Publications by authors named "Susan L Slager"

231 Publications

Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans.

Leukemia 2021 Jul 20. Epub 2021 Jul 20.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.

Monoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.
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http://dx.doi.org/10.1038/s41375-021-01344-9DOI Listing
July 2021

Occupational insecticide exposure and risk of non-Hodgkin lymphoma: A pooled case-control study from the InterLymph Consortium.

Int J Cancer 2021 Jul 16. Epub 2021 Jul 16.

Division of Population Health, Centre for Occupational and Environmental Health, University of Manchester, Manchester, UK.

Evidence for the human health effects of pesticides is needed to inform risk assessment. We studied the relationship between occupational insecticide use and risk of non-Hodgkin lymphoma (NHL) by pooling data from nine case-control studies participating in the InterLymph Consortium, including 7909 cases and 8644 controls from North America, the European Union and Australia. Insecticide use was coded using self-report or expert assessment, for insecticide groups (eg, organophosphates, pyrethroids) and active ingredients (eg, malathion, permethrin). Associations with insecticides were estimated using logistic regression to produce odds ratios (ORs) and 95% confidence intervals (CI) for all NHL and NHL subtypes, with adjustment for study site, demographic factors and use of other pesticides. Occupational insecticide use, overall, was not associated with risk of NHL. Use of organophosphate insecticides was associated with increased risk of all NHL and the subtype follicular lymphoma, and an association was found with diazinon, in particular (ever use: OR = 2.05, 95%CI: 1.24-3.37). The carbamate insecticide, carbaryl, was associated with risk of all NHL, and the strongest associations were found with T-cell NHL for ever-use (OR = 2.44, 95%CI: 1.13-5.28) and longer duration (>8 years vs never: OR = 2.90, 95%CI: 1.02-8.25). There was no association of NHL with other broad groups of insecticides, including organochlorines and pyrethroids, and some inverse associations were estimated in relation to historical DDT use. Our findings contribute to the totality of evidence available to help inform risk decisions by public health and regulatory agencies of importance given continued, widespread use of organophosphate and carbamate insecticides.
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http://dx.doi.org/10.1002/ijc.33740DOI Listing
July 2021

Distinct immune signatures in chronic lymphocytic leukemia and Richter syndrome.

Blood Cancer J 2021 May 10;11(5):86. Epub 2021 May 10.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Richter syndrome (RS) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. RS is known to be associated with a number of genetic alterations such as TP53 and NOTCH1 mutations. However, it is unclear what immune microenvironment changes are associated with RS. In this study, we analyzed expression of immune checkpoint molecules and infiltration of immune cells in nodal samples, and peripheral blood T-cell diversity in 33 CLL and 37 RS patients. Compared to CLL, RS nodal tissue had higher PD-L1 expression in histiocytes and dendritic cells (median 16.6% vs. 2.8%, P < 0.01) and PD1 expression in neoplastic B cells (median 26.0% vs. 6.2%, P < 0.01), and higher infiltration of FOXP3-positive T cells (median 1.7% vs. 0.4%, P < 0.01) and CD163-positive macrophages (median 23.4% vs. 9.1%, P < 0.01). In addition, peripheral blood T-cell receptor clonality was significantly lower in RS vs. CLL patients (median [25th-75th], 0.107 [0.070-0.209] vs. 0.233 [0.111-0.406], P = 0.046), suggesting that T cells in RS patients were significantly more diverse than in CLL patients. Collectively these data suggest that CLL and RS have distinct immune signatures. Better understanding of the immune microenvironment is essential to improve immunotherapy efficacy in CLL and RS.
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http://dx.doi.org/10.1038/s41408-021-00477-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110984PMC
May 2021

Anthracycline treatment, cardiovascular risk factors and the cumulative incidence of cardiovascular disease in a cohort of newly diagnosed lymphoma patients from the modern treatment era.

