The genetics of familial leukemia

Abstract

mechanisms operating in the common, sporadic cases. AnticiKeywords: leukemia; familial; anticipation pation occurs in Huntington disease, myotonic dystrophy, and other inherited neurodegenerative illness where it results from the expansion of unstable trinucleotide repeat sequences. IntroductionSince this remains as the only molecularly defined instrument for anticipation, I weigh the possibility that an analogous situ-A family history of leukemia in a first degree relative increases ation holds for leukemia genes. I also review evidence that the risk for leukemia by approximately three-to five-fold. 1,2anticipation may be present in other types of familial cancer, The magnitude of this risk elevation is equivalent to or even including those in which the gene has been characterized and greater than that exhibited for malignancies well known to does not contain trinucleotide repeat tracts, but is involved have a substantial proportion of cases resulting from autosoin maintaining genome integrity. Here I propose a novel and mal dominant inheritance of a mutant tumor suppressor gene, alternative hypothesis for anticipation in familial cancer based such as breast cancer 3 and colorectal carcinoma. 4 On the on the inheritance of a cascade of de novo mutations in secother hand, familial leukemia is exceptionally rare, and only a ondary tumor suppressor genes resulting from a primary defect few pedigrees obviously transmitting leukemia have ever been in a gene responsible for DNA fidelity. recognized. This paradox and other observations suggest that the fraction of leukemia attributable to heritable factors could be markedly under appreciated. First, acute lymphocytic leuLeukemia as part of a syndrome kemia (ALL) is predominately a disease of childhood. 5 In other childhood malignancy, such as retinoblastoma and Wilm's Several syndromic illnesses have leukemia as a component tumor, a large proportion of cases are the result of germline feature (Table 1) Since M7 AML is relatively rare in the general population, the

Anticipation in familial chronic lymphocytic leukaemia

“…20 An analysis of seven published families reported that age at diagnosis of CLL is lower for affected offspring than for the affected parental generation. 21,22 The decline in age at diagnosis was 21 years (s.e. = 4.1 years) (P = 0.001).…”

CBFA2, frequently rearranged in leukemia, is not responsible for a familial leukemia syndrome

“…Evidence in support of the multistep pathogenesis of AML includes: (1) clonal remission from AML; 43 (2) preleukemic syndromes, such as MDS, which progress to AML with associated acquisition of karyotype abnormalities; 44 and (3) rare families with an inherited predisposition to develop AML. 3,45 By establishing linkage to chromosome 21q22. SSCP analysis of IFNAR1.…”

Role of autophagy in the progression and suppression of leukemias

“…Exposure to ionizing radiation also increases the incidence of AML as observed in the surviving population of Japan after atomic bombing [14]. There are also documented cases in which AML was developed by multiple members of a family exceeding the predictions of random chance events suggesting that there might also be a hereditary basis of the disease [15,16]. In part because of these differences, this malignancy is grouped under four categories according to WHO classification [17]: AML with recurrent genetic abnormalities, AML with multilineage dysplasia, therapy related AML; and myelodysplastic syndrome (MDS), and lastly, AML cases that are not suitable for classification in the previously groups.…”