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We previously reported the significant presence of moderate and severe chronic renal lesions (CRL) in Romania and Serbia (OR=2.96; p<0.05) by morphological evaluation of 1012 nontumoral (NT) tissues of RCC patients by that a possible link with renal carcinogenesis was thought (Abedi-Ardekani B. et al. 2020). Recently, we conducted one of the most comprehensive genomic studies of cancers, the Mutographs study (www.mutographs.org), focused on analysis of mutational signatures-patterns of somatic DNA alterations- by whole genome sequencing (WGS) of thousands of different cancers from five continents, including 962 clear cell RCC (ccRCC) tissues from 11 countries with variable incidence of ccRCC. Our study revealed the presence of mutational signatures caused by aristolochic acid (AA) exposure, SBS22, in ccRCC from Romania, Serbia, and Thailand, and rare elsewhere. SBS40 with unknown etiology was also detected ubiquitously and associated with ccRCC incidence (Senkin S. et al. 2023). Interestingly, SBS22 was also detected in NT tissues of patients in these countries by subsequent WGS of 256 paired NT renal tissues. Here we provide illustrative information regarding our initial publication by an integrated analysis of genomic and pathology data.
Our recent rich data from genomics of ccRCC provided us as an opportunity to run a deeper investigation on our previous report about CRL in specific geographical localizations. We performed a comprehensive analysis of the WGS data of 962 ccRCC and 256 paired NT tissues, the histopathological assessment of 557 normal tissues, and untargeted metabolomics scan of plasma of 909 patients. CRL were graded from minimal to severe by standard assessment of renal parenchymal elements (Sethi S. et al. 2017).
CRL was found in normal tissues of 87 (15.6%) ccRCC patients distributed across all countries. The presence of SBS22, almost exclusively in three countries, was significantly higher in tumor tissues of patients with CRL than those without (OR=2.90, p=0.005) but remained nonsignificant in normal tissues regardless of OR=2.26. No association was found with any other mutational signature. Patients with CRL accumulated more mutations with age (OR=1.07 by 1-year age increase, negative binomial regression p<0.05). This effect remained significant after excluding the mutations associated with SBS22 (p=0.002), suggesting that direct DNA damage from AA exposure alone does not explain all the alterations in normal tissues. Calculated eGFR from metabolomics data was significantly lower when CRL present and the amount of TMAP, a surrogate metabolite marker of reduced kidney function, was increased with the increased grade of CRL.
Our recent findings from genomic analyses of ccRCC enlighten the association of CRL with exposure to AA in the same countries that we alreday reported CRL. By wider coverage of countries in the Mutographs, we interestingly discovered that CRL are associated with faster accumulation of DNA damage and global mutational burden, not fully explained by exposure to AA. We provide strengthening information regarding the possible link between CRL and renal carcinogenesis, a finding that warrants further investigations. Also, our study highlights the role of pathology and histopathological evaluation to provide additional insights when interpreting the sequencing data in multidisciplinary genomic studies.