An “expressionistic” look at serrated precancerous colorectal lesions

Abstract

Background Approximately 60% of colorectal cancer (CRC) precursor lesions are the genuinely-dysplastic conventional adenomas (cADNs). The others include hyperplastic polyps (HPs), sessile serrated lesions (SSL), and traditional serrated adenomas (TSAs), subtypes of a class of lesions collectively referred to as “serrated.” Endoscopic and histologic differentiation between cADNs and serrated lesions, and between serrated lesion subtypes can be difficult. Methods We used in situ hybridization to verify the expression patterns in CRC precursors of 21 RNA molecules that appear to be promising differentiation markers on the basis of previous RNA sequencing studies. Results SSLs could be clearly differentiated from cADNs by the expression patterns of 9 of the 12 RNAs tested for this purpose (VSIG1, ANXA10, ACHE, SEMG1, AQP5, LINC00520, ZIC5/2, FOXD1, NKD1). Expression patterns of all 9 in HPs were similar to those in SSLs. Nine putatively HP-specific RNAs were also investigated, but none could be confirmed as such: most (e.g., HOXD13 and HOXB13), proved instead to be markers of the normal mucosa in the distal colon and rectum, where most HPs arise. TSAs displayed mixed staining patterns reflecting the presence of serrated and dysplastic glands in the same lesion. Conclusions Using a robust in situ hybridization protocol, we identified promising tissue-staining markers that, if validated in larger series of lesions, could facilitate more precise histologic classification of CRC precursors and, consequently, more tailored clinical follow-up of their carriers. Our findings should also fuel functional studies on the pathogenic significance of specific gene expression alterations in the initiation and evolution of CRC precursor subtypes.

A retrospective analysis of the histology of resected polyps and colonoscopy quality parameters in Belgium

“…We presume that a lot of serrated lesions in the first years of the database were not properly detected by the endoscopists and, if resected, were misclassified as hyperplastic polyps by the pathologist. Secondly, SSLs that have extensive cytologic dysplasia might be difficult to differentiate from conventional adenomas (32). Finally, hyperplastic polyps in our study were as mentioned not included in the pathology register.…”

Spatiotemporally deciphering the mysterious mechanism of persistent HPV‐induced malignant transition and immune remodelling from HPV‐infected normal cervix, precancer to cervical cancer: Integrating single‐cell RNA‐sequencing and spatial transcriptome

“…Moreover, by analysing the marker gene expression and functional pathways of these ‘HPV‐related clusters,’ we discovered that clusters 1 and 3 enriched in the normal cervix featured antineoplastic effects and highly expressed multiple tumour suppressors (SLC5A8, DERL3) (Figure 2D ), thereby suppressing cell proliferative, migratory and invasive capacities. 9 , 10 On the other hand, cluster 2, representing HSIL, manifested high cellular motor capacity, specifically expressing genes related to cell adhesion (CDH16, CDH17 and VSIG1) 11 , 12 and extracellular matrix degradation (CTSE) (Figure 2E ), thus potentially promoting the expansion of atypical cells in intraepithelial neoplasia progression. Additionally, we observed that clusters 6, 7, 9 and 13 (CASP14, PRSS27, CALML5) (Figure 2F ), which were enriched in CC, manifested high expression levels of genes related to carcinogenic pathways such as epithelial‐to‐mesenchymal transition, tumour cell proliferation, migration, invasion and angiogenesis.…”

“…This finding indicated that the protective mechanism would be activated accordingly after HPV infection. The precancerous lesion of CC, the ‘HPV‐related HSIL cluster,’ highly expressed VSIG1, which is also a biomarker of colorectal cancer precursor lesions 12 . Therefore, we hypothesized that VSIG1 might be a critical molecule in precancerous epithelial lesions, which is worth further experimental investigation.…”

“…The precancerous lesion of CC, the ‘HPV‐related HSIL cluster,’ highly expressed VSIG1, which is also a biomarker of colorectal cancer precursor lesions. 12 Therefore, we hypothesized that VSIG1 might be a critical molecule in precancerous epithelial lesions, which is worth further experimental investigation. Moreover, the ‘HPV‐related CA cluster’ specifically expressed CALML5, which is closely associated with recurrence and survival outcomes in patients with HPV‐related cancers such as head‐and‐neck carcinoma and oropharyngeal cancer.…”

V-Set and immunoglobulin domain containing (VSIG) proteins as emerging immune checkpoint targets for cancer immunotherapy

“…In contrast, VSIG1 seemed to be upregulated in a variety of nongastric carcinomas ( 30 , 44 , 46 , 47 ). It was identified as a signature gene for gastric-type differentiation of serrated pathway-associated colon carcinoma ( 47 – 49 ) and lung adenocarcinoma ( 50 ). The coexpression of VSIG1 in the cytoplasm of hepatocytes with thyroid transcription factor 1 (TTF1) was also considered to be a potential lineage shift indicator of conventional to gastric-type hepatocellular carcinoma (HCC) ( 51 ).…”