Novel biomarker SARIFA in colorectal cancer: highly prognostic, not genetically driven and histologic indicator of a distinct tumor biology

Abstract

SARIFA (Stroma AReactive Invasion Front Areas) has recently emerged as a promising histopathological biomarker for colon and gastric cancer. To elucidate the underlying tumor biology, we assessed SARIFA-status in tissue specimens from The-Cancer-Genome-Atlas (TCGA) cohorts COAD (colonic adenocarcinoma) and READ (rectal adenocarcinoma). For the final analysis, 207 CRC patients could be included, consisting of 69 SARIFA-positive and 138 SARIFA-negative cases. In this external validation cohort, H&E-based SARIFA-positivity was strongly correlated with unfavorable overall, disease-specific, and progression-free survival, partly outperforming conventional prognostic factors. SARIFA-positivity was not associated with known high-risk genetic profiles, such as BRAF V600E mutations or microsatellite-stable status. Transcriptionally, SARIFA-positive CRCs exhibited an overlap with CRC consensus molecular subtypes CMS1 and CMS4, along with distinct differential gene expression patterns, linked to lipid metabolism and increased stromal cell infiltration scores (SIIS). Gene-expression-based drug sensitivity prediction revealed a differential treatment response in SARIFA-positive CRCs. In conclusion, SARIFA represents the H&E-based counterpart of an aggressive tumor biology, demonstrating a partial overlap with CMS1/4 and also adding a further biological layer related to lipid metabolism. Our findings underscore SARIFA-status as an ideal biomarker for refined patient stratification and novel drug developments, particularly given its cost-effective assessment based on routinely available H&E slides.

The Concept of Stroma AReactive Invasion Front Areas (SARIFA) as a new prognostic biomarker for lipid-driven cancers holds true in pancreatic ductal adenocarcinoma

“…The estimated optimal cut-off threshold based on the percentage of slides showing SARIFA was 0.6680 (95% confidence interval: 0.5842—0.711). By using this cut-off, we reached a SARIFA-positive frequency of 31.9%, which is similar to the SARIFA frequency in colorectal and gastric cancer [ 8 , 15 , 25 ]. For more details on our biomarker cut-off, refer to Figure S1.…”

“…An alternative pathway of transportation of saturated and unsaturated lipids and fatty acids between tumour cells and adipocytes is conducted through fatty acid binding protein 4 (FABP4) [ 13 , 14 ]. Both CD36 and FABP4 were shown to be upregulated in SARIFA-positive colorectal and gastric carcinomas [ 8 , 15 ], an observation suggesting an altered lipid metabolism, which is a promising target for the development of new therapy concepts [ 16 ].…”