Familial Leukaemia: A Study of 909 Families

Abstract

A family survey was conducted among 909 patients with leukaemia of all types, with the purpose of establishing the incidence of further cases of leukaemia among relatives. Among a total of 41,807 relatives 8,349 were deceased, and the cause of death was objectively confirmed in 5,011. 72 patients had one or more relatives with leukaemia. First degree relatives with leukaemia were much more frequent in families of patients with chronic lymphocytic than in those! of patients with chronic granulocytic leukaemia. The incidence of leukaemia among first degree relatives was established to be 2.8-3.0 times, among more distant relatives about 2.3 times, and overall about 2.5 times that expected. This excess is of the order of that observed in relatives of patients with certain solid tumors. Genetic factors may have accounted for much of the excess incidence in chronic lymphocytic and acute leukaemia, but there was little evidence for a genetic background in chronic granulocytic leukaemia. With the possible exception of one family with muitiple cases, a simple Mendelian mechanism did not appear to be involved in the leukaemia families investigated. It appeared more likely that a polygenic mechanism led to a heightened susceptibility to the disease in these families.

Genetic predispositions to childhood leukemia

“…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.…”

The molecular basis of familial chronic lymphocytic leukemia

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

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

“…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.…”

“…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?…”