Tumour Genetic Variants Linked to Immunotherapy Toxicity Risk in Urothelial Cancer
Key Insights
An exploratory study of 102 urothelial carcinoma (search) patients identified tumour SNPs associated with immune-related adverse events from checkpoint inhibitor therapy.
The SNP rs1738074 in the TAGAP (search) gene was linked to a nearly 5-fold increased risk of overall toxicity and significantly higher risks of pneumonitis and dermatitis.
SNP rs2301756 in PTPN11 (search) conferred a 29-fold greater risk of ICI-induced pneumonitis, while rs11571302 and rs66502444 showed protective effects against asthenia.
A multicentre observational study from Madrid has identified several tumour-derived single nucleotide polymorphisms (SNPs) that may help predict which urothelial carcinoma (search) patients are at heightened risk of developing immune-related adverse events (irAEs) during checkpoint inhibitor therapy. The findings, published in The Pharmacogenomics Journal, offer preliminary evidence that tumour biopsy genotyping could complement clinical assessment in personalizing immunotherapy for bladder and urinary tract cancers.
The study enrolled 102 patients with urothelial carcinoma (search) treated with immune checkpoint inhibitor (ICI) monotherapy — predominantly atezolizumab (75.5%), followed by avelumab (13.7%), pembrolizumab (7.8%), and nivolumab (3%) — across four university hospitals in Madrid between 2017 and 2024. The median age at diagnosis was 71 years (IQR 64–76), and 80.4% of participants were male.
ICI-induced adverse events were observed in 36.3% of the cohort: 25.5% experienced moderate symptoms, 9.8% had severe symptoms, and one patient died due to treatment-related toxicity. Asthenia was the most frequent irAE (18.6%), followed by dermatitis (8.8%), hepatitis (3.9%), pneumonitis (3.9%), colitis (2.9%), anaemia (2.9%), and thyroid dysfunction (2.9%).
TAGAP (search) variant emerges as a key risk factor
Among the 49 SNPs genotyped from formalin-fixed paraffin-embedded tumour biopsies, rs1738074 in the TAGAP (search) gene stood out for its broad association with toxicity. Patients homozygous for the variant allele (v/v) showed an almost 5-fold greater risk of developing any irAE compared with wild-type and heterozygous carriers (OR 4.93; 95% CI: 2.06–11.79; p < 0.001).
When specific toxicities were examined, the same SNP was significantly associated with both pneumonitis and dermatitis. All patients who developed pneumonitis carried the v/v genotype (p = 0.020), and the variant conferred a 15.74-fold increased risk of dermatitis (95% CI: 1.88–131.59; p = 0.002). The TAGAP (search) gene encodes a Rho GTPase-activating protein implicated in autoimmune diseases including multiple sclerosis and rheumatoid arthritis, and the same variant has previously been linked to severe irAEs in melanoma patients.
PTPN11 (search) variant and pneumonitis risk
The SNP rs2301756 in the PTPN11 (search) gene — encoding a protein tyrosine phosphatase involved in cell growth, differentiation, and oncogenic transformation — was associated with a 29.33-fold greater risk of ICI-induced pneumonitis among patients carrying at least one variant allele (95% CI: 2.76–312.19; p = 0.005). ICI-induced pneumonitis is a relatively rare but potentially life-threatening complication, with overall incidence estimated between 5% and 19% for any grade and approximately 6% for high-grade events.
Dermatitis-associated SNPs
Beyond rs1738074, two additional SNPs were linked to increased dermatitis risk. The variant rs55733913 in the PACRG (search) gene, previously associated with autoimmune thyroid diseases, increased dermatitis risk by 6.4-fold (95% CI: 1.27–32.91; p = 0.026). Similarly, rs2117997 in the LOC124902908 non-coding RNA region conferred a 6.5-fold elevated risk (95% CI: 1.49–28.18; p = 0.021).
Protective variants against asthenia
Two SNPs near the CTLA4 (search) gene region appeared to protect against ICI-induced asthenia. The presence of at least one variant allele of rs11571302 was significantly associated with lower asthenia rates (p = 0.012), while rs66502444 in the PACRG (search) gene was linked to a 5-fold reduced risk (OR 0.20; 95% CI: 0.04–0.94; p = 0.030). These findings align with prior observations by Abdel-Wahab and colleagues, who reported a protective effect of rs66502444 against irAEs in melanoma patients receiving ICIs.
Hepatitis and the IL1RL1 (search) variant
For ICI-induced hepatitis, the SNP rs4988956 in the IL1RL1 (search) gene showed significant differences across the three genotype groups (p = 0.027). Although grouped genotype comparisons did not reach statistical significance, a tentative risk effect was noted: 91.5% of patients without hepatitis carried either the wt/wt or wt/v genotype.
Clinical context and limitations
Urothelial carcinoma (search) accounts for over 90% of bladder cancer cases and is closely linked to advanced age, with a median diagnosis age of 73 years. Platinum-based regimens have been the standard of care since 2000, but only 15% of patients survive to five years. The recent introduction of ICIs and, since 2024, the combination of enfortumab vedotin with pembrolizumab — which doubled median overall survival to nearly 34 months — has transformed the treatment landscape.
The authors acknowledge the study's exploratory nature and limited sample size as key constraints. "Despite its limited sample size, this exploratory study offers interesting preliminary data about SNPs associated with overall toxicity and with specific adverse effects such as pneumonitis, asthenia, dermatitis or hepatitis," the researchers note, adding that "no single biomarker is likely sufficient to address the heterogeneity linked to UC."
The study employed rigorous genotyping methodology using iPlexGold chemistry on the MassARRAY platform, with all SNPs genotyped twice in independent assays. Internal controls demonstrated 100% reproducibility, and 96% of analysed SNPs were in Hardy-Weinberg equilibrium, indicating population genetic stability.