ABSTRACT Acute lymphoblastic leukemia (ALL) is a precursor cell neoplasm and the commonest childhood cancer, and Hodgkin and non-Hodgkin lymphoma (HL) are forms of lymphoma that arise in both children and adults. Both are multi-genic diseases characterized by multiple subtypes and distinct constellations of somatic genetic changes. There is growing evidence for a genetic predisposition to both diseases, demonstrated by genome- wide association studies that have identified associations between common variants in transcription factors and tumor suppressors and ALL risk, subtype and outcome, and the identification of highly penetrant mutations in transcription factor and tumor suppressor genes in familial ALL. However, the landscape of germline predisposition variants that drive familial and sporadic hematological malignancies (HM) are unknown. In this study we will address this knowledge gap by performing whole genome sequencing of kindreds with familial, coupled with recurrence screening of extended cohorts of ALL and HL and integration of germline and somatic data. We have collected over 60 familial HM kindreds that will be subjected to tumor and germline whole genome sequencing (WGS) supported by this grant mechanism (Specific Aim 1). We will examine the frequency of novel variants, and mutations in newly identified genes, in large cohorts of sporadic ALL/HL (Specific Aim 2, funded separately) and examine associations between germline mutations in familial and sporadic ALL and clinical, pathologic and somatic genomic features (Specific Aim 3, funded separately). The project will be conducted by a group of co-investigators at St Jude Children’s Research Hospital with complementary expertise in clinical genetics (Nichols, Kesserwan), germline predisposition (Yang, Mullighan), clinical aspects of ALL and HL (Sandlund, Metzger) and computational approaches (Rampersaud). We have established collaborations with the COG and assembled the recurrence testing cohorts. Many of the familial tumor and germline samples are in hand, with acquisition of relative material ongoing to submit samples for sequencing by study activation. Together, this represents a logical framework to comprehensively dissect the interaction of germline and somatic genetic alterations in HM, and will provide important mechanistic insights, opportunity for clinical translation, and an invaluable public resource of genomic data.