Familial Leukaemia: A Study of 909 Families

Gunz, F. W.; Gunz, Joan P.; Veale, A. M. O.; Chapman, Cyril; Houston, I. B.

doi:10.1111/j.1600-0609.1975.tb01063.x

Cited by 98 publications

(29 citation statements)

References 27 publications

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“…However, it should be noted that other cytopenias such as neutropenia and thrombocytopenia can be seen without concomitant leukemia in these disorders, thereby displaying other hematologic manifestations. While there have been many case reports detailing family pedigrees with an increased incidence of leukemia in the absence of a known inherited mutation [Goldgar et al 1994;Gunz et al 2009], to date there have been three genes identified that can be inherited in an autosomal dominant fashion and specifically predispose people to the development of leukemia: CEPBA, RUNX1, and GATA2. In this section we also discuss familial inheritance of monosomy 7 and its unique association with predisposing individuals to leukemia.…”

Section: Familial Leukemiamentioning

confidence: 99%

Genetic predispositions to childhood leukemia

Stieglitz

Loh

2013

Therapeutic Advances in Hematology

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While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review article, we describe a number of these mutations and their clinical features. These predispositions can be broadly classified as those leading to bone marrow failure, those involving tumor suppressor genes, DNA repair defects, immunodeficiencies or other congenital syndromes associated with transient myeloid disorders. While leukemia can develop as a secondary event in the aforementioned syndromes, there are also several syndromes that specifically lead to the development of leukemia as their primary phenotype. Many of the genes discussed in this review can also be somatically mutated in other cancers, highlighting the importance of understanding shared alterations and mechanisms underpinning syndromic and sporadic leukemia.

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Section: Familial Leukemiamentioning

confidence: 99%

Genetic predispositions to childhood leukemia

Stieglitz

Loh

2013

Therapeutic Advances in Hematology

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“…4,[6][7][8][9][10] Collectively these data provide evidence for a 2 to 8-fold elevated risk of CLL in case relatives.…”

Section: Familial Risks Of Chronic Lymphocytic Leukemiamentioning

confidence: 84%

The molecular basis of familial chronic lymphocytic leukemia

Crowther-Swanepoel¹,

Houlston²

2009

Haematologica

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It is now well established that inherited genetic predisposition plays an important part in defining individual susceptibility to most common solid tumors. Paradoxically, despite chronic lymphocytic leukemia (CLL) being the most common lymphoid malignancy in Western countries 1 and having a strong familial risk, our understanding of the genetic basis of CLL is only just starting to be recognized and its etiology elucidated. Familial clustering of chronic lymphocytic leukemiaOver the last seven decades more than 100 families have been reported in the literature in which clustering of CLL has been documented. While not exclusively a consequence of genetic predisposition, familial aggregation provides strong evidence to support the role of inherited genetic factors in disease etiology. In a number of the families reported, CLL cosegregates with other B-cell lymphoproliferative disorders (LPD) such as Hodgkin's lymphoma (HL) suggesting that part of the familial predisposition could be mediated through pleiotropic mechanisms.2-4 While most of the CLL pedigrees are nuclear families in which less than 4 family members have been affected, some spectacular multigenerational pedigrees have been described. 2,5 In addition to such families providing evidence for a strong familial basis to CLL the pattern of disease transmission in the pedigrees appears compatible with a model of inheritance where dominantly acting mutations confer a substantive risk of CLL. Familial risks of chronic lymphocytic leukemiaOver the last 34 years, eight epidemiological casecontrol and cohort studies have systematically enumerated the risk of relatives of CLL patients developing CLL or other LPDs. 4,[6][7][8][9][10] Collectively these data provide evidence for a 2 to 8-fold elevated risk of CLL in case relatives.In this issue of the journal, Goldin et al. have published the most comprehensive study of the risk of CLL and other LPDs in first-degree relatives of CLL cases to date.11 This study was based on an analysis of 9,717 CLL cases and 38,159 controls ascertained through the Swedish Cancer Registry. Findings underscored CLL being characterized by a high familial relative risk (RR) -the RR of CLL in first-degree relatives of cases in this study was seen to be increased 8.5-fold. Furthermore, the risk of other non-Hodgkin's lymphoma was observed to be increased 1.9-fold. Evaluating NHL subtypes revealed a striking excess of indolent B-cell NHL, specifically lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and hairy cell leukemia. These findings substantiate a relationship between the risk of CLL and other LPDs which has previously been anecdotally noted in case reports of single families and that may reflect the pleiotropic effects of an inherited predisposition.The general incidence rates for CLL are nearly twice as high in men as in women. With familial CLL, however, the proportion of affected females is higher when The molecular basis of familial chronic lymphocytic leukemiaDalemari Crowther-Swanepoel, and Richard S. Houlston Section ...

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“…This testing is performed on a clinical basis whenever possible. Germ line analysis is also imperative for: (1) biallelic CEBPA, as 7% to 11% of these individuals possess germ line CEBPA mutations 55,56 ; (2) a deleterious GATA2 mutation, especially in children/adolescents with MDS, as germ line GATA2 mutations are present in 7% of these cases overall and up to 72% of patients with monosomy 7 (many of these will be de novo germ line mutations with no family history or clinical features [ Families clustering mixed myeloid and lymphoid malignancies or lymphoid malignancies alone are more challenging, as the genes responsible for the majority of these families are largely unknown, although a pathogenic germ line variant of the KDR gene is associated with familial Hodgkin lymphoma. 61 We consider clinical testing for these families on a case-by-case basis based on specific HMMS patterns.…”

Section: Case 1 (Continued)mentioning

confidence: 99%

“…1 These physicians often described phenotypic features that are now known to be associated with specific genetically defined hereditary myeloid malignancy syndromes (HMMSs). 2 Why, then, is the diagnosis of HMMS only now starting to be considered in the evaluation of the average adult patient with MDS/AL?…”

Section: Introductionmentioning

confidence: 99%

How I diagnose and manage individuals at risk for inherited myeloid malignancies

Churpek

Godley

2016

Blood

157

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Although inherited hematopoietic malignancies have been reported clinically since the early twentieth century, the molecular basis for these diseases has only recently begun to be elucidated. Growing utilization of next-generation sequencing technologies has facilitated the rapid discovery of an increasing number of recognizable heritable hematopoietic malignancy syndromes while also deepening the field’s understanding of the molecular mechanisms that underlie these syndromes. Because individuals with inherited hematopoietic malignancies continue to be underdiagnosed and are increasingly likely to be encountered in clinical practice, clinicians need to have a high index of suspicion and be aware of the described syndromes. Here, we present the methods we use to identify, test, and manage individuals and families suspected of having a hereditary myeloid malignancy syndrome. Finally, we address the areas of ongoing research in the field and encourage clinicians and researchers to contribute and collaborate.

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Familial Leukaemia: A Study of 909 Families

Cited by 98 publications

References 27 publications

Genetic predispositions to childhood leukemia

Genetic predispositions to childhood leukemia

The molecular basis of familial chronic lymphocytic leukemia

How I diagnose and manage individuals at risk for inherited myeloid malignancies

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