Molecular Characterization of sessile serrated adenoma/polyps from a large African American cohort.
Ajay Goel Ph.D.
Ashktorab, H., D. Delker, P. Kanth, A. Goel, J. M. Carethers and H. Brim (2019). “Molecular Characterization of sessile serrated adenoma/polyps from a large African American cohort.” Gastroenterology Apr 17. [Epub ahead of print].
Colorectal cancer is the second leading cause of cancer-related deaths in the United States and rates are highest among African Americans (AAs). Sessile serrated adenoma/polyps (SSA/Ps) may be precursors of up to 30% of colorectal cancers. Flat and mucinous features make SSA/Ps difficult to detect and similarities to histological features of benign hyperplastic polyps (HPs) make them difficult to be accurately diagnosed. As such, there is a need for specific sensitive molecular biomarkers for accurate and reliable diagnosis. Our aim was to assess the diagnostic value of molecular biomarkers that may distinguish SSA/Ps from HPs among AA patients . . . The prevalence of SSA/Ps in our study was 2.5% (252/10,027 colonoscopies) which is higher than that published by other groups. Moreover, these lesions were primarily distal which could associate with a different molecular profile. Indeed, neither CIMP nor MSI appear to be potential markers for these distal SSA/Ps. In addition to location, age might also be a determining factor for CIMP and MSI status. Indeed, Lui et al. reported that SSA methylation increased dramatically with age and associated with dysplasia. Our SSA/Ps patients were generally young (mean 56 years) and displayed no dysplasia. This is possibly one of the reasons why CIMP was not a distinguishing criterion in our cohort. MSI, a by-product of CIMP when it affects MLH1, was also not a differentiating feature between SSA/Ps and HPs in our AA population. Nearly 60% of our SSA/P cases displayed BRAF V600E mutation which has been previously associated with hypermethylation. This is not the case in our study, perhaps because the CIMP marker panel we used was not specific for SSA/Ps, particularly distally located ones. In a genome-wide DNA methylation and gene expression study in SSA/Ps and conventional adenomas, Parker et al. established a test panel of six hypermethylated regions (LOX, LEF1-AS1, SFRP4, ZNF793, SYT9, and LINC00693) that distinguished pre-cancers from normal mucosa and SSA/Ps from conventional adenomas with high accuracy. The test panel we used in our study differed from the ones established in their study. MUC6 demonstrated the highest fold-difference suggesting that its high expression might correlate with SSA/P pathogenesis. Three other genes (SEMG1, TRNP1 and FSCN1) also showed significantly higher expression in AA SSA/Ps. Several studies have shown that among four mucin genes clustered on chromosome 11 (MUC2, MUC5AC, MUC5B and MUC6), MUC2 and MUC5B are highly subject to DNA methylation and histone modification, whereas MUC5AC is rarely influenced by epigenetic regulation and MUC6 does not undergo significant epigenetic regulation. Indeed, Parker et al. also demonstrated that SSA/Ps have high expression of MUC6 and SEMG1, among others. It is worth noting that MUC6 fold difference in SSA/Ps vs. HPs (37.2X) was much higher than that noted for SSA/Ps compared to uninvolved normal colon (12.9X). Therefore, these difficult-to-diagnose lesions could be evaluated for MUC6 and SEMG1 expression in addition to BRAF V600E to differentiate SSA/Ps from HPs. Among AA SSA/Ps, it remains to be seen if TRNP1 and FSCN1 elevated expression solely segregates with race. However, these factors individually, or collectively, may lead to better SSA/P detection and early diagnosis, particularly through non-invasive colorectal cancer screening approaches. (Excerpt from text, manuscript in process, p. 1, 3.)