Aristolochic Acid and Alternative Lengthening of Telomeres Mechanisms Underlie Liver Angiosarcoma Pathogenesis

Our previous epidemiological study revealed a significantly higher incidence of liver angiosarcoma in Asian patients than that in their European counterparts. Elucidating the etiology and hallmarks of this aggressive malignancy may offer insights into the development of novel therapeutic strategies.

We analyzed samples from liver and non-liver angiosarcoma patients treated at the National Taiwan University Hospital, as well as data from the angiosarcoma cohort of the Count Me In Project. Hepatocellular carcinoma (HCC) samples were used as controls for liver tumors. Whole-exome sequencing and de novo extraction of single-base substitution mutation signatures were performed. Transcriptomic profiling was used to assess oncogenic pathways and the tumor microenvironment. Telomere lengths were estimated using TelSeq and telomeric repeat-containing RNA levels were quantified using TERRA-QUANT.

De novo extraction identified four mutation signatures (A-D). Signature A exhibited high similarity to SBS22 (cosine similarity = 0.93), which was associated with aristolochic acid exposure. This signature showed a significantly greater contribution to liver angiosarcoma and HCCs but not to non-liver angiosarcomas. According to the mSigAct analysis, 80% (8/10) of liver angiosarcoma cases displayed a significant SBS22 signature. Moreover, liver angiosarcomas demonstrated a significantly higher tumor mutation burden, increased frequencies of TP53 and ATRX mutations, and greater T-cell infiltration than non-liver angiosarcomas. Telomere length was significantly longer in liver angiosarcomas than in matched normal tissues, a pattern that was not observed in Taiwanese non-liver angiosarcomas or HCCs. Notably, liver angiosarcomas exhibited markedly lower telomerase activity than their non-liver counterparts and HCCs, suggesting a reliance on the alternative lengthening of telomere (ALT) pathway.

Our study provides compelling evidence that aristolochic acid exposure is associated with liver angiosarcoma, and elaboration of ALT activation in liver angiosarcomas offers new insights into their underlying biology and may guide the development of targeted therapeutic approaches.