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Investigating the genetic predisposition for familial haematological malignancies

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Tegg, EM 2011 , 'Investigating the genetic predisposition for familial haematological malignancies', PhD thesis, University of Tasmania.

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Abstract

Haematological malignancies (HMs) include cancer and related disorders of the cells of the blood, bone marrow or lymphatic systems. Currently the most widely used classification system is the World Health Organization classification system of HMs. This classification system classifies HMs into 12 broad categories based upon clinical, morphological, immunophenotypic and genetic characteristics of the tumour cells. Approximately 250 new cases of HMs are diagnosed in Tasmania each year.
Familial aggregation of HMs has been repeatedly described in the literature, but the genetic contributors to this disease in most families remains unknown. The only germline mutation found to date is a DAPK1 mutation which was found in a family with chronic lymphocytic leukaemia (CLL). In this family additional down-regulation of DAPK1 was still needed before CLL developed.
Mature haematological cells originate from a common precursor cell (haematopoietic stem cell (HSC)) that has the capacity to differentiate to any of the mature cell types and to self renew. It has been established that for a cell to become malignant multiple genetic mutations must occur in the same cell. In familial cancer families it is reported that the first hit is the germline mutation that is inherited in these families. A two-hit theory for cancer (Knudsen’s two hit hypothesis) for retinoblastoma was first published in 1971, where in the dominantly inherited form of retinoblastoma one mutation is inherited through the germ-cells and a second mutation occurs in somatic cells; in the non-inherited (sporadic) form both mutations occur in somatic cells. It is now clear that many more than two hits are required for a cancer to develop and this is now referred to as the progressive multi-hit model of gene mutation ; and that initial gene mutations promote genetic instability and therefore promote the occurrence of further abnormalities. This theory also encompasses that the same gene can be involved in a familial cancer as well as in a sporadic form of the disease.
Acquired cytogenetic abnormalities characteristically feature in many types of HMs. These abnormalities can be classified as numerical or structural chromosomal abnormalities. Of the numerical abnormalities, there is a specific pattern as to which chromosomes are lost or gained regardless of the type of HM. Also, for the structural abnormalities that occur, certain genes are frequently involved regardless of the type of HM. It should be noted that people born with constitutional disorders of these genes or chromosomes that are commonly mutated in HMs are also at an increased risk of developing a HM. The classic example is trisomy 21; people born with this have a substantially increased risk of developing leukaemia and trisomy 21 is commonly found in HMs.
A known predisposing factor for the development of a HM is a family history of a HM, suggesting a genetic risk for these types of disorders. There are many reports of familial HMs, particularly for one subtype of HM, chronic lymphocytic leukaemia (CLL). The relative risk for relatives of people with CLL has been reported to be 7.52, and 1.45 for non-Hodgkin lymphoma (NHL) and 2.35 for Hodgkin lymphoma (HL). An interesting aspect of CLL is that it is the most common leukaemia in western countries but rarely seen in Asian countries(35), and if a person of Asian ethnicity moves to a western country they keep their low risk.This supports a genetic rather than an environmental risk with exposure of all family members to the same environmental risk factors. There is also a reported increased risk (double) for identical twins if one twin develops a HM by the age of 15. This strongly supports a role for genetic factors this disease.
It is hypothesized that in these HM families there is a predisposition allele and if additional acquired mutations occur then a HM develops. The type of HM depends upon which cell receives a second, third or fourth hit.

Item Type: Thesis - PhD
Authors/Creators:Tegg, EM
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Copyright © 2011 the author

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