The prognosis of advanced/metastatic biliary tract cancers (BTCs) remains poor¹, despite approval of novel therapies targeting FGFR2 gene fusions and IDH mutations^2,3. Unfortunately, only a minor fraction of BTC patients are eligible for these specific treatments. In recent years the chromatin remodeling system has gained increased attention as a potential therapeutic target in several tumor types. Chromatin remodeling is a tightly regulated process controlling gene accessibility for transcription and thus regulating gene expression^4,5. The Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex represents a key component of chromatin remodeling⁶. Dysregulation of SWI/SNF due to loss of function mutations in genes—such as ARID1A, SMARCB1, and Polybromo-1 (PBRM1; also known as BAF180)—is present in up to 20% of malignancies⁷, but, to date, no targeted treatment related to the chromatin remodeling process has been approved.

In BTCs, PBRM1 mutations are present in 5–21% of cases^8,9. In addition to chromatin remodeling, PBRM1 further participates in the repair of DNA double-strand breaks (DSB) via ATM phosphorylation¹⁰. Most genetic alterations of PBRM1 induce loss of function, consequently impairing DNA damage repair. Thus, PBRM1-mutated (mut) BTCs might be sensitive to agents targeting DNA damage repair. Indeed, the synthetic lethal effect of poly-(ADP-Ribose) polymerase (PARP) inhibitors (PARPi) has been suggested in an in vitro renal cell carcinoma model harboring PBRM1 mutations¹¹. PARPi induces synthetic lethality in cells lacking the ability to repair DSBs, which was first demonstrated in Breast Cancer Gene 1 or 2 (BRCA1 or BRCA2)-mut tumors. Thus, PARPi has been approved for the treatment of BRCA-mut breast^12,13,14, ovarian^15,16,17, pancreatic¹⁸, and prostate cancer¹⁹. PARPi are currently under clinical investigation in several malignancies harboring mutations in genes involved in DNA damage repairs, such as RAD51^20,21, PALB2²², or ARID1A^23,24. Moreover, combinations of PARPi with inhibitors of the DNA-damage repair protein ATR (Ataxia Telangiectasia and Rad3 related) are currently under investigation to overcome PARPi resistance²⁵.

To the best of our knowledge, the genomic context of PBRM1 mutations in BTCs has not been investigated so far. Therefore, we aimed to characterize the molecular landscape of PBRM1-mut BTCs and investigate the potential therapeutic role of PARP/ATRi in PBRM1-mut BTCs.

Patient characteristics

In total, 1848 BTC samples were centrally analyzed. Of these, 67.5% (n = 1249) were derived from primary tumor sites and 32.5% from metastatic lesions (n = 593). Altogether, 232 samples harbored different variants within the PBRM1 gene and 150 (8.1%) of these alterations were classified as pathogenic (frameshift: 51.4%; nonsense: 32.0%; splicing: 16.6%). The most frequently detected PBRM1 point mutation was the p.N258fs variant (n = 10, 6.6%; c.773delA (n = 3) and c.773dupA (n = 7)) followed by the p.R850* variant (n = 4, 2.6%; all c.2548 C > T; Fig. 1a). All pathogenic/likely pathogenic variants identified in the cohort are provided in Supplementary Table 1.