Am J Hematol 2021 Aug 27;96(8):979-988. Epub 2021 May 27.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

The development of cardiovascular disease (CVD) in long-term survivors of lymphoma is of increasing importance. Here, we characterize the cumulative incidence and risk factors for CVD in lymphoma patients diagnosed in the current treatment era. From 2002-2015, newly diagnosed lymphoma patients (>18 years) were enrollment into a prospective cohort study that captured incident CVD, consisting of congestive heart failure (CHF), acute coronary syndrome (ACS), valvular heart disease (VHD), and arrhythmia. The cumulative incidence of CVD was calculated with death modeled as a competing risk. We estimated the association of treatment with anthracyclines or radiotherapy and traditional CVD risk factors with incidence of CVD using hazard ratios (HR) and 95% confidence intervals (CI) estimated from Cox regression. After excluding prevalent CVD at lymphoma diagnosis, the study consisted of 3063 patients with a median age of 59 years (range 18-95). The cumulative incidence of CVD at 10-years was 10.7% (95% CI, 9.5%-12.1%). In multivariable analysis, increasing age (HR = 1.05 per year, p < 0.001), male sex (HR = 1.36, p = 0.02), current smoker (HR = 2.10, p < 0.001), BMI > 30 kg/m (HR = 1.45, p = 0.01), and any anthracycline treatment (HR = 1.57, p < 0.001) were all significantly associated with risk of CVD. Anthracyclines were associated with increased risk of CHF (HR = 2.71, p < 0.001) and arrhythmia (HR = 1.61, p < 0.01), but not VHD (HR = 0.84, p = 0.58) or ACS (HR = 1.32, p = 0.24) after adjustment for CVD risk factors. Even in the modern treatment era, CVD remains common in lymphoma survivors and preventive efforts are required that address both treatment and CVD risk factors.
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http://dx.doi.org/10.1002/ajh.26230DOI Listing
August 2021

The CLL International Prognostic Index predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL.

Blood 2021 07;138(2):149-159

Division of Hematology, Stanford University School of Medicine, Palo Alto, CA.

The utility of the chronic lymphocytic leukemia-international prognostic index (CLL-IPI) in predicting outcomes of individuals with Rai 0 stage CLL and monoclonal B-cell lymphocytosis (MBL) is unclear. We identified 969 individuals (415 MBL and 554 Rai 0 CLL; median age, 64 years; 65% men) seen at Mayo Clinic between 1 January 2001 and 1 October 2018, and ascertained time to first therapy (TTFT) and overall survival (OS). After a median follow up of 7 years, the risk of disease progression needing therapy was 2.9%/y for MBL (median, not reached) and 5%/y for Rai 0 CLL (median, 10.4 years). Among patients with low, intermediate, and high/very high-risk CLL-IPI risk groups, the estimated 5-year risk of TTFT was 13.5%, 30%, and 58%, respectively, P< .0001 (c-statistic = 0.69); and the estimated 5-year OS was 96.3%, 91.5%, and 76%, respectively, P< .0001 (c-statistic = 0.65). In a multivariable analysis of absolute B-cell count with individual factors of the CLL-IPI, the absolute B-cell count was associated with shorter TTFT (hazard ratio [HR] for each 10 × 109/L increase: 1.31; P< .0001) and shorter OS (HR: 1.1; P = .02). The OS of the entire cohort was similar to that of the age- and sex-matched general population of Minnesota (P = .17), although Rai 0 CLL patients with high and very high-risk CLL-IPI score had significantly shorter OS (P= .01 and P= .0001, respectively). The results of this study demonstrate the ability of CLL-IPI to predict time from diagnosis to first treatment (an end point not affected by therapy) in a large cohort of patients whose only manifestation of disease is a circulating clonal lymphocyte population.
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http://dx.doi.org/10.1182/blood.2020009813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288657PMC
July 2021

Epigenetic alteration contributes to the transcriptional reprogramming in T-cell prolymphocytic leukemia.

Sci Rep 2021 Apr 15;11(1):8318. Epub 2021 Apr 15.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

