Anticipation in familial chronic lymphocytic leukaemia

Abstract

Summary. Anticipation, a phenomenon in which an inherited disease is diagnosed at an earlier age in each successive generation of a family, has been demonstrated in certain heritable neurological disorders and in multiple myeloma, non-Hodgkin's lymphoma and other haematological neoplasms. The present study was conducted to determine whether anticipation occurs in familial chronic lymphocytic leukaemia (CLL). Fourteen published reports of multigenerational familial CLL were analysed for anticipation, together with 10 previously unreported families with familial CLL, and the difference in disease-free survival between generations was determined. The difference between age at onset for each affected parent±child pair was tested against the null hypothesis that there was no difference in age at onset. The age at onset of the studied cases was also compared with that of the Surveillance Epidemiology and End Results (SEER) Program of the U.S. National Cancer Institute. The median ages at onset in the child and parent generations of all families (51´0 and 72´0 years respectively) were significantly different (P , 0´000001), and the null hypothesis was rejected (P , 0´000001). A significant difference was observed between the ages of onset of the child generation and the SEER population (P , 0´00001), but not between the parent generation and the SEER population. Anticipation characterizes familial CLL.

No Evidence for Anticipation in Lymphoproliferative Tumors in Population-Based Samples

“…Our findings contradict several published articles that reported anticipation in familial non -Hodgkin's lymphoma (18), CLL (3,17,19,20), and Hodgkin's lymphoma (16). However, most of these findings relied on data from multiplex families that had been ascertained for genetic studies.…”

“…Although some studies have reported anticipation among familial lymphoproliferative cancers (3,(16)(17)(18)(19)(20), our preliminary results on CLL from the Swedish Family Cancer Database, a population-based sample, did not support these findings (21). Thus, we have conducted a more detailed study of anticipation in lymphoproliferative tumors including nonHodgkin's lymphoma, Hodgkin's lymphoma, CLL, and multiple myeloma using registry data from Sweden and Denmark.…”

Genetic alteration associated with chronic lymphocytic leukemia

“…Analysis of family pedigrees with B-CLL showed a significant reduction in the age of onset, approximately 20 years between generations (Horwitz et al, 1996;Yuille et al, 1998;Goldin et al, 1999;Wiernik et al, 2001) with evidence of more severe disease in successive generations (Goldin et al, 1999;Yuille et al, 2000). These descriptions of anticipation were not a new phenomenon and had previously been reported in other familial cancer syndromes (Horwitz et al, 1996;Fraser, 1997;De Lord et al, 1998;Deshpande et al, 1998;Wiernik et al, 2000), but the scientific basis was unclear.…”

“…A number of studies suggested that families with B-CLL display the phenomenon of anticipation (Horwitz et al, 1996;Horwitz, 1997;Yuille et al, 1998Yuille et al, , 2000Goldin et al, 1999;Wiernik et al, 2001), an increase in severity or earlier age of onset of a disease occurring with each subsequent generation, in an autosomal dominant manner (Sutherland and Richards, 1995). Analysis of family pedigrees with B-CLL showed a significant reduction in the age of onset, approximately 20 years between generations (Horwitz et al, 1996;Yuille et al, 1998;Goldin et al, 1999;Wiernik et al, 2001) with evidence of more severe disease in successive generations (Goldin et al, 1999;Yuille et al, 2000).…”

Anticipation in Families with Chronic Lymphocytic Leukemia and Other Lymphoproliferative Disorders

“…[2][3][4][5][6][7][8][9] However, anticipation could not be verified by means of life-table methods and marginal survival methods in a population-based sample from Sweden, neither in CLL nor in other types of LPD. 10,11 Anticipation is part of the pathogenesis of about twenty degenerative neurological disorders such as Huntington's disease, familial Parkinson's disease and the fragile X syndrome, where anticipation is caused by intergenerational increase of unstable nucleotide repeats in the disease-related genes, viz.…”