Multiple Myeloma (MM) is a hematological neoplasm that represent about 1% of all hematological malignancies. Several evidences have suggested the presence of genetic factor able to confer susceptibility to MM. The study of the role of Single Nucleotide Polymorphisms (SNPs) in MM risk and in MM pharmacogenetics is still lacking of strong associations, although some loci have been shown to affect MM risk. In this context, we performed three different case-control studies on MM susceptibility selecting more than 75 SNPs in genes acting in different pathways relevant for cancer risk. In particular, the role of eight variants in Interleukin-1B (IL1B), Interleukin-2 (IL2), Interleukin-6 (IL6), Tumor Necrosis Factor alpha (TNF-α), Interleukin-1 Receptor 1 (IL1R1), Interleukin-2 receptor beta (IL2RB), Interleukin-6 receptor (IL6R) and TNF receptors superfamily 1 member B (TNFRS1B) genes have been investigated in a case-control study on 202 MM patients and 235 healthy controls. Interestingly, when stratifying the entire populations in two groups by age, genotype at the IL6 locus 597A>G (rs1800797) showed a significantly different distribution between cases and controls in the >60 years stratum. In particular, carriers of the A allele (A/G+A/A) showed a 45% lower risk to develop MM compared to the G/G individuals of the same age strata (OR: 0.55, C.I.: 0.31-0.95, p-value: 0.03). Thus, we can conclude that IL6 could play an age-dependent role in MM susceptibility. Response to treatments, Progression Free Survival (PFS) and Overall Survival (OS) was evaluated in a subset of 91 patients. We found that PFS of patients ≥60 years is influenced by genotype at the TNF-α locus -308G>A (rs1800629). Carriers of the A allele showed a worse PFS, with a 2.5-fold higher risk of progression respect to the patients with G/G genotype. Therefore, in the older group, a higher production of TNF-α, associated with the A allele at the -308G>A (rs1800629) locus, could potentiate the pro-apoptotic effect of TNF-α and result in a better PFS for A carriers. In a second study, we evaluated the impact of SNPs in ATP-Binding Cassette (ABC) superfamily members B1 (ABCB1), G2 (ABCG2), C2 (ABCC2), C1 (ABCC1) and C3 (ABCC3) genes on MM susceptibility in a case control study on 523 cases and 677 controls. Of the 57 SNPs genotyped, three in ABCB1 (rs2214102, rs2235074, rs10276499) and one in ABCG2 (rs2725248) showed a positive association at a conventional p<0.05 with MM risk. When correcting for multiple testing, none of the positive hits found reached the threshold p-value (p<0.001), even if the two ABCB1 SNPs rs2235074 and rs10276499 showed trends close to significance. With the aim to further investigate these associations, we replicated the 4 SNPs in an independent population of 588 MM cases and 1509 controls of German origin. We did not find any statistically significant association if considering the replication population alone. However, analyzing the two sets jointly, we found that ABCB1 SNP rs2235074 showed a statistically significant associations for the trend test with a decreased risk of MM (p=0.018). Therefore, we cannot exclude a role, albeit minor, of ABCB1 polymorphisms in MM risk. Finally, on the same population of 523 MM cases and 677 controls, a third study of variants in Nuclear Receptor 1, Type II (NR1I2 or PXR) and Nuclear Receptor 1, Type III (NR1I3 or CAR) genes have been conducted. Of the 17 SNPs successfully genotyped, three variants in CAR (rs3003596, rs11265571, rs4233368) showed a positive association at a conventional p-value of 0.05 with MM risk. In particular, carriers of the G allele for the rs3003596 showed a 42% increased risk to develop MM when compared with A/A individuals (OR: 1.42, C.I.: 1.09 – 1.85, p=0.009). Thus, we can conclude that CAR could play an important role in MM susceptibility, even if further investigation are needed. We can conclude that our studies covered several well studied genes in relation to different types of cancer, adding a significant gain of knowledge to genetics of MM.

