Identifying Germline Mutations In Young Patients with MDS
This study will be the first to examine the frequency of germline mutations in MDS patients 40 years old or younger, generating data on new alleles that are likely to disrupt bone marrow function and normal blood cell development. This work will also define a group of patients in this cohort with no recognizable mutations by MarrowSeq screening, who will serve as subjects for future non-biased sequencing studies (examining the entire exome) to discover new genes implicated in familial hematopoietic malignancies. Other studies using the MarrowSeq panel are also possible, including examining patients with refractory idiopathic thrombocytopenic purpura, a fraction of whom is likely to also have a genetic basis for their disease.
Overall Project Goal
Several syndromes conferring a predisposition to hematopoietic malignancies are currently known, including familial platelet disorder with predisposition to myeloid malignancies/germline RUNX1 mutations; as well as germline mutations in GATA2, CEBPA, ANKRD26, SRP72, PAX5, MLL, SH2B3 1-3, Li-Fraumeni syndrome/germline TP53 mutations 4; and inherited bone marrow failure syndromes, including those with autosomal dominant transmission, such as dyskeratosis congenita and Diamond Blackfan anemia 1. Although some of these syndromes have been known for many years, many have just recently been defined. New DNA sequencing technologies have facilitated the development of gene panels that allow the sequencing of many candidate genes simultaneously as well as the identification of novel predisposition alleles.
Although familial hematopoietic malignancies are traditionally considered quite rare, there is an increasing sense within the hematology community that these cancers are more common than previously appreciated. A hallmark of cancer driven by a germline mutation is the diagnosis of cancer in an individual younger than a typical age. I hypothesize that some young patients with myelodysplastic syndrome, a cancer usually diagnosed in the elderly population, have a germline mutation that drives the development of their malignancy. I propose to determine the frequency of germline variants in candidate genes in a cohort of patients with myelodysplastic syndromes, who are 40 years old or younger at the time of diagnosis.
This project will be a joint effort between the University of Chicago and the University of Calgary and funding will be split between the two principle investigators.
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