T cell prolymphocytic leukemia (T-PLL) is a rare disease with aggressive clinical course. Cytogenetic analysis, whole-exome and whole-genome sequencing have identified primary structural alterations in T-PLL, including inversion, translocation and copy number variation. Recurrent somatic mutations were also identified in genes encoding chromatin regulators and those in the JAK-STAT signaling pathway. Epigenetic alterations are the hallmark of many cancers. However, genome-wide epigenomic profiles have not been reported in T-PLL, limiting the mechanistic study of its carcinogenesis. We hypothesize epigenetic mechanisms also play a key role in T-PLL pathogenesis. To systematically test this hypothesis, we generated genome-wide maps of regulatory regions using H3K4me3 and H3K27ac ChIP-seq, as well as RNA-seq data in both T-PLL patients and healthy individuals. We found that genes down-regulated in T-PLL are mainly associated with defense response, immune system or adaptive immune response, while up-regulated genes are enriched in developmental process, as well as WNT signaling pathway with crucial roles in cell fate decision. In particular, our analysis revealed a global alteration of regulatory landscape in T-PLL, with differential peaks highly enriched for binding motifs of immune related transcription factors, supporting the epigenetic regulation of oncogenes and genes involved in DNA damage response and T-cell activation. Together, our work reveals a causal role of epigenetic dysregulation in T-PLL.
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http://dx.doi.org/10.1038/s41598-021-87890-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050249PMC
April 2021

Sequencing at lymphoid neoplasm susceptibility loci maps six myeloma risk genes.

Hum Mol Genet 2021 Jun;30(12):1142-1153

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Inherited genetic risk factors play a role in multiple myeloma (MM), yet considerable missing heritability exists. Rare risk variants at genome-wide association study (GWAS) loci are a new avenue to explore. Pleiotropy between lymphoid neoplasms (LNs) has been suggested in family history and genetic studies, but no studies have interrogated sequencing for pleiotropic genes or rare risk variants. Sequencing genetically enriched cases can help discover rarer variants. We analyzed exome sequencing in familial or early-onset MM cases to identify rare, functionally relevant variants near GWAS loci for a range of LNs. A total of 149 distinct and significant LN GWAS loci have been published. We identified six recurrent, rare, potentially deleterious variants within 5 kb of significant GWAS single nucleotide polymorphisms in 75 MM cases. Mutations were observed in BTNL2, EOMES, TNFRSF13B, IRF8, ACOXL and TSPAN32. All six genes replicated in an independent set of 255 early-onset MM or familial MM or precursor cases. Expansion of our analyses to the full length of these six genes resulted in a list of 39 rare and deleterious variants, seven of which segregated in MM families. Three genes also had significant rare variant burden in 733 sporadic MM cases compared with 935 control individuals: IRF8 (P = 1.0 × 10-6), EOMES (P = 6.0 × 10-6) and BTNL2 (P = 2.1 × 10-3). Together, our results implicate six genes in MM risk, provide support for genetic pleiotropy between LN subtypes and demonstrate the utility of sequencing genetically enriched cases to identify functionally relevant variants near GWAS loci.
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http://dx.doi.org/10.1093/hmg/ddab066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188404PMC
June 2021

Common genetic polymorphisms contribute to the association between chronic lymphocytic leukaemia and non-melanoma skin cancer.

Int J Epidemiol 2021 Mar 22. Epub 2021 Mar 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Background: Epidemiological studies have demonstrated a positive association between chronic lymphocytic leukaemia (CLL) and non-melanoma skin cancer (NMSC). We hypothesized that shared genetic risk factors between CLL and NMSC could contribute to the association observed between these diseases.

Methods: We examined the association between (i) established NMSC susceptibility loci and CLL risk in a meta-analysis including 3100 CLL cases and 7667 controls and (ii) established CLL loci and NMSC risk in a study of 4242 basal cell carcinoma (BCC) cases, 825 squamous cell carcinoma (SCC) cases and 12802 controls. Polygenic risk scores (PRS) for CLL, BCC and SCC were constructed using established loci. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Higher CLL-PRS was associated with increased BCC risk (OR4th-quartile-vs-1st-quartile = 1.13, 95% CI: 1.02-1.24, Ptrend = 0.009), even after removing the shared 6p25.3 locus. No association was observed with BCC-PRS and CLL risk (Ptrend = 0.68). These findings support a contributory role for CLL in BCC risk, but not for BCC in CLL risk. Increased CLL risk was observed with higher SCC-PRS (OR4th-quartile-vs-1st-quartile = 1.22, 95% CI: 1.08-1.38, Ptrend = 1.36 × 10-5), which was driven by shared genetic susceptibility at the 6p25.3 locus.

