Causation of chronic lymphocytic leukemia—insights from familial disease

doi:10.1016/S0145-2126(03)00023-7

Leukemia Research

Volume 27, Issue 10, October 2003, Pages 871-876

https://doi.org/10.1016/S0145-2126(03)00023-7 Get rights and content

Abstract

In Western countries B-cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia. Evidence from epidemiological studies and family studies strongly supports the notion that a subset of CLL involves inherited susceptibility. Identification of genes predisposing to CLL should be useful for diagnosis and treatment, as well as serving as a model for B-cell tumorigenesis in general. Here, we review the current status of knowledge about inherited susceptibility to CLL.

Introduction

In Western countries leukemia affects ∼2% of the population [1]. B-cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia accounting for ∼30% of all cases [2].

Acute leukemia occurs at a higher frequency in individuals with constitutional chromosome anomalies and is feature of a number of Mendelian cancer syndromes. While such associations are well established, inherited susceptibility has not until recently been recognized in CLL and other related B-cell lymphoproliferative disorders (LPDs). Evidence from epidemiological studies and family studies, however, strongly supports the notion that a subset of CLL involves inherited susceptibility. Identification of genes predisposing to CLL should be useful for diagnosis and treatment, as well as serving as a model for B-cell tumorigenesis in general. Here, we review the current status of knowledge about inherited susceptibility to CLL.

Section snippets

Epidemiological studies

Seven epidemiological studies have systematically examined the risk for the development of CLL and other LPDs in relatives of patients [3], [4], [5], [6], [7], [8], [9] (Table 1). All of the case-control studies that examined the risk of leukemia in relatives of CLL patients found elevated risks in relatives. The three cohort studies were all retrospective in design. The study reported by Gunz et al. [4] was based on a survey of 909 families ascertained through leukemia cases. The study

Characteristics of familial chronic lymphocytic leukemia

A survey of the clinical features of 28 CLL families containing 73 cases recently reported suggests that familial cases present ∼10 years earlier than sporadic cases, implying a more aggressive clonal expansion [11]. A higher frequency of second primary tumors, but not large-cell Hodgkin’s lymphoma (Richter’s syndrome), was seen.

The phenotype of earlier age of onset and increased risk of second tumors is a classical feature of many familial cancers. There is, however, a caveat to derive

Models of inherited predisposition detection of susceptibility alleles

To date little is known about genes conferring susceptibility to CLL. However, as previously stated, the risk for close relatives of a CLL case, averaged across all ages, is increased nearly three-fold. The majority of this familial risk is probably genetic in origin. Such moderate familial risks are entirely compatible with a wide range of gene frequencies and modes of inheritance (Table 2), therefore the underlying genetic model cannot be inferred from estimates of relative risks in

Candidate CLL predisposition genes

To date little is known about the genetic basis of CLL and the search for predisposition genes is currently restricted to the evaluation of candidates for which there is a priori evidence suggesting involvement in the disease.

Conclusions

There is increasing evidence for the existence of an inherited predisposition to CLL and other associated B-cell LPDs. It is probable that in addition to alleles conferring a significant risk part of the inherited susceptibility to the disease is mediated through low risk alleles.

Identification of the genes involved in inherited forms of CLL should provide insights into the pathogenesis of CLL in general. At present, there is no compelling evidence that any specific gene acts as a major

Acknowledgements

The authors’ work is supported by the Leukaemia Research Fund.

Contributions. R.S. Houlston provided the concept and design, drafted the article and gave final approval. G. Sellick, M. Yuille, E. Matutes and D. Catovsky contributed to the drafting of the article, provided critical revisions and gave final approval.

