Anticipation in families with Hodgkin's and non-Hodgkin's lymphoma in their pedigree

Abstract

Anticipation is an earlier onset and/or increasing severity in successive generations. This study was conducted to determine whether anticipation occurs in families that exhibit both Hodgkin's (HD) and non-Hodgkin's (NHL) lymphoma in their pedigrees. Nine published reports of multi-generational lymphoma and 33 previously unreported families with both lymphomas were analysed for evidence of anticipation. The difference between age at onset for each affected related pair was tested against the null hypothesis that there is no difference in age at onset. Differences between disease-free survival in affected generations were determined. These analyses were also conducted separately using only parent -child pairs with an age of onset above 25 years in an effort to avoid ascertainment bias. Age at onset in studied cases was also compared with the HD and NHL series from the Surveillance Epidemiology and End Results (SEER) Program of the US National Cancer Institute. The mean age at onset in the child and parent generations of all case families (60.2 and 35.7 years, respectively) and in the selected pairs (61.5 and 45.6, years) were significantly different (mean difference 724.5 years; P 5 0.00001, and 715.9 years, P 5 0.00001, respectively). Mean anticipation for parents with HD and children with NHL was 76.8 years (P ¼ 0.01) for the unpublished and 714.4 years (P ¼ 0.002) for the published families (overall anticipation 710.1 years). Mean anticipation for parents with NHL and children with HD was 734.4 years (P 5 0.0001) for the unpublished and 732.7 years (P 5 0.0001) for the published families (overall anticipation 734.2 years, P 5 0.0001). The signed rank test rejected the null hypothesis which stated that there was no difference in age at onset between parents and children for overall, as well as selected pairs (P 5 0.00001). The null hypothesis was also rejected for both the parents with HD/children with NHL group and the parents with NHL/children with HD group pairs (P 5 0.0001). Age at onset distributions were significantly different for all generations with HD or NHL when compared to the SEER population (P 5 0.00001), except for the parents with NHL, which showed no difference. In addition, this study reports four previously unpublished families with three generations of lymphoma in their pedigrees. These data suggest that anticipation occurs in families that exhibit both HL and NHL and that both neoplasms may have a common genetic basis.

Anticipation in multiple-case lymphoid cancer families after controlling for ascertainment biases

“…Most types of familial lymphoid malignancies occurred, on average, at a substantially younger age than sporadic cases, even after controlling for age incidence patterns, sex, and subtype. The younger onset of familial cases is consistent with other studies [4,5,[8][9][10]. We also observed anticipation across 3 or more generations of lymphoid cancer families for NHL, DLBCL, LPL/WM, CLL and HL cases.…”

“…Anticipation is an inheritance pattern where disease severity increases and/or age of onset decreases in successive generations. It has been documented in neurodegenerative disorders [1,2], autoimmune diseases [2], and several cancers, including familial leukemias and lymphomas [2][3][4][5][6][7][8][9][10]. In neurodegenerative disorders such as Huntington's disease, genetic anticipation is due to the expansion of trinucleotide repeat sequences [1]; in cancer, the molecular mechanism remains unknown.…”

Family history of cancer and risk of pediatric and adolescent Hodgkin lymphoma: A Children's Oncology Group study

“…8,15,[28][29][30] In other families, multiple generations are affected with LN, 15,30,31 implying the transmission of highly penetrant, possibly dominant, pleiotropic genetic traits. In a subset of families, there is evidence for genetic anticipation, where the age of diagnosis in subsequent generations is successively lower, 19,32 indicative of a non-Mendelian mechanism. In this study, there were few siblings affected with cancer and none affected with HL; thus, most of the observed LN aggregation was attributable to affected case parents (Supporting Information Table S5).…”

Hodgkin Lymphoma: An Update on its Biology with New Insights into Classification

“…Anticipation (i.e. earlier onset and/or increasing severity in successive generations) occurs in families that exhibit both HL and NHL and it has been suggested that both neoplasms may have a common genetic basis 152. The relative risk of the development of HL increases approximately 100-fold in monozygous twins 153, 154 and seven-fold in siblings of patients less than 45 years of age 155.…”