Clinicopathological and Molecular Characteristics of Serrated Lesions in Japanese Elderly Patients

Abstract

Background: The population in Japan is aging more rapidly than in any other country. However, no studies have determined the characteristics of the large population of elderly patients with colorectal tumors. Therefore, we examined the clinicopathological and molecular features of these tumors in elderly patients. Methods: In total, 1,627 colorectal tumors (393 serrated lesions, 277 non-serrated adenomas and 957 colorectal cancers) were acquired from patients. Tumor specimens were analyzed for BRAF and KRAS mutations, CpG island methylator phenotype-specific promoters (CACNA1G, CDKN2A, IGF2 and RUNX3), IGFBP7, MGMT, MLH1 and RASSF2 methylation, microsatellite instability (MSI) and microRNA- 31 (miR-31). Results: The frequency of elderly patients (aged ≥75 years) with sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that of those with other serrated lesions and non-serrated adenomas (p < 0.0001). In elderly patients, all SSAs were located in the proximal colon (particularly the cecum to ascending colon). High miR-31 expression, MLH1 methylation and MSI-high status were more frequently detected in SSAs from elderly patients than in those from non-elderly patients. In contrast, no significant differences were found between older age of onset and high-grade dysplasia for traditional serrated adenomas or non-serrated adenomas in any of these molecular alterations. Conclusion: In elderly patients, all SSAs were located in the proximal colon. Furthermore, cytological dysplasia and molecular alterations were more frequently detected in elderly patients with SSAs than in non-elderly patients. Thus, careful colonoscopic examinations of the proximal colon are necessary for elderly patients because SSAs in those patients may exhibit malignant potential.

Analysis of the molecular features of rectal carcinoid tumors to identify new biomarkers that predict biological malignancy

“…The BRAF, KRAS , and NRAS mutations are widely recognized to be the major causes of RAS/RAF/MEK/ERK pathway dysregulation in colorectal cancer [ 2 , 9 , 41 , 42 ]. Previous studies reported that BRAF, KRAS , and NRAS mutations occur in 10%–15% [ 2 , 35 , 36 , 47 ], 35–40% [ 36 , 37 , 42 , 48 ], and 2–7% of colorectal cancers [ 42 , 49 ], respectively. The PIK3CA gene encodes the catalytic subunit p110 alpha of PI3K.…”

“…Genomic DNA was used for PCR and targeted pyrosequencing of BRAF (codon 600), KRAS (codon 12, 13, 61, or 146), NRAS (codon 12, 13, or 61), and PIK3CA (exon 9 or 20) as previously described [ 2 , 42 , 47 , 49 , 50 , 52 ]. MSI analysis was performed using two markers (BAT25 and BAT26) as previously described [ 2 , 48 ].…”

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

“…Of note, only 2-5% of SSLs (< 0.5% of serrated polyps) progress towards invasive CRCs and the hallmark of this progression potential is the dysplasia [56][57][58] characterized by architectural changes (crowded and elongated crypts with increased branching complexity, cribriforming, and villous architecture) and cytological atypia (from subtle hypermucinous changes to overt dysplastic changes) [59]. The molecular landscape of SSLs is characterized by wild type KRAS, mutated BRAF, CIMP-H phenotype (acquired in early phase) with methylated MLH1 which result in MSI or methylated MGMT with MSS status, WNT pathway activation and in a minority of cases p16 silencing and TP53 mutation (acquired in late phase with dysplasia) [60].…”

Clinicopathological factors associated with BRAF‐V600E mutation in colorectal serrated adenomas

“…Forty studies assessing 3511 serrated adenomas were included . The whole process of study selection is reported schematically in Figure .…”