Genetic susceptibility and pharmacogenetics of Multiple Myeloma

2011

Abstract

Multiple Myeloma (MM) is a hematological neoplasm that represent about 1% of all hematological malignancies. Several evidences have suggested the presence of genetic factor able to confer susceptibility to MM. The study of the role of Single Nucleotide Polymorphisms (SNPs) in MM risk and in MM pharmacogenetics is still lacking of strong associations, although some loci have been shown to affect MM risk. In this context, we performed three different case-control studies on MM susceptibility selecting more than 75 SNPs in genes acting in different pathways relevant for cancer risk. In particular, the role of eight variants in Interleukin-1B (IL1B), Interleukin-2 (IL2), Interleukin-6 (IL6), Tumor Necrosis Factor alpha (TNF-α), Interleukin-1 Receptor 1 (IL1R1), Interleukin-2 receptor beta (IL2RB), Interleukin-6 receptor (IL6R) and TNF receptors superfamily 1 member B (TNFRS1B) genes have been investigated in a case-control study on 202 MM patients and 235 healthy controls. Interestingly, when stratifying the entire populations in two groups by age, genotype at the IL6 locus 597A>G (rs1800797) showed a significantly different distribution between cases and controls in the >60 years stratum. In particular, carriers of the A allele (A/G+A/A) showed a 45% lower risk to develop MM compared to the G/G individuals of the same age strata (OR: 0.55, C.I.: 0.31-0.95, p-value: 0.03). Thus, we can conclude that IL6 could play an age-dependent role in MM susceptibility. Response to treatments, Progression Free Survival (PFS) and Overall Survival (OS) was evaluated in a subset of 91 patients. We found that PFS of patients ≥60 years is influenced by genotype at the TNF-α locus -308G>A (rs1800629). Carriers of the A allele showed a worse PFS, with a 2.5-fold higher risk of progression respect to the patients with G/G genotype. Therefore, in the older group, a higher production of TNF-α, associated with the A allele at the -308G>A (rs1800629) locus, could potentiate the pro-apoptotic effect of TNF-α and result in a better PFS for A carriers. In a second study, we evaluated the impact of SNPs in ATP-Binding Cassette (ABC) superfamily members B1 (ABCB1), G2 (ABCG2), C2 (ABCC2), C1 (ABCC1) and C3 (ABCC3) genes on MM susceptibility in a case control study on 523 cases and 677 controls. Of the 57 SNPs genotyped, three in ABCB1 (rs2214102, rs2235074, rs10276499) and one in ABCG2 (rs2725248) showed a positive association at a conventional p<0.05 with MM risk. When correcting for multiple testing, none of the positive hits found reached the threshold p-value (p<0.001), even if the two ABCB1 SNPs rs2235074 and rs10276499 showed trends close to significance. With the aim to further investigate these associations, we replicated the 4 SNPs in an independent population of 588 MM cases and 1509 controls of German origin. We did not find any statistically significant association if considering the replication population alone. However, analyzing the two sets jointly, we found that ABCB1 SNP rs2235074 showed a statistically significant associations for the trend test with a decreased risk of MM (p=0.018). Therefore, we cannot exclude a role, albeit minor, of ABCB1 polymorphisms in MM risk. Finally, on the same population of 523 MM cases and 677 controls, a third study of variants in Nuclear Receptor 1, Type II (NR1I2 or PXR) and Nuclear Receptor 1, Type III (NR1I3 or CAR) genes have been conducted. Of the 17 SNPs successfully genotyped, three variants in CAR (rs3003596, rs11265571, rs4233368) showed a positive association at a conventional p-value of 0.05 with MM risk. In particular, carriers of the G allele for the rs3003596 showed a 42% increased risk to develop MM when compared with A/A individuals (OR: 1.42, C.I.: 1.09 – 1.85, p=0.009). Thus, we can conclude that CAR could play an important role in MM susceptibility, even if further investigation are needed. We can conclude that our studies covered several well studied genes in relation to different types of cancer, adding a significant gain of knowledge to genetics of MM.
18-feb-2011
Italiano
Rossi, Anna Maria
Barale, Roberto
Pozzi, Gianni
Cavallo, Rossana
Università degli Studi di Pisa
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14242/149203
Il codice NBN di questa tesi è URN:NBN:IT:UNIPI-149203