Inherited Drivers of Thrombocytosis: Platelet PRS as RCC Survival Marker

At the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, Pablo Barrios, MD, and Mustafa Saleh, MD, presented groundbreaking data linking inherited genetics to clinical outcomes in renal cell carcinoma (RCC). Their study, which utilized the STITCH pipeline to impute germline DNA from tumor sequencing in a cohort of 495 patients, identified a germline platelet polygenic risk score (PRS) as a significant predictor of overall survival. Specifically, the analysis of over 300 polygenic risk scores revealed that patients with a higher platelet PRS faced a 37% higher risk of death.

Crucially, the researchers found that this genetic signal "washed out" when adjusted for clinical platelet levels, confirming that the survival impact is directly mediated through sustained thrombocytosis. This finding suggests that elevated platelets in RCC are not merely reactive to the tumor or therapy but are partially driven by a patient’s baseline genetic set point. While higher platelet counts are already an established component of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, these findings add a layer of inherited predisposition to the prognostic landscape. However, the authors noted that the study was restricted to patients of European ancestry, highlighting the need for future validation across diverse ethnic populations to ensure the PRS platform’s global portability and utility.

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.

CancerNetwork: What was the rationale for the study, and can you provide any relevant background information?

Barrios: We know that polygenic risk scores in kidney cancer have already been established in a predictive of incidents previously, but we have not yet seen any inherited germline data predicting outcomes before. That was part of the rationale that [partially] triggered all of this, something well established is that higher platelet counts are associated with worse prognosis in kidney cancer. Platelet counts are a risk factor at the IMDC risk score that's well established.

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

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. And 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 end up with a cohort of patients that have germline genetics and specific outcomes that were measured and collected through clinical data operation. And we tested the association of multiple polygenic risk scores that Barrios mentioned in the literature. 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 also confirmed with false discovery rate, and most interestingly was the polygenic risk score of platelets. And it tells us the results are that patients that have a higher score of polygenic risk scores of platelets have 37% higher risk of death, and this is specifically the main result. Other things that we also studied is looking at the adjustment of platelet levels in these patients. What happens after we adjust for the platelet counts that we have? And when we adjusted for this platelet level, we interestingly saw that the polygenic risk score signal that we were seeing washed out. And 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.

This is very important, because we have the IMDC score that has already platelet counts involved. This adds to this another layer to how we look at thrombocytosis in patients with kidney cancer. And it tells us from the beginning, from baseline, germline DNA, how this can affect survival in these patients that have kidney cancer.

All in all, it's telling us that patients that have thrombocytosis, it's not only due to the therapy that the patient is receiving, and it's not only due to the cancer diagnosis that patients have, it's also due to their germline characteristics that they have that influence thrombocytosis and has impact on the platelet levels and survival. Basically, patients with a higher risk score have higher platelet levels and therein, they have worse survival.

How much of the observed thrombocytosis in patients with RCC do you believe was truly reactive versus a baseline genetic set point that the tumor simply might have amplified?

Saleh: We didn't get into this specific analysis, but that's something we could potentially do in the future. One way we could look at it is stratifying the patients based on [those] that have a higher score of polygenic risk score vs the patients that have low scores based on a median cutoff and look at how patients’ platelet levels differ after therapy and before therapy.

Barrios: We need to have levels pre and post levels.

How well does your PRS platform perform across diverse ethnic populations?

Saleh: [That’s a question] that we didn't tackle in the paper, but that's a good question, because… this cohort of patients that we used were patients with European ancestry, and we did a PCA analysis, and we restricted to patients with European ancestries. What we're looking at is only the association of patients from European ancestry.

If you would look at other ancestries, that would be also a great aspect to look at it, because what we're seeing in the germline genetics for it right now is that not all polygenic risk scores results that we're seeing are seen in other ancestries, and this is what we call portability of polygenic risk scores, if we're able to actually take this polygenic prescript to another ancestry and see the same result that we're seeing. We didn't tackle this in our study, but this is something very relevant to look at.

Is there anything else that you would like to highlight that we might not have discussed?

Barrios: Next steps are validating [this platform] into bigger [populations] in the independent cohorts. We'll see if that's coming up.

Saleh: Another thing that would be interesting to look at is progression-free survival, if it can predict response to therapy, and as well, disease-free survival. See patients that had surgery and see if it can predict recurrence after surgery. Another thing that I got from the poster session that would be interesting is to look at another cohort of patients that would be a control of patients without cancer and see their polygenic risk from probably the UK biobank that would be a great cohort to work with.

Reference

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