Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility

Abstract

Therapy-related acute myeloid leukemia (t-AML) is a rare but fatal complication of cytotoxic therapy. Whereas sporadic cancer results from interactions between complex exposures and lowpenetrance alleles, t-AML results from an acute exposure to a limited number of potent genotoxins. Consequently, we hypothesized that the effect sizes of variants associated with t-AML would be greater than in sporadic cancer, and, therefore, that these variants could be detected even in a modest-sized cohort. To test this, we undertook an association study in 80 cases and 150 controls using Affymetrix Mapping 10K arrays. Even at nominal significance thresholds, we found a significant excess of associations over chance; for example, although 6 associations were expected at P less than .001, we found 15 (P enrich ‫؍‬ .002). To replicate our findings, we genotyped the 10 most significantly associated single nucleotide polymorphisms (SNPs) in an independent t-AML cohort (n ‫؍‬ 70) and obtained evidence of association with t-AML for 3 SNPs in the subset of patients with loss of chromosomes 5 or 7 or both, acquired abnormalities associated with prior exposure to alkylator chemotherapy. Thus, we conclude that the effect of genetic factors contributing to cancer risk is potentiated and more readily discernable in t-AML compared with sporadic cancer.

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

“…156 The investigators identified three polymorphisms (rs1394384, intronic to ACCN1 ; rs1381392, intergenic; and rs1199098, in linkage disequilibrium with IPMK ) to be associated with tMDS/AML with chromosome 5 and/or 7 abnormalities. Although the investigators were able to confirm findings in an independent replication cohort, the utilization of a non-cancer healthy control group raises concerns about the case-control differences being generated by the genetics of the primary cancer versus tMDS/AML.…”

Subsequent Malignant Neoplasms After Hematopoietic Cell Transplantation

“…Knight et al utilized a case-control study design to conduct a GWAS in patients who had developed therapy-related leukemia (cases) and healthy controls (83) abnormalities. rs1394384 is intronic to ACCN1, a gene encoding an amiloride-sensitive cation channel that is a member of the degenerin/ epithelial sodium channel; rs1199098 is in LD with IPMK, which encodes a multikinase that positively regulates the prosurvival AKT kinase and may modulate Wnt/beta-catenin signaling; rs1381392 is not near any known genes, miRNAs, or regulatory elements, although it lies in a region recurrently deleted in lung cancer.…”

Neurexophilin 1 suppresses the proliferation of hematopoietic progenitor cells

“…The differing responses of these populations to recombinant NXPH1 may also explain the correlation between high levels of NXPH expression and aggressive cancers. [20][21][22][23] If cancer stem cells are protected from NXPH in a manner similar to HSCs, secreted NXPH would inhibit hematopoietic cells involved in the immune response while leaving the cancer cells relatively unaffected.…”

“…11,17,18 Furthermore, microarray data has implicated high NXPH2 expression in macrophages during immune system exhaustion 19 and many members of the family as a prognostic factor in cancers with a negative prognosis. [20][21][22][23] Given its inhibitory role in a neuronal context as well as its presence in immunosuppressive conditions, we hypothesized that NXPH plays an inhibitory role in hematopoiesis.…”