The scope of the lab includes 1) discovery/characterization of mechanisms of inherited cancer predisposition, 2) genetic epidemiologic, computational as well as functional genomic approaches to germline cancer susceptibility, and 3) translation of germline cancer genetics to the clinic.
1) Studies of the genetics of cancer predisposition utilize population-based statistical approaches, e.g. SMAHD1 identification in 37K prostate cases (Mitchell Nat Comm 2025), NBN1 and pan cancer risk in >20K cases (Belhadj CCR 2023), KEAP1 in hereditary renal cancer (Carlo, unpublished), ATM and BRCA2 in lung cancer (via R01 CA263320 01A1 and Mukherjee CCR 2020, CEBP 2022 and 2026 submitted); and lymphoma and myeloma subtypes (Joseph, Leukemia 2022, 2026 submitted). A current focus is on utilization of imputed common variants from off-target reads (>100K MSK IMPACT) to study correlations with somatic rare variants (Carrot Zhang) and multiple primary cancers (Marderstein, Joseph, Amsalem, Mukherjee).
2) Functional characterization of driver and modifier pathways identified by germline/somatic analysis, including nucleotide excision repair (NER) pathway mutations, seen in ~ 12% of MSK IMPACT patients (Cancer Disc 2016; Clin Cancer Res 2020). Via an NIH STTR (1 R41 CA275627-01) with colleagues, we analyzed candidate synthetic lethal genes identified in a NER-D CRISPR screen and characterized small molecules by synthetic lethal hits in NER-D cells. We have identified a top candidate, with colony assays validating synthetic lethality with ERCC2, ERCC3, ERCC4 and ERCC5. Separately, based on a clinical trial offering polygenic risk scores (PRS) to men and women with BRCA mutations (R01 HG011914 01A1), an ongoing project is focusing on mechanisms of modification of BRCA risk in breast and prostate cancer. We are studying disruption of the STARD13, a putative BRCA breast risk modifier from GWAS studies, and LATS2 phenotypes in breast epithelial cells, and utilizing organoids from these patients seeking to functionally characterize SNPs of interest. Using Functional Potential Scores (FPS), assembled from disease-relevant annotations of chromatin accessibility, histone marks, and transcriptional factor (TF) binding, we identified loci with a lead SNP or strongly correlated variant (r2>0.80), typically mapping to a predicted enhancer region. Thus far, three of the four candidate enhancer fragments tested exhibit enhancer activity in at least two prostate-derived cell lines: 10q25 (near TCCF7L2), 11q13 and 19p13. SNP genotyping of the human organoids is in progress. Dr. Matt Buas group is identifying candidate risk genes for Barretts esophagus and pathways via eQTL colocalization and network-based analysis, identifying target genes of risk enhancers via CRISPR-mediated enhancer deletion and RNA-Seq, (R01 DK128615 R01 CA266386 to Buas).
3) Clinical translation. Via P01 CA228696 01A1 we designed a bespoke panel for targeted sequencing of homologous repair (HR) pathways in >2,000 high-risk localized prostate cancer from MSK and Harvard; BRCA2 variant carriers did not demonstrate worse metastasis-free survival compared to non-carriers of HR variants (Stopsack, CCR, 2025), expanding on our earlier work (NEJM, 2016). We are now analyzing polygenic modifiers of BRCA2 and employing Mendelian randomization (Joseph). A urology trainee in the lab will be exploring genomic features of extreme early onset prostate cancer.
As a lab-based programs in MSK’s Population Sciences Research Program, work of our group was featured in the recent successful CCSG renewal. Publications supported by the Niehaus Center for Inherited Cancer Genomics are listed at https://www.mskcc.org/research-programs/robert-and-kate-niehaus-center-inherited-cancer-genomics/selected-publications