Conclusion: These findings highlight the role of pleiotropy regarding the pathogenesis of CLL and NMSC and shows that a single pleiotropic locus, 6p25.3, drives the observed association between genetic susceptibility to SCC and increased CLL risk. The study also provides evidence that genetic susceptibility for CLL increases BCC risk.
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http://dx.doi.org/10.1093/ije/dyab042DOI Listing
March 2021

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Int J Cancer 2021 Jul 30;149(2):327-336. Epub 2021 Mar 30.

Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

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 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.
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http://dx.doi.org/10.1002/ijc.33547DOI Listing
July 2021

Aspirin and other nonsteroidal anti-inflammatory drugs, statins and risk of non-Hodgkin lymphoma.

Int J Cancer 2021 Aug 8;149(3):535-545. Epub 2021 Mar 8.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

Non-steroidal anti-inflammatory drugs (NSAIDs) and statin drugs may protect against the development of non-Hodgkin lymphoma (NHL), but data are limited, particularly for NHL subtypes. Furthermore, some in vitro, animal and epidemiologic data suggest there may be a synergistic effect of these two agents, but there has been no test of this hypothesis in NHL. We evaluated the self-reported use of NSAIDs and statins in a clinic-based study of 1703 NHL patients and 2199 frequency-matched controls. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for potential confounding variables. We observed an inverse association of regular use of low-dose aspirin with risk of NHL (OR = 0.82; 95% CI 0.70-0.96) that was stronger with longer duration of use (P < .01). There were no associations for use of regular or extra-strength aspirin, ibuprofen, other NSAIDs, statins or other cholesterol-lowering drugs with NHL risk, while an inverse association with COX-2 inhibitors was equivocal. There was also no interaction of low-dose aspirin and statins on NHL risk. Inverse associations of similar magnitude to all NHL were observed for regular use of low-dose aspirin with diffuse large B-cell, follicular, marginal zone and all other lymphomas, although not all associations were statistically significant. In conclusion, low-dose aspirin but not regular/extra strength aspirin, other NSAIDs or statin use was associated with lower risk of NHL. Beyond the potential for the primary prevention of NHL, these data also point to a role of anti-platelet or other effects of low-dose aspirin in lymphomagenesis that warrant follow-up.
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http://dx.doi.org/10.1002/ijc.33541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192479PMC
August 2021

Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy.

Blood Cancer Discov 2021 Jan 3;2(1):54-69. Epub 2020 Dec 3.

Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.

Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in pre-neoplastic monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significantly differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and post-therapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state, and a distinct expression profile together with MBL cells compared to normal B cells. Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically-driven growth dynamics and together with its persistent presence suggests a central role in the normal-to-cancer transition.
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http://dx.doi.org/10.1158/2643-3230.BCD-19-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888194PMC
January 2021

Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families.

Blood 2021 Apr;137(15):2046-2056

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.
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http://dx.doi.org/10.1182/blood.2020006322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057266PMC
April 2021

Disease Flare During Temporary Interruption of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia.

Oncologist 2020 11 20;25(11):974-980. Epub 2020 Sep 20.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Background: Approximately 25% of patients with chronic lymphocytic leukemia (CLL) experience a flare of disease following ibrutinib discontinuation. A critical question is whether this phenomenon may also occur when ibrutinib is temporarily held. This study aimed to determine the frequency and characteristics of disease flares in this setting and assess risk factors and clinical outcomes.

Materials And Methods: We identified all patients with CLL seen at Mayo Clinic between October 2012 and March 2019 who received ibrutinib. Temporary interruptions in treatment and associated clinical findings were ascertained.

Results: Among the 372 patients identified, 143 (38%) had at least one temporary interruption (median 1 hold, range 1-7 holds) in treatment. The median duration of interruption was 8 days (range 1-59 days) and the most common indication was periprocedural. Among the 143 patients with ≥1 hold, an associated disease flare was seen in 35 (25%) patients: mild (constitutional symptoms only) in 21 patients and severe (constitutional symptoms with exam/radiographic findings or laboratory changes) in 14 patients. Disease flare resolved with resuming ibrutinib in all patients. Predictive factors of disease flare included progressive disease at time of hold and ≥ 24 months of ibrutinib exposure. The occurrence of disease flare with an ibrutinib hold was associated with shorter event-free survival (hazard ratio 2.3; 95% confidence interval 1.3-4.1; p = .007) but not overall survival.