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Inherited factors that increase cancer susceptibility can be due to mutations in rare, high-penetrance genes, less rare moderate susceptibility genes, or a combination of common genetic variants of small effect. These genes can be tumor suppressor genes (TSGs), DNA repair genes or oncogenes, and others such as those involved in the immune response or vascular growth promotion. Mutations in TSGs can cause conditions with a distinct phenotype such as familial adenomatous polyposis; DNA repair gene alterations can cause breast/ovarian cancer susceptibility and Lynch syndrome. The underlying causes of leukemia include rare mutations in highly penetrant genes but more commonly is multifactorial.
The principles of genetic counseling are based on the knowledge of these genetic mechanisms, predicated on the facility for making a molecular diagnosis in an affected proband, which then allows cascade predictive testing in the at-risk relatives of cases. There are important issues of the ownership of genetic information and confidentiality, which need to be taken into account when delivering genetic counseling. Predictive tests can allow appropriate clinical risk-reducing management to be developed for tested individuals.
Relationship between MTHFR gene polymorphisms (C677T and A1298C) and chronic lymphocytic leukemia in the Turkish population
2018, Meta Gene
Citation Excerpt :
Even though older age, male gender, the white race, the history of hematologic malignancy of family have recognized as risk factors, the etiology of CLL is not yet known (Sgambati et al., 2001). Several studies reported that genetic predisposition to CLL has significantly recognized 3- to 7-fold highly risk in primary relatives of CLL cases (Houlston et al., 2003). Folate metabolism plays a major role in carcinogenesis because of its association in DNA methylation and nucleotide synthesis.
Chronic lymphocytic leukemia (CLL) is a neoplastic disease that influences B cell lymphocytes. CLL is the most common kind of leukemia accounting for approximately 30% of all hematological malignancies. The functions of MTHFR enzyme are a critical juncture in the DNA synthesis, and in methylation of metabolic reactions. Two common genetic polymorphisms, C677T and A1298C, are associated with reduced enzyme activity. We evaluated the association between MTHFR gene polymorphisms and the CLL risk.
In the present study, MTHFR gene polymorphisms were investigated in a case-control study of 91 patients with CLL and 101 healthy control subjects using real time polymerase chain reaction (RT-PCR) assay in the Turkish population.
The patients carrying 1298C allele or 1298CC genotype had a higher risk of CLL (P = .04, P = .005, respectively). Moreover, the patients carrying 677TT genotype had a lower risk of CLL than the other patients carrying 677CC and 677CT genotypes in recessive model (P = .03). Additionally, the CA haplotype block showed a protective effect against the risk of CLL (the C677/A1298, P = .0013).
In conclusion, our results demonstrate for the first time MTHFR gene C677T and A1298C polymorphisms, especially A1298C, have a major effect on the risk of CLL in the Turkish patients. We suggest that considering the first contradictory results in Caucasians, further additional studies are necessary to elucidate the relationship of these polymorphisms with the risk of CLL disease in Caucasian populations.
Fine-mapping of HLA associations with chronic lymphocytic leukemia in US populations
2014, Blood
Citation Excerpt :
CLL occurs more commonly in Western populations, is less common in African Americans, and is relatively rare in Asians.4-6 Differences in incidence persist despite immigration,7-11 and first-degree relatives of CLL patients have a two- to sevenfold elevated risk of developing the disease,12,13 implicating genetic predisposition rather than environmental factors in the pathogenesis of CLL. HLA plays a central role in immune surveillance, and HLA polymorphisms may impact the ability of the immune system to identify malignant cells and target them for T cell-mediated elimination.14
Chronic lymphocytic leukemia (CLL) displays remarkable ethnic predisposition for whites, with relative sparing of African-American and Asian populations. In addition, CLL displays among the highest familial predispositions of all hematologic malignancies, yet the genetic basis for these differences is not clearly defined. The highly polymorphic HLA genes of the major histocompatibility complex play a central role in immune surveillance and confer risk for autoimmune and infectious diseases and several different cancers, the role for which in the development of CLL has not been extensively investigated. The National Marrow Donor Program/Be The Match has collected HLA typing from CLL patients in need of allogeneic hematopoietic stem cell transplant and has recruited millions of volunteers to potentially donate hematopoietic stem cells. HLA genotypes for 3491 US white, 397 African-American, and 90 Hispanic CLL patients were compared with 50 000 controls per population from the donor registry. We identified several HLA alleles associated with CLL susceptibility in each population, reconfirming predisposing roles of HLA-A*02:01 and HLA-DRB4*01:01 in whites. Associations for haplotype DRB4*01:01∼DRB1*07:01∼DQB1*03:03 were replicated across all 3 populations. These findings provide a comprehensive assessment of the role of HLA in the development of severe CLL.
Chronic Lymphocytic Leukemia
2012, Disease-a-Month
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Because CLL is an uncommon cancer, patients who have at least 1 relative with CLL are considered “familial” and others are considered “sporadic.” In population-based samples, approximately 5% of patients with CLL reported a family history of leukemia (reviewed in Houlston et al4).5 There is no documented association of CLL with exposure to radiation, alkylating agents, or known leukemogenic chemicals.
Racial differences in the presentation and outcomes of chronic lymphocytic leukemia and variants in the United States
2011, Clinical Lymphoma, Myeloma and Leukemia
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The majority of CLL and PLL cases occur sporadically in individuals who have had no known exposure to leukemogens. Familial CLL has also been reported, but is uncommon.10-12 The majority of patients with CLL initially present with asymptomatic disease that does not require immediate treatment.
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the United States, and prolymphocytic leukemia (PLL) is a related, rare chronic lymphoproliferative disorder.
Using the United States Surveillance, Epidemiology and End Results (SEER) data from 13 registries, we examined differences in incidence and survival for CLL, small lymphocytic lymphoma (SLL) and PLL by race. International Classification of Diseases for Oncology 3^rd edition histology codes 9670, 9823, and 9632-34 were used to identify cases.
From 1992 to 2007, 30,622 cases of CLL/SLL and 268 cases of PLL were recorded. Males had higher incidence than females (male-to-female incidence rate ratio CLL/SLL 1.89, 95% confidence interval (CI) 1.85-1.94 and PLL 2.47, 95%CI 1.90-3.20). Black patients were diagnosed at younger age compared to white patients (mean age at diagnosis for white versus black patients for CLL/SLL, 70 versus 67 years, P < .001; for PLL, 71 versus 61 years, P < .001). Greater proportion of black patients with SLL presented with B symptoms, extranodal primary site, and advanced disease compared to white patients (P = .003, P = .012, and P = .009 respectively). White patients with CLL/SLL had better survival rates than black patients (5-year relative survival rate 77.1% versus 63.9%, P < .01). In univariate Cox regression models, black race, male gender, age at diagnosis > 65 years, advanced stage, and B-symptoms were predictors of worse survival (P < .01) among CLL/SLL patients.
Black patients with CLL/SLL and PLL present at younger age and black patients with CLL/SLL have worse survival than white patients. Epidemiological studies examining the biological variants of these diseases in concert with race are needed to elucidate the etiology of these disparities.
Diagnostic issues in chronic lymphocytic leukaemia (CLL)
2010, Best Practice and Research: Clinical Haematology
Citation Excerpt :
MBL in the general population has been reported with a variable frequency ranging from 3% to 12%[7] but it appears to be higher (up to 17%) in relatives from CLL patients.[8] This, together with epidemiological data from large-scale studies showing a high relative risk of CLL and other lymphoid disorders in first degree relatives,[9] supports an inherited basis of CLL. The change in the definition for CLL made by the IWCLL group has important implications as up to 40% of cases that in the past were considered early stage CLL (Rai 0/I and Binet A) are now designated MBL.
The diagnosis of chronic lymphocytic leukaemia (CLL) is based on clinical and laboratory features. Morphology and immunophenotype are the initial diagnostic investigations. In atypical cases, these tests should be complemented with molecular genetics and/or histology to exclude other B-cell disorders of small lymphocytes. Morphologically, CLL can be classified into typical and atypical. Immunophenotyping is the only method that can establish or confirm the diagnosis as CLL lymphocytes have a distinct immunophenotypic signature. A scoring system compounding the results with a set of markers allows firming up the diagnosis. Other immunological markers such as CD38 and ZAP-70 have an important prognostic impact. Fluorescence in situ hybridization (FISH) analysis, chiefly by detecting 17p (TP53 locus) and 11q (ATM) deletions and mutational status of the IgVH gene, also provides prognostic information and may determine the type of therapy. In atypical CLL, histology and/or molecular genetics may be required to exclude other B-cell disorders.

