Histopathology and levels of proteins in plasma associate with survival after colorectal cancer diagnosis

Abstract

Background: The TNM system is used to assess prognosis after colorectal cancer (CRC) diagnosis. Other prognostic factors reported include histopathological assessments of the tumour, tumour mutations and proteins in the blood. As some of these factors are strongly correlated, it is important to evaluate the independent effects they may have on survival.

Methods: Tumour samples from 2162 CRC patients were visually assessed for amount of tumour stroma, severity of lymphocytic infiltrate at the tumour margins and the presence of lymphoid follicles. Somatic mutations in the tumour were assessed for 2134 individuals. Pre-surgical levels of 4963 plasma proteins were measured in 128 individuals. The associations between these features and prognosis were inspected by a Cox Proportional Hazards Model (CPH).

Results: Levels of stroma, lymphocytic infiltration and presence of lymphoid follicles all associate with prognosis, along with high tumour mutation burden, high microsatellite instability and TP53 and BRAF mutations. The somatic mutations are correlated with the histopathology and none of the somatic mutations associate with survival in a multivariate analysis. Amount of stroma and lymphocytic infiltration associate with local invasion of tumours. Elevated levels of two plasma proteins, CA-125 and PPP1R1A, associate with a worse prognosis.

Conclusions: Tumour stroma and lymphocytic infiltration variables are strongly associated with prognosis of CRC and capture the prognostic effects of tumour mutation status. CA-125 and PPP1R1A may be useful prognostic biomarkers in CRC.

Fig. 1. Data availability.

Shown are the numer of CRC cases available for each type of analysis.

Fig. 2. Representative examples of tumour samples.

a lymphoid follicles in tumour sample; b tumour sample with a low (<10%) amount of stroma; c tumour sample with an intermediate (10–50%) amount of stroma; d tumour sample with a high (>50%) amount of stroma; e tumour sample with a low severity of lymphocytic infiltrate at the tumour margin; f tumour sample with a high severity of lymphocytic infiltrate at the tumour margin.

Fig. 3. Kaplan–Meier curves of estimates of CRC-specific survival after CRC diagnosis.

Stratification by a amount of tumour stroma; b presence of lymphoid follicles; c severity of lymphocytic infiltrate at the tumour margin; d proximal vs. distal tumour location; e TMB-L vs TMB-H; f MSI-L vs. MSI-H; g presence of pathogenic mutation in TP53; h presence of pathogenic mutation in BRAF; i stage IIB/C vs IIIA.