Combined linkage and association analysis of classical Hodgkin lymphoma

// Alastair Lawrie 1 , Shuo Han 1, 7 , Amit Sud 2 , Fay Hosking 2 , Timothee Cezard 3 , David Turner 4 , Caroline Clark 5 , Graeme I. Murray 1 , Dominic J. Culligan 6 , Richard S. Houlston 2 and Mark A. Vickers 1, 4 1 School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom 2 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK 3 The Genepool, University of Edinburgh, Edinburgh, United Kingdom 4 Scottish National Blood Transfusion Service, Edinburgh, United Kingdom 5 Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, United Kingdom 6 Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, United Kingdom 7 Current address: Clinical Trials Manager, MD Anderson Cancer Centre Investigational Cancer Therapeutics, Houston, TX, USA Correspondence to: Alastair Lawrie, email: a.lawrie@nhs.net Amit Sud, email: amit.sud@icr.ac.uk Keywords: genetics; Hodgkin lymphoma; mutation; cancer; lymphoma Received: July 07, 2017      Accepted: March 01, 2018      Published: April 17, 2018 ABSTRACT The heritability of classical Hodgkin lymphoma (cHL) has yet to be fully deciphered. We report a family with five members diagnosed with nodular sclerosis cHL. Genetic analysis of the family provided evidence of linkage at chromosomes 2q35-37, 3p14-22 and 21q22, with logarithm of odds score >2. We excluded the possibility of common genetic variation influencing cHL risk at regions of linkage, by analysing GWAS data from 2,201 cHL cases and 12,460 controls. Whole exome sequencing of affected family members identified the shared missense mutations p.(Arg76Gln) in FAM107A and p.(Thr220Ala) in SLC26A6 at 3p21 as being predicted to impact on protein function. FAM107A expression was shown to be low or absent in lymphoblastoid cell lines and SLC26A6 expression lower in lymphoblastoid cell lines derived from p.(Thr220Ala) mutation carriers. Expression of FAM107A and SLC26A6 was low or absent in Hodgkin Reed-Sternberg (HRS) cell lines and in HRS cells in Hodgkin lymphoma tissue. No sequence variants were detected in KLHDC8B , a gene previously suggested as a cause of familial cHL linked to 3p21. Our findings provide evidence for candidate gene susceptibility to familial cHL.