Conclusion: Temporary interruptions in ibrutinib treatment of patients with CLL are common, and one quarter of patients who held ibrutinib in this study experienced a disease flare. Resolution with resuming ibrutinib underscores the importance of awareness of this phenomenon for optimal management.

Implications For Practice: Ibrutinib is a very effective treatment for chronic lymphocytic leukemia (CLL) but needs to be taken continuously. Side effects, such as increased bleeding risk with procedures, require temporary interruptions in this continuous treatment. Rapid CLL progression following ibrutinib discontinuation has been increasingly recognized. This study demonstrates that similar flares in disease signs or symptoms may occur during ibrutinib holds as well. Importantly, management with restarting ibrutinib led to quick clinical improvement. Awareness of this phenomenon among clinicians is critical to avoid associated patient morbidity and premature cessation of effective treatment with ibrutinib if the flare is misidentified as true progression of disease.
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http://dx.doi.org/10.1634/theoncologist.2020-0388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648348PMC
November 2020

Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci.

Hum Mol Genet 2020 09;29(16):2761-2774

Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined. Here, we examined the genetic and epigenetic features associated with 12 index variants, along with any correlated (r2 ≥ 0.5) variants, at the CLL risk loci located outside of gene promoters. Based on publicly available ChIP-seq and chromatin accessibility data as well as our own ChIP-seq data from CLL patients, we identified six candidate functional variants at six loci and at least two candidate functional variants at each of the remaining six loci. The functional variants are predominantly located within enhancers or super-enhancers, including bi-directionally transcribed enhancers, which are often restricted to immune cell types. Furthermore, we found that, at 78% of the functional variants, the alternative alleles altered the transcription factor binding motifs or histone modifications, indicating the involvement of these variants in the change of local chromatin state. Finally, the enhancers carrying functional variants physically interacted with genes enriched in the type I interferon signaling pathway, apoptosis, or TP53 network that are known to play key roles in CLL. These results support the regulatory roles for inherited noncoding variants in the pathogenesis of CLL.
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http://dx.doi.org/10.1093/hmg/ddaa165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530532PMC
September 2020

Delineation of clinical and biological factors associated with cutaneous squamous cell carcinoma among patients with chronic lymphocytic leukemia.

J Am Acad Dermatol 2020 Dec 16;83(6):1581-1589. Epub 2020 Jul 16.

Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background: The incidence of cutaneous squamous cell carcinoma (SCC) in patients with chronic lymphocytic leukemia (CLL) is significantly higher compared with age- and sex-matched controls.

Objective: To evaluate the association of factors associated with SCC risk.

Methods: Clinical CLL and SCC data were obtained from Mayo Clinic CLL Resource and self-reported questionnaires among patients with newly diagnosed CLL. We computed the CLL International Prognostic Index (CLL-IPI) from CLL prognostic factors, and a polygenic risk score from SCC susceptibility variants. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Among 1269 patients with CLL, the median follow-up was 7 years, and SCC subsequently developed in 124 patients. Significant associations with SCC risk were history of skin cancer (HR=4.80; 95% CI: 3.37-6.83), CLL-IPI (HR=1.42; 95% CI: 1.13-1.80), and polygenic risk score (HR=2.58; 95% CI: 1.50-4.43). In a multivariable model, these factors were independent predictors (C statistic = 0.69; 95% CI: 0.62-0.76). T-cell immunosuppressive treatments were also associated with SCC risk (HR=2.29; 95% CI: 1.47-3.55; adjusted for age, sex, and prior SCC).

Limitations: The sample size decreases when combining all risk factors in a single model.

Conclusion: SCC risk includes history of skin cancer, an aggressive disease at time of CLL diagnosis, receiving T-cell immunosuppressive treatments, and high polygenic risk score. Future studies should develop prediction models that include these factors to improved screening guidelines.
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http://dx.doi.org/10.1016/j.jaad.2020.06.1024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669637PMC
December 2020

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Nat Commun 2020 07 3;11(1):3353. Epub 2020 Jul 3.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
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http://dx.doi.org/10.1038/s41467-020-16483-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335068PMC
July 2020

Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.

Blood Adv 2020 06;4(12):2789-2797

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN.

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] ±0.04) and 15% (SE ±0.11) for MM and MGUS risk, respectively, and a 55% (SE ±0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.
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http://dx.doi.org/10.1182/bloodadvances.2020001435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322948PMC
June 2020

Atrial fibrillation in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib: risk prediction, management, and clinical outcomes.

