Biomedical subjects

Nathaniel Rothman

Publications and source records attributed to Nathaniel Rothman.

3 recordsLinked to original sources

PubMed2026

Multi-population GWAS meta-analysis identifies bladder cancer susceptibility loci and highlights genetic regulation of smoking-related risk.

Bladder cancer is the ninth most common cancer worldwide, caused by genetic and environmental risk factors. Here, we report the findings of a multi-population meta-analysis of genome-wide association studies, including 32,470 individuals with and 1,753,462 without bladder cancer. We identify 70 independent risk loci, of which 43 are novel. Using a 70-marker polygenic risk score (HR = 1.63 per standard deviation), we increase the area under the curve from 0.71 (baseline risk model) to 0.75. Integrative analyses reveal the enrichment of the associated variants within accessible chromatin regions, and of the prioritized genes within pathways for xenobiotic metabolism and smoking behavior. Specifically, we show that the 15q25.1 variant rs71581744-ACCCC/A co-localizes with tissue-specific CHRNA3 expression, modulates mRNA stability, and associates with risk of muscle-invasive bladder cancer among current smokers. Together, these findings substantially expand the known genetic architecture of bladder cancer risk and highlight the germline regulation of smoking behavior as a mechanism driving bladder cancer susceptibility.

Humans↗

PubMed2025

Panorama of Chromosomal Instability in Lung Cancer.

Lung cancer is a highly heterogeneous disease primarily driven by tobacco smoking. About 20% of lung cancers occur among patients who have never smoked (LCINS) with differences in patient ancestry, sex, tumor histology, and clinical features. Our understanding of chromosomal instability in lung cancer, especially LCINS, is still limited. Here, we perform a comprehensive study of 182,429 somatic structural variations (SVs) detected in 1,209 whole-genome sequenced lung cancers, of which 864 LCINS. SVs are more abundant in tumors from patients who have smoked (LCSS); however, they are more complex and play more important roles in tumorigenesis in LCINS. EGFR mutations and KRAS mutations profoundly and independently shape the SV landscape. EGFR-mutant tumors have higher SV burden and more cancer-driving SVs. In contrast, KRAS mutations are associated with lower SV burden and less driver SVs. We decompose 16 SV signatures for both complex and simple SVs that likely represent divergent molecular mechanisms. The SV breakpoints have distinct distributions across the genome depending on the signatures due to mutagenic mechanisms and positive selection. Many established cancer-driving genes are recurrently rearranged by multiple SV signatures suggesting functional convergence of these genome instability mechanisms.

Journal Article↗

PubMed2025

A prognostic signature for lung adenocarcinoma in people who have never smoked.

Knowledge of tumor cell dynamics can inform prognosis and treatment yet is largely lacking for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA-seq data from 684 NS-LUAD and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histological data further characterized the subtypes. 'Steady', marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver genes' alterations, is linked to prolonged survival and low immune evasion. 'Proliferative' shows high proliferation markers, TP53 mutations, and gene fusions. 'Chaotic', with high epithelial-to-mesenchymal transition markers, has the worst prognosis even within stage I tumors. Lacking known molecular or histological characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the overall classification and strongly predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving NS-LUAD prognostication in clinical settings.

Journal Article↗