Inherited predisposition to chronic lymphocytic leukemia

Brown, Jennifer R.

doi:10.1586/17474086.1.1.51

Cited by 20 publications

(20 citation statements)

References 111 publications

(98 reference statements)

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“…Asians have also significantly lower rates of CLL than Caucasian Europeans or Americans do [25]. This, coupled with the familial aggregation often observed in families with CLL, might argue in favor of a potential gene-inherited status, perhaps including UGT1A1, among others, as one of the possible shared predisposing factors to CLL of the western world [26]. …”

Section: Discussionmentioning

confidence: 99%

UGT1A1*28 Polymorphism in Chronic Lymphocytic Leukemia: The First Investigation of the Polymorphism in Disease Susceptibility and Its Specific Cytogenetic Abnormalities

Karakosta

Kalotychou²,

Kostakis³

et al. 2014

Acta Haematol

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Chronic lymphocytic leukemia (CLL) has been recently attributed to a combination of genetic predisposition and exposure to environmental factors. UDP-glucuronosyltransferase (UGT)1A1*28 is an inborn polymorphism that results in significant downregulation of uridine diphosphate glucuronyltransferase 1-1 (UGT1A1) activity, one of the most critical metabolizing enzymes involved in the detoxification of toxic substances, some of which contribute to CLL pathogenesis. Here, for the first time, we investigated the putative impact of UGT1A1*28 on CLL incidence and on the formation of the most common chromosomal abnormalities of CLL. UGT1A1*28 was investigated in 109 CLL patients and 108 healthy controls, and was associated with karyotypic and fluorescence in situ hybridization (FISH) results. A significant high frequency of the mutant genotype was observed in patients carrying abnormal FISH patterns, especially del(11q) and +12, which are CLL-specific abnormalities. We also observed a significant association between UGT1A1*28 and the intermediate to unfavorable cytogenetic CLL risk groups. No difference, though, was observed in genotypes between patients and controls. Therefore, we could suggest that UGT-deficient individuals may be at a greater risk for developing CLL-specific abnormalities. Our study might serve as a starting point to consider UGT1A1*28 polymorphism as one of the possible predisposing factors of CLL pathogenesis.

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Section: Discussionmentioning

confidence: 99%

UGT1A1*28 Polymorphism in Chronic Lymphocytic Leukemia: The First Investigation of the Polymorphism in Disease Susceptibility and Its Specific Cytogenetic Abnormalities

Karakosta

Kalotychou²,

Kostakis³

et al. 2014

Acta Haematol

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“…Finally, this study identified linkage to 6p22, the site of the MHC locus, in familial CLL. Many early studies of specific HLA loci in relation to familial CLL have yielded conflicting results and as yet there is little clarity on the significance if any of this association [Brown, 2008]. Thus, the overall results of the largest linkage analysis performed across multiple families in CLL have unfortunately been largely inconclusive.…”

Section: Early Studies Looking For Genesmentioning

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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“…Moreover, these technologies are likely to be applied to studying inherited predisposition for CLL [108,109], as this disease has a high incidence of familial cases. This area of investigation might provide important clues to the interaction between existing germline mutations and acquired somatic mutagenesis.…”

Section: Discussionmentioning

confidence: 99%

Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics

Landau

2013

Genome Medicine

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Chronic lymphocytic leukemia (CLL) has been consistently at the forefront of genetic research owing to its prevalence and the accessibility of sample material. Recently, genome-wide technologies have been intensively applied to CLL genetics, with remarkable progress. Single nucleotide polymorphism arrays have identified recurring chromosomal aberrations, thereby focusing functional studies on discrete genomic lesions and leading to the first implication of somatic microRNA disruption in cancer. Next-generation sequencing (NGS) has further transformed our understanding of CLL by identifying novel recurrently mutated putative drivers, including the unexpected discovery of somatic mutations affecting spliceosome function. NGS has further enabled in-depth examination of the transcriptional and epigenetic changes in CLL that accompany genetic lesions, and has shed light on how different driver events appear at different stages of disease progression and clonally evolve with relapsed disease. In addition to providing important insights into disease biology, these discoveries have significant translational potential. They enhance prognosis by highlighting specific lesions associated with poor clinical outcomes (for example, driver events such as mutations in the splicing factor subunit gene SF3B1) or with increased clonal heterogeneity (for example, the presence of subclonal driver mutations). Here, we review new genomic discoveries in CLL and discuss their possible implications in the era of precision medicine.

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Inherited predisposition to chronic lymphocytic leukemia

Cited by 20 publications

References 111 publications

UGT1A1*28 Polymorphism in Chronic Lymphocytic Leukemia: The First Investigation of the Polymorphism in Disease Susceptibility and Its Specific Cytogenetic Abnormalities

UGT1A1*28 Polymorphism in Chronic Lymphocytic Leukemia: The First Investigation of the Polymorphism in Disease Susceptibility and Its Specific Cytogenetic Abnormalities

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

Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics

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