Biology subjects

Sokol, E. S.

Publications and source records attributed to Sokol, E. S..

6 recordsLinked to original sources

bioRxiv2026

Breast cancer ovarian metastases show increased activity of GPCR pathways

Treatment resistance and metastases occur in 10-20% of patients with invasive lobular carcinoma (ILC), the most common special histological subtype of breast cancer. ILC metastasizes to the ovary more frequently than no special type (NST) tumors, also known as invasive ductal carcinoma (IDC). To characterize the genomic landscape of breast cancer ovarian metastases, we analyzed 15,613 local breast cancers, 22,010 non-ovarian metastases, and 246 ovarian metastases sequenced using FoundationOne(R)CDx or FoundationOne(R) assays. Ovarian metastases had enriched CDH1, PIK3CA, and TBX3 mutations and depleted TP53 and MYC alterations relative to local breast cancers, with additional depletion of ESR1 mutations compared to non-ovarian metastases. CDH1 mutations were less frequent in ovarian metastases (47%) than local ILC (81.3%), with reduced 16q loss (64% vs 84%), indicating that ovarian metastases also arise from non-ILC tumors. We extended these findings to a UPMC cohort of 27 ovarian metastases (13 ILC, 8 IDC, 6 mixed ductal-lobular carcinoma) with patient-matched primary tumors in most cases. In both cohorts, patients with ovarian metastases were significantly younger than those with other metastatic sites. In the UPMC cohort, the most frequent mutations were in PIK3CA, CDH1, KMT2C, FOXA1, and RUNX1. Transcriptomic analysis identified upregulated G protein-coupled receptor (GPCR) pathways, including metabotropic glutamate receptor signaling. Functional studies showed that calcium-sensing receptor (CaSR), a GPCR overexpressed in ovarian metastases, drives MEK/ERK-dependent migration and F-actin reorganization in ILC cell lines, enhanced by estrogen and blocked by calcilytic, MEK, or anti- estrogen treatment. Our findings inform future therapeutic targeting of ovarian metastasis.

cancer biology↗

bioRxiv2026

Landscape of reversion alterations in homologous recombination genes reveals evolutionary constraints

Reversion mutations (REVs) restore homologous recombination repair (HRR) and confer resistance to PARP inhibitors (PARPi) in HR-deficient cancers. Yet, their prevalence, mechanisms, and biological constraints remain undefined. We analyzed genomic profiling of 609,464 tissue and liquid biopsy samples across multiple cancer types to delineate the pan-cancer landscape of REVs. REVs were identified in eight HRR genes, most frequently BRCA2 and BRCA1 and notably never in ATM or CHEK2. REVs exclusively impacted truncating pathogenic variants, predominantly through large in-frame and exon-level deletions, associated with repetitive sequences. Conserved functional domains are relatively depleted of REVs. Structural modeling and functional studies support that exon-level deletions preserve critical domain architecture and confer PARPi resistance. The study establishes HRR reversion as a structurally permissive, yet evolutionarily constrained, resistance mechanism with implications on response, monitoring, and therapeutic strategy. One Sentence SummaryHomologous recombination reversion evolves through structurally tolerated, microhomology-driven alterations that restore DNA repair under therapeutic selection across cancers.

cancer biology↗

bioRxiv2025

Deficiency in POLE exonuclease causes synthetic lethality in highly aneuploid cancer cells

Aneuploidy is a hallmark of cancer and is associated with drug resistance and poor clinical outcomes across diverse cancer types. However, no therapies have been clinically established to target highly aneuploid tumors. By analyzing a real-world dataset comprising nearly half a million tumor samples subjected to comprehensive genomic profiling, we identified a striking mutual exclusivity between POLE exonuclease domain mutations and high aneuploidy burden. This observation was independently validated using data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). Probabilistic modeling revealed that the elevated quantity and unique spectrum of mutations induced by POLE exonuclease deficiency increase the likelihood of inactivating essential genes on chromosome arms harboring losses, leading to a synthetic lethal phenotype in highly aneuploid cells. Functional experiments demonstrated that POLE exonuclease activity is essential for the viability of highly aneuploid cancer cell lines but is dispensable in diploid cells. These findings suggest that selective inhibition of POLE exonuclease may represent a promising therapeutic strategy for targeting highly aneuploid tumors.

