Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic ...cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two‐sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom) = 1.78, 95% confidence interval (CI) = 1.26–2.52, p = 1.19 × 10−3 and ORdom = 1.74, 95% CI = 1.15–2.63, p = 8.57 × 10−3, respectively). Neither mutation was significantly associated with risk of developing early‐onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non‐genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high‐risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.
What's new?
Mutations in BRCA2 and CHEK2 are associated with susceptibility to many cancers, including pancreatic. The survival rate for pancreatic cancer remains abysmal, and early diagnostic markers are urgently needed. Here, the authors investigated the effect of a truncating BRCA2 variant (rs11571833) and a missense CHEK2 variant (rs17879961) on sporadic pancreatic ductal adenocarcinoma risk. Using data from the PANDoRA consortium, they tested a large number of samples, making this the first high‐power study to investigate these variants. Both variants, they found, increased the risk of non‐familial PDAC, and these variants may contribute to polygenic risk scores that help identify at‐risk individuals.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome‐wide significant loci shared across cancer and ...noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4‐rs34517439‐A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13‐1.32, P = 4.81 × 10−7). rs34517439‐A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA‐binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4‐rs34517439 as a potentially novel MM risk locus.
What's new?
Genetic variants can have multiple, seemingly unrelated, effects. Often, these so‐called “pleiotropic” variants play a role in cancer. Here, the authors set out to identify new pleiotropic variants involved in multiple myeloma (MM) risk. They analyzed 28,684 independent single nucleotide polymorphisms (SNPs) that had been identified in genome‐wide association studies as having an effect on a human trait. This analysis revealed an association between increased MM risk and a variant called DNAJB4‐rs34517439‐A. That variant has been associated with changes in expression of a DNA‐ and RNA‐binding protein that helps regulate cell cycle genes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Background:
Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., ...colorectum and melanoma), risk loci have also been associated with patient survival.
Methods:
We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed.
Results:
SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007 and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant.
Conclusions:
Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS.
Impact:
This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.
Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the ...massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs;
< 1 × 10
) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci,
,
,
,
,
, and
associated with MM risk (
= 4.47 × 10
-5.79 × 10
). Mechanistically, we found that the
SNP correlated with circulating concentrations of vitamin D3 (
= 4.0 × 10
), whereas the
SNP correlated with the number of transitional CD24
CD38
B cells (
= 4.8 × 10
) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (
= 3.6 × 10
). We also found that the
SNP correlated with numbers of CD19
B cells, CD19
CD3
B cells, CD5
IgD
cells, IgM
cells, IgD
IgM
cells, and CD4
CD8
PBMCs (
= 4.9 × 10
-8.6 × 10
) and circulating concentrations of interleukin (IL)-20 (
= 0.00082). Finally, we observed that the
SNP correlated with levels of CD4
EMCD45RO
CD27
cells (
= 9.3 × 10
). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3
, MCP-2
, and IL20-dependent pathways.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide ...polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype‐tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10−7 either in EBV‐transformed B‐lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression‐free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4‐rs1992292, TBRG4‐rs2287535 and ENTPD1‐rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta‐analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4‐rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04‐1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.
What's new?
Multiple myeloma (MM) remains incurable for most patients, although recent therapeutic advances have extended survival. MM is highly heterogeneous, but gene expression profiling can identify patients with poor outcomes and classify patients by how they will respond to drugs. Here, the authors evaluate certain genetic loci that influence the amount of RNA transcript produced, called expression quantitative trait loci (eQTLs). They found two eQTLs of genes associated with MM prognosis that were directly associated with adverse outcomes. These results provide a proof‐of‐concept that eQTLs can serve as a surrogate for gene expression profile as a predictor of survival, and they are much easier to measure.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Genome-wide association studies (GWAS) of multiple myeloma (MM) in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g. colorectum and ...melanoma), risk loci have also been associated with patient survival.
We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with MM overall survival (OS) in multiple populations of EA (IMMEnSE consortium, InterLymph consortium, CoMMpass and the German GWAS) for a total of 3748 MM cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed.
SNP associations were meta-analyzed. From the meta-analysis, two MM risk SNPs were associated with OS (p<0.05), specifically POT1-AS1-rs2170352 (HR=1.37, 95% C.I.=1.09-1.73, p=0.007) and TNFRSF13B-rs4273077 (HR=1.19, 95% C.I.=1.01-1.41, p=0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant.
Overall, our results did not support an association between the majority of MM risk SNPs and OS.
This is the first study to investigate the association between MM PRS and OS in MM.
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