Signet ring cell colorectal cancer: genomic insights into a rare subpopulation of colorectal adenocarcinoma

Abstract

Background Signet ring cell carcinoma (SRCC) is a rare subtype of colorectal cancer (CRC). The aim of this study was to characterise the genomic alterations and outcomes of SRCC. Methods Medical records of metastatic CRC (mCRC) patients whose tumours were evaluated by NGS analysis were reviewed. SC-mCRC were classified into two groups: SRCC (>50% signet ring cells) and adenocarcinoma (AC) with SC component (≤50% signet ring cells). Results Six hundred and sixty-five mCRC patients were included. Of the 93 mCRC cases with SC features, 63 had slides for review. Of those 63 cases, 35 were confirmed SRCC, and 28 were AC with SC component. Compared with AC group, KRAS and PIK3CA mutations (mts) were found in only 11% (OR: 0.13) and 3% (OR: 0.15) of SRCC cases, respectively. In contrast to the 44% rate of APC mts in AC group, only 3% of SRCC patients had APC mts (OR = 0.04). Conclusions SRCC has distinct molecular features, including low rates of KRAS , PIK3CA and APC mts. Further study to identify activation pathways and potential therapeutic targets are needed.

Frequent RNF43 mutation contributes to moderate activation of Wnt signaling in colorectal signet-ring cell carcinoma

“…1D). Lower mutation rates of PIK3CA and KRAS in SRCC have also been reported recently (Korphaisarn et al, 2019). The phospho-ERK and phospho-S6 signals, indicators of MAPK and PI3K activities respectively, were much lower in SRCC, which was consistent with mutation data (Fig.…”

“…1C,1D, S4 and S5). APC mutation was most prevalent in AC (∼80%) and MAC (∼70%) (TCGA, 2012), whereas it only occurred in one (3.4%) hypermutated SRCC, this is consistent with recent reports (Nam et al, 2018;Korphaisarn et al, 2019). Interestingly, SRCC was associated with frequent mutations in RNF43, with nonsense mutations (p.Glu43* and p.Arg132*) enriched at the N-terminus, regardless of mutation burden ( Fig.…”

“…Due to low incidence and occasionally mixed presence of SRCC with AC or MAC, genome-wide characterization of SRCC at a large scale is challenging. Limited whole-exome sequencing (n = 5) and gene panel sequencing (n = 35) results indicate that, most driver mutations associated with CRC, such as APC, KRAS, and PIK3CA, are mutated at lower rates in SRCC (Nam et al, 2018;Korphaisarn et al, 2019). Mutations and signaling pathways responsible for the tumorigenesis of SRCC remains to be uncovered.…”

Subdivision of metastatic colorectal cancer for identifying patients who benefit more from primary tumor resection

“…Primary colorectal signet-ring cell carcinoma has distinct molecular features [17], aggressive behavior and worse prognosis[18] as compared to other histological subtypes. Our study found that primary tumor resection only decreased 37.7% mortality risk for patients with signet ring cell carcinoma.…”

Subdivision of metastatic colorectal cancer for identifying patients who benefit more from primary tumor resection

“…Primary colorectal signet-ring cell carcinoma has distinct molecular features [17], aggressive behavior and worse prognosis [18] as compared to other histological subtypes. Our study found that primary tumor resection only decreased 37.7% mortality risk for patients with signet ring cell carcinoma.…”