Abstract 2063: SAMD9/SAMD9L mutations in familial monosomy 7

The purpose of this study was to define the mutations causing familial monosomy 7 with myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). We have previously reported frequent germline mutations in the genes SAMD9 and SAMD9L in pediatric MDS. We obtained samples on 32 individuals in 7 families with multiple siblings affected with MDS/AML and monosomy 7. We conducted targeted sequencing of genes frequently mutated in MDS/AML and amplicon sequencing of SAMD9 and SAMD9L. We performed cell cycle analysis assays on SAMD9/9L mutations to study their effects on cell proliferation. Our data show that 5 of the 7 families have germline pathologic mutations in SAMD9 (n=1) and SAMD9L (n=4), with significant clinical variability in the phenotypes displayed, ranging from transient monosomy 7 to overt AML with monosomy 7. Consistent with previous data, the mutant SAMD9 or SAMD9L allele was underrepresented in the bone marrow. This decrease in the mutant allele paralleled the extent of monosomy 7, suggesting that only the wild-type allele was retained in cells with monosomy 7. Functional analysis revealed that all germline SAMD9/9L mutations displayed a gain-of-function ability to suppress cell cycle progression. The patients with more aggressive disease were found to harbor somatic mutations in SETBP1, ETV6 or RUNX1. In many individuals we found additional somatic revertant mutations in cis with the germline mutation, which overcame the growth-suppressive effects of the germline mutation. Our data show that germline mutations in SAMD9/9L represent a new class of predisposition genes for familial monosomy 7 with MDS/AML and should be screened for in all children with MDS. Citation Format: Victoria Bryant, Jasmine Wong, Jason Schwartz, Tamara Lamprecht, Jing Ma, Charles Mullighan, Mignon Loh, Kevin Shannon, Jeffery Klco. SAMD9/SAMD9L mutations in familial monosomy 7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2063.