Single nucleotide polymorphisms and inherited risk of chronic lymphocytic leukemia among African Americans

Coombs, Catherine C.; Rassenti, Laura Z.; Falchi, Lorenzo; Slager, Susan L.; Strom, Sara S.; Ferrajoli, Alessandra; Weinberg, J. Brice; Kipps, Thomas J.; Lanasa, Mark C.

doi:10.1182/blood-2012-02-408799

Cited by 18 publications

(13 citation statements)

References 22 publications

(24 reference statements)

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“…A recent study looked at the frequency of the known GWAS alleles in an African-American population and found that most of these alleles were less common in African-American CLL patients compared with Caucasian patients [Coombs et al 2012]. Furthermore the allele frequency was not different among African-Americans with CLL compared with African-American control populations, suggesting that these alleles are not major contributors to disease risk in African-Americans [Coombs et al 2012]. Further work will be required to define genetic risk in African-Americans as well as other ethnic groups.…”

Section: Moving To Genomewide Analyses: Associationmentioning

confidence: 99%

Inherited susceptibility to chronic lymphocytic leukemia: evidence and prospects for the future

Brown

2013

Therapeutic Advances in Hematology

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Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States and one of the most heritable cancers. A family history of the disease is perhaps the best defined risk factor, and approximately 15–20% of CLL patients have a family member with CLL or a related lymphoproliferative disorder. Much effort has been devoted to trying to elucidate the mechanisms underlying this genetic risk. Familial CLL appears to be clinically and biologically similar to sporadic CLL, and most if not all CLL appears to be preceded by monoclonal B-cell lymphocytosis (MBL), which does appear to occur at higher frequency in relatives in families with CLL. Neither linkage studies nor candidate gene association studies have proven particularly informative in CLL, but genomewide association studies have identified multiple low-risk variants that together explain about 16% of the familial risk of CLL. Studies of individual families have identified higher-risk single nucleotide polymorphisms or copy number variants associated with disease risk in those families. Current efforts to identify additional risk loci are focused on applying next-generation sequencing to the germline of informative CLL families as well as individuals with sporadic CLL.

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Section: Moving To Genomewide Analyses: Associationmentioning

confidence: 99%

Inherited susceptibility to chronic lymphocytic leukemia: evidence and prospects for the future

Brown

2013

Therapeutic Advances in Hematology

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“…Together with the MD Anderson Cancer Center, we previously found that African Americans with CLL have inferior clinical outcomes compared to Whites with CLL (Falchi et al , ), although the underlying reason for this is unknown (Coombs et al , ). Our current work demonstrates that African Americans with CLL had lower CD5 expression than Whites with CLL, suggesting that at least part of the differences in clinical outcomes may be related to CD5 expression and downstream signalling.…”

Section: Discussionmentioning

confidence: 99%

Clinical outcomes in chronic lymphocytic leukaemia associated with expression of CD5, a negative regulator of B‐cell receptor signalling

et al. 2018

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Summary: Chronic lymphocytic leukaemia (CLL) is characterized by expression of CD5 on clonal B cells, and is partly driven by activated B-cell receptor (BCR) signalling. While CD5 is known to be a negative regulator of BCR signalling, it is unknown if variability in CD5 expression exists among patients and whether CLL cell CD5 expression affects CLL clinical outcomes. We assessed the extent to which CD5 expression is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated CD5 expression from 1275 blood samples, established prognostic markers and time to event data from 423 CLL patients followed at the Duke University and Durham VA Medical Centers. CD5 median fluorescence intensity (MFI) was largely stable over time in ssindividual patients, but ranged between 0.5 and 760 in the entire cohort. Lower CD5 MFI was significantly associated with a shorter time to first therapy. CD5 MFI, combined with established clinical and molecular prognostic markers, significantly improved risk-stratification. CD5 may affect disease outcomes by suppressing signalling through the BCR. Thus, a strategy to modulate CLL cell CD5 expression or function could be a therapeutic approach in CLL.

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“…Data that supported differential genetic risk for CLL exists between Black and White CLL patients led to the belief that biological differences might exist between W and NW CLL patients [15]. In fact, Falchi and colleagues analyzed outcomes of untreated African American patients as compared with non-black reference patients [16].…”

Section: Discussionmentioning

confidence: 99%

Analysis of racial variations in disease characteristics, treatment patterns, and outcomes of patients with chronic lymphocytic leukemia

et al. 2016

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The impact of race on outcomes of patients with chronic lymphocytic leukemia (CLL), the most common leukemia in the west, is not well studied. We aimed to understand racial variations in clinical and disease characteristics, treatment patterns, and outcomes in patients with CLL. We utilized the Mayo Clinic CLL database to perform an analysis of these characteristics and natural history of non-white (NW) compared to white (W) CLL patients. Differences by race in median overall survival (OS) and time-to-first-treatment (TTFT) were investigated. Of the 4215 CLL patients, 4114 (97.6%) were W and 101 (2.4%) were NW. NW patients were younger (median age at diagnosis 59.4 vs. 63.4; P 5 0.003) and more likely to have an elevated LDH (28.0% vs. 16.2%; P 5 0.02). No differences in prognostic parameters were noted. No major differences were observed in treatment selection. OS and TTFT were similar between both groups. In the largest analysis of NW-CLL patients in North America, and contrary to historical retrospective reports, W and NW patients appear to have comparable outcomes when treated similarly. These findings suggest previously noted outcome differences may be due to disparities in access to care and management rather than differences in disease biology.

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Single nucleotide polymorphisms and inherited risk of chronic lymphocytic leukemia among African Americans

Cited by 18 publications

References 22 publications

Inherited susceptibility to chronic lymphocytic leukemia: evidence and prospects for the future

Inherited susceptibility to chronic lymphocytic leukemia: evidence and prospects for the future

Clinical outcomes in chronic lymphocytic leukaemia associated with expression of CD5, a negative regulator of B‐cell receptor signalling

Analysis of racial variations in disease characteristics, treatment patterns, and outcomes of patients with chronic lymphocytic leukemia

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