Applying a Weight-of-Evidence Approach to Evaluate Relevance of Molecular Landscapes in the Exposure-Disease Paradigm

Table 1

(a) MDS molecular landscape. (b) Benzene molecular landscape.

(a)

Gene	Function	Reference
Somatic mutations
CTCF	Zinc finger protein	[30]
FANCL	DNA cross-link repair in Fanconi anemia	[30]
BRCC3	Cohesin	[30]
MPL	Cohesin	[30]
RAD21	Cohesin complex-sister chromatid separation	[30, 31]
SMC1A	Cohesin complex-sister chromatid separation	[30, 31]
SMC3	Cohesin complex-sister chromatid separation	[30, 31]
STAG2	Cohesin complex-sister chromatid separation	[30, 31]
TET2	DNA hydroxymethylation	[30, 31]
IDH1/2	DNA methylation	[30]
DNMT3A	DNA methylation	[30, 31]
SETBP1	Gain of function	[31]
ASXL1	Histone modification	[30, 31]
EZH2	Histone modification	[30, 31]
LAMB4	Loss of expression in cancer with microsatellite instability	[30]
NF1	Ras pathway	[30]
RIT1	Ras pathway activation	[31]
JAK2	Signal transduction	[30, 31]
N-/K-RAS	Signal transduction	[30, 31]
LUC7L2	Spicing	[30]
SF3B1	Spliceosome	[30, 31]
ZRSR2	Spliceosome	[30, 31]
SRSF2	Spliceosome	[30, 31]
U2AF1	Spliceosome	[30, 31]
ETV6	Transcription factor	[30, 31]
IRF1	Transcription factor	[30]
RUNX1	Transcription factor	[30, 31]
CEBPA	Transcription factor myeloid differentiation	[31]
WT1	Transcription factor myeloid differentiation	[31]
TP53	Transcription factor, tumor suppressor	[30, 31]
BCOR/L1	Transcription repressor	[30, 31]
PHF6	Transcription factor	[30]
ATM	Ataxia telangiectasia mutated gene	[30]
Polymorphisms
ATM	Recognizing and repairing DNA lesions	[42]
JAK3	Variants unrelated to MDS	[42]
KDR	Mediates VEGF’s responses to angiogenesis	[42]
STK11	Variants unrelated to MDS	[42]
VEGF/VEGFR	Controversial findings with cancer risk	[42]
RAD51	DNA repair	[48]
XRCC5	DNA repair	[48]
XRCC6	DNA repair	[48]
TGF	MDS disease progression	[49]
TNF-	Increase anemia and thrombocytopenia in MDS	[38]
GSTP1	Increased risk in MDS	[35]
GSTT1	Increased risk MDS	[50]
RAD51	Increased risk MDS	[41]
MDR-1	Multidrug resistant, protective against MDS	[36]
TNF-	No effect in MDS	[49]
NQO1	No effect in MDS	[35]
TP53	Polymorphism not involved in MDS	[51]
BCL2L10	Reduced risk MDS	[42]

(b)

Gene	Function	Reference
Somatic mutations caused by benzene
DNMT1	Decreased mRNA expression	[45]
DNMT3A	Decreased mRNA expression	[45]
DNMT3B	Decreased mRNA expression	[45]
MBD2	Decreased mRNA expression	[45]
PARP1	Decreased mRNA expression	[45]
p15	Hypermethylation	[52]
MAGE-1	Hypomethylation	[52]
Glycophorin A	Induction of gene duplication	[47]
RUNX1	Transcription factor	[43]
Polymorphism of benzene susceptibility
BLM	Modulation of DNA repair	[29, 39]
RAD51	Modulation of DNA repair	[29, 39]
TP53	Modulation of DNA repair	[29, 39]
WDR79	Modulation of DNA repair	[29, 39]
WNR	Modulation of DNA repair	[22]
XRCC1	Modulation of DNA repair	[37]
VCAM1	Altered adhesion	[53]
IL-12	Altered function polymorphism	[43]
MPO	Altered function polymorphism	[43]
NQO1	Altered function polymorphism	[52]
IL-10	Cytokine activity	[32]
IL-12A	Cytokine activity	[32]
IL-1a	Cytokine activity	[32]
IL-4	Cytokine activity	[32]
GSTM1	Detoxification of exogenous compounds	[54]
VEGF	Endothelial cytokine	[53]
TNF-	Inflammatory cytokine	[39]
APEX1	Male restricted DNA repair mechanism	[46]
p14	p53 dependent modulation	[55]
p21	p53 dependent modulation	[55]
MSH2	Repair of mismatched DNA	[56]
Biomarkers of benzene exposure in blood
Urinary sPMA	Increases in urine of exposed individuals	[27]
Hemoglobin adducts	4-month duration in blood	[25]
Albumin adducts	Duration in blood unclear	[26, 28]