Predicting tumor mutation burden and VHL mutation from renal cancer pathology slides with self-supervised deep learning.

Background: Tumor mutation burden (TMB) and VHL mutation play a crucial role in the management of patients with clear cell renal cell carcinoma (ccRCC), such as guiding adjuvant chemotherapy and improving clinical outcomes. However, the time-consuming and expensive high-throughput sequencing methods severely limit their clinical applicability. Predicting intratumoral heterogeneity poses significant challenges in biology and clinical settings. Our aimed to develop a self-supervised attention-based multiple instance learning (SSL-ABMIL) model to predict TMB and VHL mutation status from hematoxylin and eosin-stained histopathological images.

Methods: We obtained whole slide images (WSIs) and somatic mutation data of 350 ccRCC patients from The Cancer Genome Atlas for developing SSL-ABMIL model. In parallel, 163 ccRCC patients from Clinical Proteomic Tumor Analysis Consortium cohort was used as independent external validation set. We systematically compared three different models (Wang-ABMIL, Ciga-ABMIL, and ImageNet-MIL) for their ability to predict TMB and VHL alterations.

Results: We first identified two groups of populations with high- and low-TMB (cut-off point = 0.9). In two independent cohorts, the Wang-ABMIL model achieved the highest performance with decent generalization performance (AUROC = 0.83 ± 0.02 and 0.8 ± 0.04 in predicting TMB and VHL, respectively). Attention heatmaps revealed that the Wang-ABMIL model paid the highest attention to tumor regions in high-TMB patients, while in VHL mutation prediction, non-tumor regions were also assigned high attention, particularly the stromal regions infiltrated by lymphocytes.

Conclusions: Our results indicated that SSL-ABMIL can effectively extract histological features for predicting TMB and VHL mutation, demonstrating promising results in linking tumor morphology and molecular biology.