Genetic Basis of Familial Lymphoma Predisposition
Year: 2013
Type: dissertation
Study design: Observational Study
Abstract: Lymphomas are classified into Hodgkin and non-Hodgkin lymphomas (HL and NHL), and they are further categorized into tens of different subtypes. This thesis has focused on two rare lymphoma subtypes: nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and primary mediastinal large B-cell lymphoma (PMBCL). Although the majority of lymphomas are sporadic, a familial component has been observed in both HL and NHL. The aim of this thesis was to study the genetic background of familial NLPHL and PMBCL predisposition. HL is classified into NLPHL and classical Hodgkin lymphoma (cHL). Germline mutations of the KLHDC8B gene have been observed in some families with cHL. In this study, the KLHDC8B gene was analyzed in four families with NLPHL, but mutations were not detected. The results suggest that germline mutations of KLHDC8B do not underlie familial NLPHL susceptibility. To clarify the genetic basis of NLPHL predisposition, a Finnish family with NLPHL susceptibility was studied with new genome-wide methods, SNP microarray and exome sequencing. Data from these two efforts were integrated, and a germline deletion of two nucleotides (c.2437-2438delAG) was observed in the NPAT gene. Subsequently, NPAT was screened in a number of familial and sporadic HL cases, and an in-frame deletion of one serine residue was found to be more frequent in the cases versus healthy controls (odds ratio 4.11, p = 0.018). Thus, NPAT was identified as a candidate gene for NLPHL predisposition. The familial risk in NLPHL was studied by using the Finnish Cancer Registry (FCR) and the Finnish Population Registries. Altogether 693 patients with NLPHL were identified, and a family member cohort comprising of the first-degree relatives of 692 patients was collected. Cancer data for the relatives was derived from the FCR. We calculated the standardized incidence ratios (SIRs) for all cancers, NHL, cHL and NLPHL in the family member cohort. In addition, the primary tumor samples from 20 first-degree relatives with HL diagnosis were histopathologically reviewed. In the family member cohort, the SIR for NLPHL was 19. Thus, a high familial risk in NLPHL was observed, suggesting that familial factors contribute to NLPHL susceptibility. An increased relative risk for NHL and cHL was also observed. We studied a family of three siblings with PMBCL and a cousin affected by diffuse large B-cell lymphoma (DLBCL). Re-examination of tumor samples revealed that all four tumors resembled each other histopathologically, proposing a common background. Genome-wide SNP array, linkage analysis and exome sequencing were performed to identify the genetic factor underlying PMBCL/DLBCL in this family. A missense change c.5533C>A (His1845Asn) was detected in the MLL gene and was the only non-database variation residing in linked regions and segregating in lymphoma affected family members. To our knowledge, this is the first description of familial clustering of PMBCL. Our findings suggest that sometimes PMBCL may arise in the context of familial predisposition, and MLL was identified as a candidate gene for PMBCL susceptibility. However, our observations are preliminary, and need to be confirmed in future studies.
Source: Työväentutkimus Vuosikirja
Author: Silva Saarinen
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1562671506