Genome Wide Association Studies of Familial Waldenstrom's Macroglobulinemia (WM) Reveals a Loss of GSTM1 Is Common in Families with a History of B-Cell Disorders but Not in Those with a History Specific for WM.
Authors: Hunter Zachary , Hanzis Christina , Ioakimidis Thea , Patterson Christopher J , Ciccarelli Bryan , Lewicki Megan , Manning Robert , Xu Lian , Liu Xia , Tseng Hsiuyi , Gong Ping , Sun Jenny , Zhou Yangsheng , Yang Guang , Sheehy Patricia , Fox Edward A. , Treon Steven 
Published: October 2019

Abstract
Abstract 762

Background:
The existence of a familial form of Waldenstrom's Macroglobulinemia (WM) has previously been described by us and others. Up to 20% of WM patients have a first degree relative with either WM, or a closely related B-cell disorder. The genetic basis for these findings has so far remained elusive.

Patients and Methods:
As part of these efforts, we enrolled 482 WM patients and their first and second degree family members, for a total of 148 families. Families were then classified as follows: Sporadic (Only 1 case of WM present); Familial WM Only (if ≥ 2 cases of WM were present); Familial Mixed B-cell (if only the proband had WM, and other B-cell disorders were present in other family members). Detailed medical as well as familial history for cancer and autoimmune disorders was collected, along with complete blood counts, quantitative immunoglobulins, and serum protein electrophoresis for all participants. Buccal and peripheral blood DNA samples were also collected. Genome wide association studies were run on peripheral blood DNA samples using SNP 6.0 platform from Affymetrix, and analyzed using R (R project for statistical computing) and the Affymetrix Genotyping Console. Data from 99 individuals was available for this analysis.

Results:
Among the 148 families enrolled, 89 (60.1%), 17 (11.5%), and 42 (28.4%) were classified as Sporadic, Familial WM Only, and Familial Mixed B-cell Cohorts. Analysis of the SNP 6.0 data revealed that copy number polymorphism (CNP) 88 was strongly associated with Familial Mixed B-cell presentation. A copy number of 0 for CNP88 was found in 2/5 (40%) probands (WM patients) from the Sporadic Cohort; 1/6 (16.7%) patients from the Familial WM Only Cohort; and 8/9 (88.9%) patients from the Familial Mixed B-cell Cohort (p= 0.011 and 0.09 vs. Sporadic and Familial WM Only Cohorts, respectively). Among proband family members, a copy number of 0 for CNP88 was found in 7/15 (46.7%) individuals from the Sporadic Cohort; 9/26 (34.6%) individuals from the Familial WM Only Cohort; and 34/37 (91.9%) individuals from the Familial Mixed B-cell Cohort (p<0.0001 versus Sporadic and Familial WM Only Cohorts). Very importantly, SNP 6.0 analysis revealed that the genomic region covered by CNP88 only affected the glutathione S-transferase gene GSTM1.

Conclusions:
The results of these studies implicate the homozygous deletion of GSTM1 in the Familial Mixed B-cell presentation for Waldenstrom's Macroglobulinemia. These findings are invariably germain not only to WM predisposition, but also to other closely related B-cell disorders which cluster with Familial WM.

Disclosures:
No relevant conflicts of interest to declare.