Could Hematologic Markers Be Prognostic for Survival in RCC?

While polygenic risk scores (PRS) are well-established tools for predicting cancer incidence, their utility in prognosticating survival outcomes through inherited germline data has remained largely unrealized. The rationale for this investigation, per Pablo Barrios, MD, and Mustafa Saleh, MD, at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, stemmed from the clinical significance of platelet counts, a core component of the International Metastatic RCC Database Consortium (IMDC) risk score.¹

Using the STITCH pipeline to impute germline genetics from targeted tumor sequencing in a cohort of 495 patients at the Dana-Farber Cancer Institute, the pair evaluated more than 300 hematologic polygenic risk scores. Their findings revealed that a high platelet PRS is associated with a 37% increased risk of death in patients with renal cell carcinoma (RCC).

One key takeaway from the study was the mediation of this genetic signal. When adjusting for actual platelet levels, the association between the PRS and overall survival “washed out,” indicating that the genetic risk is expressed specifically through sustained thrombocytosis rather than an independent biological pathway. This discovery may highlight the potential for germline data to refine risk stratification, underscoring the importance of monitoring platelet-driven outcomes in the multidisciplinary management of kidney cancer.

Barrios is a postdoctoral fellow and medical oncologist at the Dana-Farber Cancer Institute. Saleh is a postdoctoral fellow at the Dana-Farber Cancer Institute.

Transcript:

Barrios: We know that polygenic risk scores in kidney cancer have already been established and predictive of incidence previously, but we have not yet seen any inherited germline data predicting outcomes before.² That was part of the rationale that [partially] triggered all of this. Platelet counts are a risk factor at the IMDC risk score; that's well established.³

To this day, we already have hundreds of polygenic risk scores that are associated with hematologic blood traits and circulated blood traits. The whole idea was to combine all [these traits] and try to answer a simple question: if we look at inherited germline determinants of hematologic blood traits, could that be associated with survival in kidney cancer?

Saleh: Going into the methods of what we did in the study, we compiled a cohort of 495 patients with kidney cancer. These patients had undergone tumor sequencing at the Dana-Farber Cancer Institute. We used the pipeline called STITCH, which was developed by our mentor, Alexander Gusev, PhD, which imputes germline genetics from targeted sequencing using a reference genome. We ended up with a cohort of patients who have germline genetics and specific outcomes that were measured and collected through clinical data operation. We tested the association of multiple polygenic risk scores that Barrios mentioned in the literature. [There were] more than 300 polygenic risk scores with the outcome of interest, which was overall survival.

Two polygenic risk scores met significant results, and this was confirmed with false discovery rate. Most interestingly, it was the polygenic risk score of platelets. It tells us the results are that patients who have a higher polygenic risk scores of platelets have a 37% higher risk of death.

Looking at the adjustment of platelet levels in these patients, what happens after we adjust for the platelet counts that we have? When we adjusted for this platelet level, we interestingly saw that the polygenic risk score signal that we were seeing washed out. This tells us that this effect that we're seeing of polygenic risk score with overall survival is mediated through platelet counts, and it's not another pathway that's being involved in here.

References

1. Saleh M, Saad E, Barrios P, et al. Germline platelet polygenic risk score predicts renal cell carcinoma survival via sustained thrombocytosis. J Clin Oncol. 2026;44(suppl 7):543. doi:10.1200/JCO.2026.44.7_suppl.543
2. Purdue MP, Dutta D, Machiela MJ, et al. Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions. Nat Genet. 2024;56:809-818. doi:10.1038/s41588-024-01725-7
3. Al Ta’ani O, Abu-Shawer O, Abdelhadi SJ, et al. The predictive value of hematological markers in renal cell carcinoma. J Clin Oncol. 2023;41(suppl 6):621. doi:10.1200/JCO.2023.41.6_suppl.621