Zhao, L.-N. | Search bioRxiv

bioRxiv2019

Single-cell dissection of a rare human prostate basal cell carcinoma

As a rare subtype of prostate carcinoma, basal cell carcinoma (BCC) has not been studied extensively and thus lacks systematic molecular characterization. Here we applied single-cell genomic amplification and RNA-Seq to a specimen of human prostate BCC (CK34{beta}E12+/P63+/PAP-/PSA-). The mutational landscape was obtained via whole exome sequencing of the amplification mixture of 49 single cells, and the 5 putative driver genes mutated are CASC5, NUTM1, PTPRC, KMT2C and TBX3. The top 3 nucleotide substitutions are C>T, T>C and C>A, similar to common prostate cancer. The distribution of the variant allele frequency values indicated these single cells are from the same tumor clone. The transcriptomes of 69 single cells were obtained, and they were clustered into tumor, stromal and immune cells based on their global transcriptomic profiles. The tumor cells specifically express basal cell markers like KRT5, KRT14 and KRT23, and epithelial markers EPCAM, CDH1 and CD24. The transcription factor (TF) co-variance network analysis showed that the BCC tumor cells have distinct regulatory networks. By comparison with current prostate cancer datasets, we found that some of the bulk samples exhibit basal-cell signatures. Interestingly, at single-cell resolution the gene expression patterns of prostate BCC tumor cells show uniqueness compared with that of common prostate cancer-derived circulating tumor cells. This study, for the first time, discloses the comprehensive mutational and transcriptomic landscapes of prostate BCC, which lays a foundation for the understanding of its tumorigenesis mechanism and provides new insights into prostate cancers in general.

cancer biology↗

bioRxiv2018

The mutational features of aristolochic acid-induced mouse and human liver cancers

Aristolochic acid (AA) derived from traditional Chinese herbal remedies has recently been statistically associated with human liver cancer; however, the causal relationships between AA and liver cancer and the underlying evolutionary process of AA-mediated mutagenesis during tumorigenesis are obscure. Here, we subjected mice, including Pten-deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and carbon tetrachloride (CCl4), which may induce liver injury. Significantly, AAI promoted the development of liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, in a dose-dependent manner, and it increased the incidence of liver cancer, together with CCl4 or Pten deficiency. AAI could lead to DNA damage and AAI-DNA adducts that initiate liver cancer via characteristic A>T transversions, as indicated by the comprehensive genomic analysis, which revealed recurrent mutations in Hras and some genes encoding components of the Ras/Raf, PI3K, Notch, Hippo, Wnt, DNA polymerase family and the SWI/SNF complex, some of which are also often found in human liver cancer. Mutational signature analysis across human cancer types revealed that the AA-related dominant signature was especially implicated in liver cancer in China, based on very stringent criteria derived from the animal cancer form, in which mutations of TP53 and JAK1 are prone to be significantly enriched. Interestingly, AAI-mediated characteristic A>T mutations were the earliest genetic event driving malignant subclonal evolution in mouse and human liver cancer. In general, this study provides documented evidence for AA-induced liver cancer with featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA-associated human cancers, especially liver cancer.

cancer biology↗