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Digital archive of theses discussed at the University of Pisa


Thesis etd-12022019-124629

Thesis type
Tesi di dottorato di ricerca
Thesis title
Identification of germline variants in risk and survival of multiple myeloma
Academic discipline
Course of study
tutor Prof. Campa, Daniele
tutor Dott. Canzian, Federico
  • multiple myeloma
  • outcome
  • risk
  • SNPs
Graduation session start date
Release date
Multiple myeloma (MM) is a plasma cell malignancy, originating from the bone marrow. Over the past decades, remarkable progress has been made in the understanding of the biology and pathogenesis of MM which, in turn, led to significant improvements in the disease treatment and patients survival, but most of the patients eventually relapse, making MM still an incurable disease.
A small number of environmental and lifestyle-related risk factors for MM have been identified. Familial aggregation of MM and its precursor monoclonal gammopathy of undetermined significance (MGUS) suggest that genetic factors play a role in risk of MM as well. Several genetic loci affecting MM risk have been identified so far with both a candidate gene approach and genome-wide analysis, even if they are still considered few comparing with other better studied and more common cancer types. The genetics behind the differences in prognosis of MM patients is still poorly known and only two genome-wide association studies (GWAS) have been attempted so far.
The main goal of this project was to discover new variants and new key genes that affect risk and outcome of MM. To achieve it, we performed several association studies in a case-control population, carried out with a candidate gene approach.
The association studies were performed in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium and for some studies a replication population was used. In particular, we used data from the InterLymph consortium, the German myeloma group and controls from the ESTHER consortium, for a total of over 3000 cases and 2000 controls. In particular, we investigated: SNPs in genes involved in the DNA repair mechanisms and their relation with both risk and survival of MM patients, expression quantitative traits loci (eQTLs) of genes whose expression is known to affect MM prognosis, SNPs in genes involved in the xenobiotic metabolisms, SNPs known to affect MM risk in association with MM survival. Additionally, we considered genetic variants not only individually but also combined in scores, and explored their performance in predicting risk and outcome of MM.
Regarding MM risk we found a new association with SNPs within genes involved in DNA repair system. We also successfully replicated the 23 risk loci emerged from GWASs that were also significantly associated with MM risk when combined in a polygenic score. In particular carriers of more than 20 risk alleles showed an increased risk of MM of almost 3 fold (OR=2.99, 95% C.I.=2.14-4.18, p=1.58×10-10).
Regarding MM survival with our approaches we found 14 new SNP associations, which were obtained using overall survival as endpoint. Combining those SNPs in a score showed promising results, indeed, we found that carriers of more than 15 “survival alleles” had shorter survival compared with carriers of less than 10 alleles (HR=1.80, 95% C.I=1.27-2.54, p=0.001).
In conclusion, our results contribute to expand the knowledge of the genetic architecture of MM. This will lead to the development of useful tools to facilitate early diagnosis by screening the general population based on their genetic risk, and to stratify patients based on their response to therapy and outcome.