cancer biology↗

bioRxiv2024

EML4-ALK variant-specific genetic interactions shape lung tumorigenesis

Oncogenic fusions of EML4 and ALK occur in [~]5% of lung adenocarcinomas. More than 15 EML4-ALK variants with distinct breakpoints within EML4 have been identified, but the functional differences between these variants remain poorly understood. Here we use CRISPR/Cas9 somatic genome editing to generate autochthonous mouse models of the two most common EML4-ALK variants, V1 and V3, and show that V3 is more oncogenic than V1. By integrating these models with multiplexed genome editing, we quantify the effects of 29 putative tumor suppressor genes on V1- and V3-driven lung cancer growth in vivo and show that many tumor suppressor genes have dramatically variant-specific effects on tumorigenesis. Analysis of a novel dataset representing the largest human EML4-ALK lung cancer cohort to date identified alterations in the genomic landscape depending on the EML4-ALK variant. These findings demonstrate functional heterogeneity among EML4-ALK variants, suggesting that EML4-ALK variants behave more like distinct oncogenes than a uniform entity. More broadly, these findings highlight the dramatic impact of oncogenic fusions partner proteins on tumor biology.

cancer biology↗

bioRxiv2020

CDKN2C homozygous loss identifies a distinct subtype of TP53/RB1-wildtype leiomyosarcoma with frequent CIC genomic alterations and 1p/19q-codeletion

PurposeLeiomyosarcomas (LMS) harbor frequent inactivation of TP53 and RB1, and extensive DNA copy number alterations. Here, we describe a distinct recurrent genomic signature in TP53/RB1-wildtype uterine LMS. MethodsTissues from 276,645 unique advanced cancers, including 2,570 uterine and soft tissue LMS were sequenced by hybrid-capture-based next-generation DNA and RNA sequencing/comprehensive genomic profiling of up to 406 genes. We characterized clinicopathologic features of relevant cases. ResultsWe identified 77 LMS with homozygous copy loss of CDKN2C at chromosome 1p32.3 (3.0% of LMS). Genomic alterations (GAs) in TP53, RB1, and ATRX were rare in comparison with the remainder of the LMS cohort (11.7% vs 73.4%, 0% vs 54.5%, 2.6% vs 24.5%, all p<0.0001). CDKN2C-null LMS cases were significantly enriched for GAs in CIC (40.3% vs 1.4%) at 19q13.2, CDKN2A (46.8% vs 7.0%), and RAD51B (16.9% vs 1.7%; all p<0.0001). Chromosome arm-level aneuploidy analysis of available LMS cases (n=1,251) found that 85% (n=33/39) of CDKN2C-null LMS cases exhibited 1p/19q-codeletion, with significant enrichment in comparison to the remainder of the evaluated LMS cohort (85% vs. 5.1%, p<0.0001). 99% of CDKN2C-null cases were in females; median age was 61 years at surgery (range, 36-81 years). 55 cases were of uterine primary, 4 cases non-uterine, and the remaining 18 of uncertain primary site. 6 patients had a prior history of leiomyomatosis or uterine smooth muscle tumor of uncertain malignant potential. 60% of cases showed at least focal epithelioid variant histology. Most cases were of known advanced stage, with 62% of confirmed uterine primary cases at FIGO stage IVB. ConclusionThe identification of this novel genomic subset may have prognostic and/or therapeutic clinical relevance, including use of specific cyclin-dependent kinase inhibitors.

cancer biology↗

bioRxiv2017

Identification of Genes under Purifying Selection in Human Cancers

There is widespread interest in finding therapeutic vulnerabilities by analyzing the somatic mutations in cancers. Most analyses have focused on identifying driver oncogenes mutated in patient tumors, but this approach is incapable of discovering genes essential for tumor growth yet not activated through mutation. We show that such genes can be systematically discovered by mining cancer sequencing data for evidence of purifying selection. We show that purifying selection reduces substitution rates in coding regions of cancer genomes, depleting up to 90% of mutations for some genes. Moreover, mutations resulting in non-conservative amino acid substitutions are under strong negative selection in tumors, whereas conservative substitutions are more tolerated. Genes under purifying selection include members of the EGFR and FGFR pathways in lung adenocarcinomas, and DNA repair pathways in melanomas. A systematic assessment of purifying selection in tumors would identify hundreds of tumor-specific enablers and thus novel targets for therapy.

cancer biology↗