Biomedical subjects

Eliezer M Van Allen

Publications and source records attributed to Eliezer M Van Allen.

5 recordsLinked to original sources

PubMed2026

Distinct endogenous retroviruses are expressed in mutational subtypes of clear cell renal cell carcinoma and are linked to improved clinical outcomes.

Distinct mutations in chromatin regulators and aberrant expression of transposable elements (TEs), have been associated with clinical benefit to immunotherapy (IO) in specific clear cell renal cell carcinoma (ccRCC) clinical contexts. However, the relationship between mutations in chromatin regulators and TE expression, and their effect on clinical outcomes, are incompletely understood. Here, we identified TEs expressed in distinct mutational subtypes of ccRCC, with endogenous retroviruses (ERVs) comprising the majority of TEs observed. Of these, ERVs 544 and 2014 were upregulated in PBRM1 mutant samples. Patients with high expression of these ERVs and somatic PBRM1 mutations had improved progression-free survival with IO monotherapy, but not targeted therapy, and their upregulation associated with expression of innate immune pathways. Chromatin accessibility increased at ERV 544 and 2014 loci in PBRM1-deficient ccRCC cells, and ERV 544 and 2014 were upregulated upon in vitro PBRM1 knockout in ccRCC cell line clones. Broadly, our study supports a link between PBRM1 mutations, subsequent chromatin accessibility changes, and aberrant but immunoresponsive ERVs in ccRCC.

CP: cancer↗

PubMed2026

Germline determinants of risk and molecular subtype in young-onset lung cancer.

Young-onset lung cancer is enriched for never-smoking and oncogene-driven tumors, yet its inherited genetic basis remains poorly defined. We performed germline whole-genome sequencing in 251 young-onset lung cancer cases (median age 37), which we jointly analyzed with never-smoking cases (n=196; median age 68) and cancer-free controls (n=1,883). We identified enrichments of rare deleterious coding variants across 55 cancer-related gene sets, including EGFR/ERBB2 signaling and genes implicated by prior lung cancer GWAS. Exome-wide analyses of rare coding variants affirmed TP53 as a penetrant lung cancer predisposition gene (odds ratio [OR]=36.1, p=1.02x10-7) and discovered two novel exome-wide significant tumor subtype-dependent associations: IREB2 in cases with fusion-driven tumors (p=1.39x10-6) and SMAD6 in fusion-negative tumors (p=2.05x10-6). Structural variants contributed distinct risk, with enrichment in constrained, lung-expressed genes (OR=5.79, p=5.8x10-5) and very large germline deletions being markedly enriched in cases with fusion-driven tumors. Polygenic risk scores for lung cancer were inversely correlated with rare variant burden, consistent with additive risk from rare and common variants. Collectively, these findings delineate a complex germline architecture underlying susceptibility and molecular subtype in young-onset lung cancer.

Journal Article↗

PubMed2026

Diverse mediators of cancer predisposition uncovered by germline whole genome sequencing of unexplained familial cancers.

Cancer frequently clusters in families due to shared environment and genetics. However, many familial cancer cases lack a clinically recognized pathogenic germline variant (PGV). We analyzed germline genomes and family history from 2,726 individuals without a PGV in the All of Us Research Program, including 1,496 cases across 18 cancer types with extensive family history and 1,230 family history-negative, cancer-free controls. We identified allelic series of rare structural variants inactivating MSH2 in individuals with phenotypes consistent with Lynch syndrome and BRCA1 in breast cancer. Cancer polygenic risk scores were enriched in cases and correlated with patterns of cancer diagnoses within families. Exome-wide rare variant analyses nominated six candidate predisposition genes, including TSTD2 and BRAT1 in thyroid and breast cancer, respectively. Overall, polygenic risk and rare variants impacting known genes explained a median of 5% of unexplained familial cancers, increasing to 11% when including newly nominated risk factors.

Journal Article↗

PubMed2025

Spatially organized lymphocytic microenvironments in high grade primary prostate tumors.

The spatial organization and composition of the tumor-immune microenvironment (TME) play a critical role in shaping the progression of many solid cancers, but the organization of the TME in primary prostate cancer (PCa) remains poorly characterized. We therefore profiled the abundance and spatial distributions of major cell types involved in adaptive immunity in 29 radical prostatectomy specimens stratified into high (HGG; n=14) and low Gleason-grade (LGG; n=15). Compared to LGG, HGG PCa exhibited significantly greater B and T cell infiltration with many immune cells organized into clusters, some of which resembled tertiary lymphoid structures (TLSs). In HGG tumors, these clusters were dense, symmetric, rich in PD-1+ T cells, and frequently proximate to the tumor compartment. LGG clusters were less well organized, and T cell depleted. Thus, a subset of high-grade PCa harbor organized immune clusters that may play a role in tumor control and contain therapeutically targetable T and B cells.

Prostate cancer↗

PubMed2025

Disruption of Microhomology-mediated End-joining in Ewing Sarcoma.

Ewing sarcoma (EwS) is a group of bone and soft tissue cancers in children and young adults. Since EwS cells have pronounced sensitivity to radiation and chemotherapy-induced DNA damage, the role of the oncoprotein, EWS-FLI1, in DNA repair is likely. Here, we demonstrate that EWS-FLI1 causes a defect in microhomology-mediated end-joining (MMEJ) repair. EWSR1 is a splicing factor that promotes the faithful splicing of the POLQ pre-mRNA, required for the expression of POLΘ, a critical protein in the MMEJ pathway. Expression of EWS-FLI1, or loss of EWSR1, causes exon 25 skipping of the POLQ transcript, decreased POLΘ expression, impaired MMEJ, and cellular sensitivity to inhibitors of the Fanconi Anemia (FA), NHEJ, or HR pathways, through the mechanism of synthetic lethality. Knockdown of EWS-FLI1 expression restores POLΘ mitotic foci and increases MMEJ activity. Inhibitors of the FA, NHEJ, or HR therefore may provide a targeted therapy for patients with EwS.

Alternative end-joining↗