title: Inherited genetic susceptibility to multiple myeloma and related diseases creator: Chattopadhyay, Subhayan subject: 610 subject: 610 Medical sciences Medicine description: Monoclonal gammopathy of undetermined significance is the most common plasma cell dyscrasia present in as high as 3.2% of general population below 50 years of age and up to 6.6% for population aged 80 years or older. It is a premalignant precursor of multiple myeloma, a malignant hematological neoplasia. People with monoclonal gammopathy go on to develop myeloma at a yearly rate of 0.5 - 1%. With a crude rate of incidence of 6.5 per 100,000 people, Europe is set to observe around 48,000 new multiple myeloma diagnosis in 2018. Overall prognosis of myeloma has not been very favorable throughout history nonetheless survival of myeloma patients is improving incrementally over the past few decades due to better management and improved treatment modality. This increased survival led to an increased number of second primary cancer diagnosis. Environmental factors, chemotherapy and radiotherapy induced DNA damage, wide-spread use of alkylating agents and possible induction of immunosuppressed state has been speculated to contribute to this. The fact that both the two diseases show familial clustering and all myeloma diagnoses are preceded by monoclonal gammopathy indicates that there is a certain amount of inherited susceptibility to these diseases. In the current study, the quantity under investigation is inherited genetic susceptibility to monoclonal gammopathy and multiple myeloma as well as the familial risk of second cancers. Three sets were queried for monoclonal gammopathy consisting genotype data on 243, 82 and 326 German individuals respectively identified during routine follow-up of unrelated condition. These three sets were used to carry out separate case-control and case-only discovery, validation and replication studies. For myeloma, patients were recruited from two separate trials in Germany and UK. The German trial consisted of 1717 myeloma patients where as the one in UK recruited 2282 patients. Controls for the investigations were obtained from Heinz-Nixdorf Recall study samples and Welcome Trust Case-Control Consortium samples. For expression quantitative trait analysis, gene expression data was obtained from plasma cell samples of 665 patients enrolled in the German trial. Written consents were obtained from the trial subjects and approval for the studies was procured from respective ethics review board. For the observational study of second cancers, the Swedish Family Cancer Database was used which includes data on all cancer diagnosis in Sweden starting 1958. This database was queried for information on about 2.1 million Swedish residents with cancers matched with their biological parents (when available). Inherited genetic susceptibility to multiple myeloma and related diseases 141 The interaction analyses with genotype data identified a number of paired susceptibility loci for monoclonal gammopathy and myeloma. These loci were found to have key roles in myeloma biology via processes such as and not restricted to Ig trait modulation, osteoclast genesis, Th cell development, interleukin secretion, bone marrow microenvironment mediation in creating myeloma niche. While subjected to enrichment analyses major biological pathways were discovered including EGFR downregulation and B cell receptor signaling pathway for monoclonal gammopathy and Circadian rhythm mediation and SMAD dependent TGFβ activation pathways in myeloma. As some of the pathways and loci were shown shared between monoclonal gammopathy and myeloma, the findings allude to shared inherited susceptibility to the two disorders. Interrogating risk of second cancer in myeloma patients stratified by history of cancer among first degree relatives, numerous cancers were noted to have excess familial risk and overall close to a 1.4-fold increased risk of second cancer was noted among people with an existing family history. Concordant family history of leukemia, lung, squamous cell skin cancer and melanoma increased risk of second cancers at the same site in myeloma patients by more than 5 folds compared to the patients without; whereas that for colorectal cancer is little over than 2-fold and for prostate cancer is 1.6-fold. Although family history was found to have a strong effect on incidence of second cancers no such effect was found in mortality pattern. No linear or multiplicative interaction was found in risks among personal, family history with history of myeloma. All the results indicate there are certain underlying mechanistic principle relating monoclonal gammopathy to myeloma which is regulated by inherited polygenic predisposition to monoclonal gammopathy and myeloma. This study speculates about possible pathways and networks that are influenced in these diseases but conformational studies need to be carried out before any definitive conclusion can be drawn. However, in context of second cancers in myeloma patients, family history of cancer was conclusively shown to have morbid impact on incidence but lack of any such impact on patient survival was also observed which mean efforts in managing second cancer diagnosis by screening with family history information will have positive impact on survival in multiple myeloma. date: 2019 type: Dissertation type: info:eu-repo/semantics/doctoralThesis type: NonPeerReviewed format: application/pdf identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/26948/1/Thesis_Final_SC.pdf identifier: DOI:10.11588/heidok.00026948 identifier: urn:nbn:de:bsz:16-heidok-269486 identifier: Chattopadhyay, Subhayan (2019) Inherited genetic susceptibility to multiple myeloma and related diseases. [Dissertation] relation: https://archiv.ub.uni-heidelberg.de/volltextserver/26948/ rights: info:eu-repo/semantics/openAccess rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html language: eng