Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies

Abstract

Background:Signet ring cell colorectal cancer (SRCCa) has a bleak prognosis. Employing molecular pathology techniques we investigated the potential of precision medicine in this disease.Methods:Using test (n=26) and validation (n=18) cohorts, analysis of mutations, DNA methylation and transcriptome was carried out. Microsatellite instability (MSI) status was established and immunohistochemistry (IHC) was used to test for adaptive immunity (CD3) and the immune checkpoint PDL1.Results:DNA methylation data split the cohorts into hypermethylated (n=18, 41%) and hypomethylated groups (n=26, 59%). The hypermethylated group predominant in the proximal colon was enriched for CpG island methylator phenotype (CIMP), BRAF V600E mutation and MSI (P<0.001). These cases also had a high CD3+ immune infiltrate (P<0.001) and expressed PDL1 (P=0.03 in intra-tumoural lymphoid cells). The hypomethylated group predominant in the distal colon did not show any characteristic molecular features. We also detected a common targetable KIT mutation (c.1621A>C) across both groups. No statistically significant difference in outcome was observed between the two groups.Conclusions:Our data show that SRCCa phenotype comprises two distinct genotypes. The MSI+/CIMP+/BRAF V600E+/CD3+/PDL1+ hypermethylated genotype is an ideal candidate for immune checkpoint inhibitor therapy. In addition, one fourth of SRCCa cases can potentially be targeted by KIT inhibitors.

Impact of histological subtype on the prognosis of patients undergoing surgery for colon cancer

“…The reasons for these disparate results are likely multifactorial and may relate to different molecular profiles of SC versus CA cancers. To this point, Alvi et al reported the molecular profiling of SC and noted characteristics of SC that were similar to those of the Consensus Molecular Subtypes 1 described by Guinney et al including high mutation count, microsatellite instability (MSI), CpG‐island methylator phenotype (CIMP), BRAF mutation, add immune infiltration . In turn, patients with SC may benefit from specific therapeutic approaches including immune checkpoint inhibitors …”

“…According to the AJCC staging system, while 11.8% (n = 20 007) and 14.4% (n = 24 380) of patients had stage T1 and T2, respectively, 57.2% (n = 96 864) and 16.6% (n = 28 184) patients had stage T3 and T4 disease. A total of 97 623 (57.0%) patients had no disease, 25.4% (n = 43 548) N1 disease, and 17.6% (n = 30 242) of patients had N2 disease.…”

“…In fact, even though the majority (80‐90%) of patients with CC has classic adenocarcinoma (CA), 10‐20% of patients has less frequent histological subtypes including mucinous adenocarcinomas (MUC) and signet‐ring cell adenocarcinoma (SC) that have been associated with distinct clinicopathological characteristics and prognosis compared with CA . MUC and SC histological subtypes have specific genetic and molecular characteristics, including a high‐degree of mutation in DNA mismatch repair genes/microsatellite instability (MSI‐H), high‐frequency of CpG island methylator phenotype (CIMP‐high), higher methylation level of long interspersed nucleotide element‐1 (LINE‐1), and frequent BRAF mutation . From a clinical point of view, while several authors have demonstrated that patients with SC are younger and often present with an advanced tumor stage, the impact of MUC histology on the survival of CC patients is still debated .…”

“…higher methylation level of long interspersed nucleotide element-1 (LINE-1), and frequent BRAF mutation. [11][12][13][14] From a clinical point of view, while several authors have demonstrated that patients with SC are younger and often present with an advanced tumor stage, the impact of MUC histology on the survival of CC patients is still debated. 6,9,10,[15][16][17][18] In particular, in an analysis of National Cancer Data Base (NCDB) that included patients undergoing surgery between 1998 and 2002, Hyngstrom et al 18 demonstrated that MUC histotype was not associated with worse survival.…”

“…Moreover, compared with CA patients, patients with SC had a number of other distinct clinicopathologic characteristics including higher CEA values (abnormal: CA, n = 36,561, 41.6% vs SC, n = 643, 56.7%), as well as a higher incidence of tumor deposits (presence: CA, n = 4182, 7.1% vs SC, n = 79, 14.1%) and perineural invasion (presence: CA, n = 7276, 12.1% vs SC, n = 208, 29.5%). BRAF mutation, add immune infiltration 14,22. In turn, patients with SC may benefit from specific therapeutic approaches including immune checkpoint inhibitors 14,22.…”