Association between polymorphisms in RMI1, TOP3A, and BLM and risk of cancer, a case-control study.
BACKGROUND
Mutations altering BLM function are associated with highly elevated cancer susceptibility (Bloom syndrome). Thus, genetic variants of BLM and proteins that form complexes with BLM, such as TOP3A and RMI1, might affect cancer risk as well.


METHODS
In this study we have studied 26 tagged single nucleotide polymorphisms (tagSNPs) in RMI1, TOP3A, and BLM and their associations with cancer risk in acute myeloid leukemia/myelodysplatic syndromes (AML/MDS; N = 152), malignant melanoma (N = 170), and bladder cancer (N = 61). Two population-based control groups were used (N = 119 and N = 156).


RESULTS
Based on consistency in effect estimates for the three cancer forms and similar allelic frequencies of the variant alleles in the control groups, two SNPs in TOP3A (rs1563634 and rs12945597) and two SNPs in BLM (rs401549 and rs2532105) were selected for analysis in breast cancer cases (N = 200) and a control group recruited from spouses of cancer patients (N = 131). The rs12945597 in TOP3A and rs2532105 in BLM showed increased risk for breast cancer. We then combined all cases (N = 584) and controls (N = 406) respectively and found significantly increased risk for variant carriers of rs1563634 A/G (AG carriers OR = 1.7 [95%CI 1.1-2.6], AA carriers OR = 1.8 [1.2-2.8]), rs12945597 G/A (GA carriers OR = 1.5 [1.1-1.9], AA carriers OR = 1.6 [1.0-2.5]), and rs2532105 C/T (CT+TT carriers OR = 1.8 [1.4-2.5]). Gene-gene interaction analysis suggested an additive effect of carrying more than one risk allele. For the variants of TOP3A, the risk increment was more pronounced for older carriers.


CONCLUSIONS
These results further support a role of low-penetrance genes involved in BLM-associated homologous recombination for cancer risk.
Broberg
Karin
K
Department of Occupational and Environmental Medicine, Lund University, Lund, Sweden. karin.broberg@med.lu.se
Huynh
Elizabeth
E
Schläwicke Engström
Karin
K
Björk
Jonas
J
Albin
Maria
M
Ingvar
Christian
C
Olsson
Håkan
H
Höglund
Mattias
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D004264:DNA Topoisomerases, Type I / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053484:RecQ Helicases / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C501527:RMI1 protein, human; C097151:Bloom syndrome protein; D053484:RecQ Helicases; D004264:DNA Topoisomerases, Type I