Evidence for a common genetic aetiology in high‐risk families with multiple haematological malignancy subtypes

Abstract

SummaryA family history of a haematological malignancy (HM) is known to be a risk factor for HMs. However, collections of large families with multiple cases of varied disease types are relatively rare. We describe a collection of 12 families with dense aggregations of multiple HM subtypes. Cases were ascertained from a population based study conducted between 1972 and 1980 in Tasmania, Australia. Diagnoses were confirmed through review and re-examination of stored tissue, pathology reports, Tasmanian Cancer Registry and flow cytometry records. Family trees were generated and kinship coefficients were calculated for all pairs of affected individuals. 120 cases were found in these families. Cases diagnosed with chronic lymphocytic leukaemia (CLL) demonstrated the most significantly increased aggregation (P < 0AE0001). There was also significant evidence that those individuals diagnosed at an older age (>53 years), did not aggregate together in families with disease that presented at an earlier age (<20 years) (P = 0AE009).

High risks of familial chronic lymphatic leukemia for specific relatives: signposts for genetic discovery?

“…6 However, we lacked information on risk factors (for example, environmental exposures) and on clinical details such as biological markers. The striking familial aggregation we observed for CLL is consistent with an inherited genetic effect that has been proposed for some time, 2 with evidence accumulated from family studies 7,8 and linkage studies. 9 Recent association studies have identified common variants associated with susceptibility to CLL, [10][11][12][13] but these may only account for a small proportion of the genetic risk.…”

“…One miRNA in particular, miR-34a, emerged as a potent tumor-suppressor miRNA with the potential to inhibit the proliferation of various DLBCL cell lines. 6 The tumor-suppressive activity of miR-34a could be attributed to the specific knockdown of FoxP1, a transcription factor and known target of miR-34a, 6,7 whose overexpression is associated with inferior prognosis in DLBCL patients. 8…”

A retrospective examination of mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study

“…As previously described ( 29 ) during the period 1972–1980 all patients with HMs diagnosed in Tasmania (the island state of Australia) were invited to participate in a population-based study examining the association of occupation and place of residence with risk of development of myeloproliferative and lymphoproliferative disorders ( 34 , 35 ). Using a genealogical database at the Menzies Research Institute Tasmania the individuals participating in the original population-based study were linked to both current generations and records from the Tasmanian Cancer Registry, which has documented cases of HMs since 1978.…”

“…The aim of the present study was to explore whether telomere length is involved in familial HMs and to find new evidence supporting telomere length as a prognostic risk factor for HMs. To this end, we examined telomere length in the Tasmanian Familial Hematological Malignancies Study (TFHMS); a genetic study comprising large Tasmanian families with multiple cases of HMs and a collection of population matched non-familial HM cases ( 29 – 31 ) and controls ( 32 , 33 ). Previously, similar collections have focused on families with one predominant subtype of HM.…”

Evaluating a CLL susceptibility variant in ITGB2 in families with multiple subtypes of hematological malignancies

“…Our study does serve to provide a necessary sequel to the study of Goldin et al, as the evaluation of a disease-associated variant in multiple cohorts is required to establish a new genetic cause of disease, as outlined in guidelines produced by MacArthur et al 12 We propose that the current conflicting findings of the rs2230531 in familial HMs, together with the biological role of ITGB2 in blood cells, creates an a priori hypothesis that genetic variation in ITGB2 contributes to HM 4 RNA, 4 and polyphosphate (polyP). 5 Contributions of extracellular nucleic acids to coagulation and inflammation are under intense investigation, with several studies reporting the procoagulant effects of DNA, [6][7][8] particularly in the context of neutrophil extracellular traps (NETs). [9][10][11] In this study, we attempted to compare the clotting activity of polyP versus cellular DNA.…”