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¹: Present address: MRC Geneservice, Babraham, Cambridge CB2 4AT, UK.

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Causation of chronic lymphocytic leukemia—insights from familial disease

Abstract

Introduction

Section snippets

Epidemiological studies

Characteristics of familial chronic lymphocytic leukemia

Models of inherited predisposition detection of susceptibility alleles

Candidate CLL predisposition genes

Conclusions

Acknowledgements

Leuk. Res.

Blood

Blood

Lancet

Blood

Blood

Blood

Blood

Lancet

Lancet

Am. J. Hum. Genet.

Biology of chronic lymphocytic leukemia

Semin. Haematol.

Myeloproliferative and lymphoproliferative disorders in Tasmania, 1972–80: occupational and familial aspects

Natl. Cancer. Inst.

Familial leukemia: a study of 909 families

Scand. J. Haematol.

Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands

J. Natl. Cancer. Inst.

Chronic lymphocytic leukemia: case-control epidemiological study in Yorkshire

Br. J. Cancer

Familial cancer history and chronic lymphocytic leukemia. A case-control study

Am. J. Epidemiol.

Cancer mortality of family members of patients with chronic lymphocytic leukemia

Eur. J. Epidemiol.

Familial chronic lymphocytic leukemia: a survey and review of published studies

Br. J. Haematol.

Clinical characteristics of familial B-CLL in the National Cancer Institute familial registry

Leuk. Lymphoma

Anticipation in familial chronic lymphocytic leukemia families

Leukemia