Banday, A. R. | bioRxiv Science

bioRxiv2018

Strenuous occupational physical activity - potential association with esophageal squamous cell carcinoma risk

The impact of leisure time or recreational physical activity (RPA) on cancer risk has been extensively studied. However, the association of the occupational physical activity (OPA), which differs in dose and intensity from RPA, with different cancers including esophageal squamous cell carcinoma (ESCC), has received less attention. Here, we present data from a case-control study which was conducted for assessing the risk factors for ESCC. Histopathologically confirmed 703 ESCC cases and 1664 controls, individually matched to the respective cases for age, sex and district of residence were recruited. Information on type, duration and intensity of physical activity was obtained in face-to-face interviews with participants using a structured questionnaire. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). A high level of occupational physical activity was associated with increased ESCC risk (OR = 2.17, 95% CI; 1.41 - 3.32), compared to subjects with moderate occupational physical activity. The association with ESCC risk was stronger in strenuous workers (OR = 3.64, 95% CI; 2.13 - 6.20). The association of strenuous OPA with ESCC risk persisted only in subjects that were involved in strenuous activities for equal to or greater than 5days/week. Our study suggests a possible association of strenuous occupational physical activity with ESCC risk. Although, our results were adjusted for multiple factors including indicators of socioeconomic status, more replicative occupational epidemiological studies are needed to rule out any residual confounding.

epidemiology↗

bioRxiv2018

Integrated proteogenomic analysis of metastatic thoracic tumors identifies APOBEC mutagenesis and copy number alterations as drivers of proteogenomic tumor evolution and heterogeneity

Elucidation of the proteogenomic evolution of metastatic tumors may offer insight into the poor prognosis of patients harboring metastatic disease. We performed whole-exome and transcriptome sequencing, copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of 37 lung adenocarcinoma (LUAD) and thymic carcinoma (TC) metastases obtained by rapid autopsy and found evidence of patient-specific, multi-dimensional heterogeneity. Extreme mutational heterogeneity was evident in a subset of patients whose tumors showed increased APOBEC-signature mutations and expression of APOBEC3 region transcripts compared to patients with lesser mutational heterogeneity. TP53 mutation status was associated with APOBEC hypermutators in our cohort and in three independent LUAD datasets. In a thymic carcinoma patient, extreme heterogeneity and increased APOBEC3AB expression was associated with a high-risk germline APOBEC3AB variant allele. Patients with CNA occurring late in tumor evolution had corresponding changes in gene expression and protein abundance indicating genomic instability as a mechanism of downstream transcriptomic and proteomic heterogeneity between metastases. Across all tumors, proteomic heterogeneity was greater than copy number and transcriptomic heterogeneity. Enrichment of interferon pathways was evident both in the transcriptome and proteome of the tumors enriched for APOBEC mutagenesis despite a heterogeneous immune microenvironment across metastases suggesting a role for the immune microenvironment in the expression of APOBEC transcripts and generation of mutational heterogeneity. The evolving, heterogeneous nature of LUAD and TC, through APOBEC-mutagenesis and CNA illustrate the challenges facing treatment outcomes.

cancer biology↗