Ann Hematol 2021 Jan 1;100(1):143-155. Epub 2020 Jun 1.

Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Background: Ibrutinib therapy is associated with an increased risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL). Risk assessment tools and outcomes of AF in these patients are not well described.

Methods: We performed a retrospective review of patients with CLL treated with ibrutinib at Mayo Clinic between October 2012 and November 2018.

Results: Two hundred ninety-eight patients were identified with a median time on ibrutinib of 19 months (range 0.23-69.7 months). Fifty-one patients developed treatment-emergent AF; the risk of treatment-emergent AF at 6 months, 1 year, and 2 years was 9%, 12%, and 16%, respectively. The following were associated with an increased risk of treatment-emergent AF on multivariable analyses: past history of AF (hazard ratio [HR] 3.5, p = 0.0072) and heart failure (HR 3.4, p = 0.0028). Most patients are able to continue ibrutinib therapy (dose reduced in 43%). Development of treatment-emergent AF was associated with shorter event-free survival (EFS; HR 2.0, p = 0.02) and shorter overall survival (OS; HR 3.2, p = 0.001), after adjusting for age, prior treatment status, TP53 disruption, heart failure, valvular disease, and past history of AF.

Conclusions: Patient comorbidities, rather than CLL-related factors, predict risk of treatment-emergent AF in patients treated with ibrutinib. Although the vast majority of patients with treatment-emergent AF are able to continue ibrutinib (with dose reduction in 43%), treatment-emergent AF appears to be associated with worse outcomes, independent of other adverse prognostic factors.
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http://dx.doi.org/10.1007/s00277-020-04094-3DOI Listing
January 2021

Incidence and risk of tumor lysis syndrome in patients with relapsed chronic lymphocytic leukemia (CLL) treated with venetoclax in routine clinical practice.

Leuk Lymphoma 2020 10 25;61(10):2383-2388. Epub 2020 May 25.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.

The risk of TLS in patients with relapsed CLL treated outside of clinical trials is not well described. Using the Mayo Clinic CLL Database, 48 patients treated with venetoclax for relapsed CLL in routine practice were identified; chart review determined baseline risk for TLS and laboratory abnormalities during venetoclax ramp-up. Overall, 6 (13%) patients developed laboratory TLS, 3 of whom demonstrated clinical TLS. The majority of patients who developed TLS were stratified as low or medium risk by the package insert. Of the 42 patients who did not meet Howard criteria for TLS, isolated hyperphosphatemia occurred in 19 patients (45%), hyperkalemia in 13 patients (31%), hyperuricemia in 2 patients (5%), and hypocalcemia in 1 patient (2%). In routine practice, the incidence of TLS appears higher than reported in clinical trials (3-6%). Half of patients who did not meet criteria for TLS developed clinically significant electrolyte abnormalities that required medical intervention.
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http://dx.doi.org/10.1080/10428194.2020.1768384DOI Listing
October 2020

Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index.

Am J Hematol 2020 08 7;95(8):906-917. Epub 2020 May 7.

Division of Hematology /Oncology, Mayo Clinic, Scottsdale, Arizona, USA.

Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10 ; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10 ). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.
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http://dx.doi.org/10.1002/ajh.25831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409825PMC
August 2020

The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice.

Cancer Med 2020 05 18;9(10):3390-3399. Epub 2020 Mar 18.

Division of Hematology, Stanford University School of Medicine, Palo Alto, CA, USA.

To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV, 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib (<420 mg daily; n = 43, physician preference; n = 33, concomitant medications; and n = 11, other). During 281 person-years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow-up of 24 months, the estimated median event-free survival (EFS) was 36 months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P = .048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P = .015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL.
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http://dx.doi.org/10.1002/cam4.2998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221301PMC
May 2020

Lipid Trait Variants and the Risk of Non-Hodgkin Lymphoma Subtypes: A Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2020 05 27;29(5):1074-1078. Epub 2020 Feb 27.

Emory University, Atlanta, Georgia.

Background: Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis.

Methods: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated ( < 5 × 10) with high-density lipoprotein (HDL, = 164), low-density lipoprotein (LDL, = 137), total cholesterol (TC, = 161), and triglycerides (TG, = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance-weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI).

