGraw, Kathy L.

AU - Cheng, Chia Ho

AU - Chen, Y. Ann

AU - Hou, Hsin An

AU - Nilsson, Björn

AU - Genovese, Giulio

AU - Cluzeau, Thomas

AU - Pellagatti, Andrea

AU - Przychodzen, Bartlomiej P.

AU - Mallo, Mar

AU - Arenillas, Leonor

AU - Mohamedali, Azim

AU - Adès, Lionel

AU - Sallman, David A.

AU - Padron, Eric

AU - Sokol, Lubomir

AU - Moreilhon, Chimene

AU - Raynaud, Sophie

AU - Tien, Hwei Fang

AU - Boultwood, Jacqueline

AU - Ebert, Benjamin L.

AU - Sole, Francesc

AU - Fenaux, Pierre

AU - Mufti, Ghulam J.

AU - Maciejewski, Jaroslaw P.

AU - Kanetsky, Peter A.

AU - List, Alan F.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.

AB - Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.

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U2 - 10.1182/bloodadvances.2019000922

DO - 10.1182/bloodadvances.2019000922

M3 - Article

C2 - 31738830

AN - SCOPUS:85076358094

SN - 2473-9529

VL - 3

SP - 3579

EP - 3589

JO - Blood Advances

JF - Blood Advances

IS - 22

ER -

Non-del(5q) myelodysplastic syndromes–associated loci detected by SNP-array genome-wide association meta-analysis

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