The molecular basis of familial chronic lymphocytic leukemia

Crowther-Swanepoel, Dalemari; Houlston, Richard S.

doi:10.3324/haematol.2009.006296

Cited by 18 publications

(9 citation statements)

References 30 publications

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“…However, studies conducted in high risk families with CLL [18], Hodgkin lymphoma [19], and Waldenstrom macroglobulinemia [20] have not detected genes with large effects. While these studies were in part hampered by relatively small sample size and disease heterogeneity [21], it also raises the hypothesis that multiple, low to moderate risk variants (∼RRs=1.1 to 1.5) that are common in the population (>5%) may be more relevant than single, highly penetrant variants that are rare in the population, which is referred to as the common-disease, common-variant hypothesis [22]. …”

Section: Evidence For An Inherited Component To Follicular Lymphoma Riskmentioning

confidence: 99%

Host genetics in follicular lymphoma

Cerhan

2011

Best Practice & Research Clinical Haematology

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The role of inherited (host) genetic susceptibility in the pathogenesis of follicular lymphoma (FL) is reviewed. First degree relatives of FL patients are at an increased risk of FL, suggesting a role for inherited factors. While there have been no linkage studies in FL families, candidate gene and genome-wide association studies have identified several risk loci which have been confirmed in independent studies. These include regions on 6p21.32-33 and TNF family members. Host genetics has also been hypothesized to influence treatment response, disease progression and overall survival. Early leads in FL prognosis include pathways that regulate immune function, antibody-dependent cellular cytotoxicity, chemotaxis, and one carbon metabolism, although few of these associations have been independently confirmed. While the use of host genetics to identify individuals at high risk of FL or to predict FL treatment response and prognosis appears to be very promising, it is not yet ready for the clinic.

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Section: Evidence For An Inherited Component To Follicular Lymphoma Riskmentioning

confidence: 99%

Host genetics in follicular lymphoma

Cerhan

2011

Best Practice & Research Clinical Haematology

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“…The CLL genome is characterized by recurrent genetic as well as epigenetic alterations [2]. Familial clustering of CLL has been described in up to 10% of cases [3], [4]. The identification of predisposing mutations, however, has been hampered due to the lack of large pedigrees with multiple affected family members.…”

Section: Introductionmentioning

confidence: 99%

Germline Allele-Specific Expression of DAPK1 in Chronic Lymphocytic Leukemia

et al. 2013

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We previously reported a rare germline variant (c.1-6531) that resulted in allele–specific expression (ASE) of death-associated protein kinase 1 (DAPK1) and predisposition to chronic lymphocytic leukemia (CLL). We investigated a cohort of CLL patients lacking this mutation for the presence of ASE of DAPK1. We developed a novel strategy that combines single-nucleotide primer extension (SNuPE) with MALDI-TOF mass spectrometry, and detected germline DAPK1 ASE in 17 out of 120 (14.2%) CLL patients associated with a trend towards younger age at diagnosis. ASE was absent in 63 healthy controls. Germline cells of CLL patients with ASE showed increased levels of DNA methylation in the promoter region, however, neither genetic nor further epigenetic aberrations could be identified in the DAPK1 5′ upstream regulatory region, within distinct exons or in the 3′-UTR. We identified B-lymphoid malignancy related cell line models harboring allelic imbalance and found that allele-specific methylation in DAPK1 is associated with ASE. Our data indicate that ASE at the DAPK1 gene locus is a recurrent event, mediated by epigenetic mechanisms and potentially predisposing to CLL.

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“…[1][2][3][4][5] However, in the literature collections of large families with multiple cases of varied types of HMs are relatively rare, 1 and most studies of familial HM focus on one major subtype in each family such as chronic lymphocytic leukemia (CLL), myeloma, acute myeloid leukemia, and Hodgkin lymphoma. 4,[6][7][8] In a number of families with HM, the phenomenon of "anticipation" has been described.…”

Section: Introductionmentioning

confidence: 99%

Anticipation in familial hematologic malignancies

Tegg

Thomson

Stankovich

et al. 2011

Blood

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We describe a collection of 11 families with > 2 generations of family members whose condition has been diagnosed as a hematologic malignancy. In 9 of these families there was a significant decrease in age at diagnosis in each subsequent generation (anticipation). The mean age at diagnosis in the first generation was 67.8 years, 57.1 years in the second, and 41.8 years in the third (P < .0002). This was confirmed in both direct parentoffspring pairs with a mean reduction of 19 years in the age at diagnosis (P ‫؍‬ .0087) and when the analysis was repeated only including cases of mature B-cell neoplasm (P ‫؍‬ .0007). We believe that these families provide further insight into the nature of the underlying genetic mechanism of predisposition in these families. (Blood. 2011;117(4):1308-1310) IntroductionStudies have established that a family history of hematologic malignancy (HM) is a risk factor for the development of a HM. [1][2][3][4][5] However, in the literature collections of large families with multiple cases of varied types of HMs are relatively rare, 1 and most studies of familial HM focus on one major subtype in each family such as chronic lymphocytic leukemia (CLL), myeloma, acute myeloid leukemia, and Hodgkin lymphoma. 4,[6][7][8] In a number of families with HM, the phenomenon of "anticipation" has been described. 4 Anticipation is defined as the onset of the disease in question at an earlier age or disease severity in successive generations, and it has implications for the nature of the genetic condition that underpins it.We are studying 13 families, ascertained from a populationbased study conducted between 1972 and 1980 in Tasmania. 9 Herein, we describe 11 of these families that have Ն 2 generations affected with a HM. These families have been updated, and the current and past generations were included and cross-referenced with names from the Tasmanian Cancer Registry and the genealogic databases of the Menzies Research Institute. These families have been recently published, 10 but they are continuously being updated with new cases of HMs. We reviewed our families to determine whether anticipation could be shown. Here, we describe 9 families with HM that exhibit anticipation. In contrast to most prior reports, we show that the phenomenon also occurs in families in which the predominant HM is other than CLL. The demonstration of anticipation is shown both by whole generational analysis and by assessment of parent-offspring pairs. Methods Families from the original studyThe families from the original study were reviewed and prioritized for further study, based on the number of cases affected, multiple generations affected, or sibling pairs affected. This study has received ethical approval from the Human Research Ethics Committee, Tasmania Network. Confirmation of diagnosisMedical and pathology records from the Royal Hobart Hospital, flow cytometric records from the University of Tasmania's Oncology and Immunology Laboratory, files from the 1970s study, 9 and records of the Tasmanian Cancer Registry we...

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The molecular basis of familial chronic lymphocytic leukemia

Cited by 18 publications

References 30 publications

Host genetics in follicular lymphoma

Host genetics in follicular lymphoma

Germline Allele-Specific Expression of DAPK1 in Chronic Lymphocytic Leukemia

Anticipation in familial hematologic malignancies

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