Results: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00-1.30) and MZL (OR = 1.09; 95% CI, 1.01-1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83-0.99), all at nominal significance ( < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99-1.19; = 0.087). No associations were noteworthy after adjusting for multiple testing.

Conclusions: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes.

Impact: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196490PMC
May 2020

Genetically Determined Height and Risk of Non-hodgkin Lymphoma.

Front Oncol 2019 28;9:1539. Epub 2020 Jan 28.

Interdisciplinary Department of Medicine, University of Bari, Bari, Italy.

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00-1.17, = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01-1.31, = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.
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http://dx.doi.org/10.3389/fonc.2019.01539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999122PMC
January 2020

Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia.

Am J Hum Genet 2020 02 30;106(2):264-271. Epub 2020 Jan 30.

Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation sets (175 cases, 1,059 controls). Combined analyses identified linked SNPs in distinct blocks within the major histocompatibility complex on 6p21. The top SNP encodes p.Met76Val in the P4 binding pocket of the HLA class II gene HLA-DPB1 (rs1042151A>G, odds ratio [OR] 1.75, 95% confidence interval [CI] 1.50-2.03, p = 1.94 × 10) and was associated with HLA-DP cell surface expression in healthy individuals (p = 2.04 × 10). Phylogenetic analyses indicate that Val76 is not monophyletic and likely occurs in conjunction with different HLA-DP binding groove conformations. Imputation of HLA-DPB1 alleles revealed increased risk of SAA associated with Val76-encoding alleles DPB103:01, (OR 1.66, p = 1.52 × 10), DPB110:01 (OR 2.12, p = 0.0003), and DPB101:01 (OR 1.60, p = 0.0008). A second SNP near HLA-B, rs28367832G>A, reached genome-wide significance (OR 1.49, 95% CI 1.22-1.78, p = 7.27 × 10) in combined analyses; the association remained significant after excluding cases with clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes (8.6% of cases and 0% of controls). SNPs in the HLA class II gene HLA-DPB1 and possibly class I (HLA-B) are associated with SAA. The replacement of Met76 to Val76 in certain HLA-DPB1 alleles might influence risk of SAA through mechanisms involving DP peptide binding specificity, expression, and/or other factors affecting DP function.
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http://dx.doi.org/10.1016/j.ajhg.2020.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010969PMC
February 2020

Pretreatment Hemoglobin Adds Prognostic Information To The NCCN-IPI In Patients With Diffuse Large B-Cell Lymphoma Treated With Anthracycline-Containing Chemotherapy.

Clin Epidemiol 2019 14;11:987-996. Epub 2019 Nov 14.

Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.

Background: Hemoglobin (Hgb) concentration at diagnosis is associated with outcome in cancer. In a recently reported simplified 3-factor prognostic score in Hodgkin lymphoma, Hgb, along with age and clinical stage, outperformed the classical International Prognostic Score with seven parameters.

Methods: In the present study, we investigated if pretherapeutic Hgb concentration added prognostic information to the NCCN-IPI in diffuse large B-cell lymphoma. We included patients from the Danish Lymphoma Registry (LYFO; N = 3499) and from the Molecular Epidemiology Resource (MER; N = 1225), Mayo Clinic and University of Iowa. Four sex-specific Hgb groups were defined: below transfusion threshold, from transfusion threshold to below lower limit of normal, from lower limit of normal to the population mean, and above the mean. We used multivariable Cox regression to estimate the hazard rate ratios (HR) and 95% CIs for overall survival (OS) and event-free survival (EFS), adjusting for sex, NCCN-IPI, comorbidity, and rituximab treatment.

Results: Approximately half of the patients had Hgb levels below the lower limit of normal. Compared to patients with Hgb levels above the mean, an inferior OS was directly correlated with lower pretreatment Hgb within the predefined groups (HR=1.23, HR=1.51, and HR=2.05, respectively). These findings were validated in the MER.

Conclusion: Based on multivariable analysis, lower pretreatment Hgb, even within the normal range but below the mean, added prognostic information to established indices such as the NCCN-IPI and the Charlson comorbidity index.
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http://dx.doi.org/10.2147/CLEP.S219595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861518PMC
November 2019
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