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

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 transcr...

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Published in:British journal of cancer Vol. 117; no. 2; pp. 203 - 209
Main Authors: Alvi, Muhammad A, Loughrey, Maurice B, Dunne, Philip, McQuaid, Stephen, Turkington, Richard, Fuchs, Marc-Aurel, McGready, Claire, Bingham, Victoria, Pang, Brendan, Moore, Wendy, Maxwell, Perry, Lawler, Mark, James, Jacqueline A, Murray, Graeme I, Wilson, Richard H, Salto-Tellez, Manuel
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 11.07.2017
Nature Publishing Group
Subjects:
631/208/727
692/4028/67/1059/2325
692/4028/67/1059/602
692/4028/67/1504/1885
Adaptive immunity
Biomedical and Life Sciences
Biomedicine
Cancer Research
Carcinoma, Signet Ring Cell - genetics
Carcinoma, Signet Ring Cell - pathology
CD3 antigen
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
CpG islands
CpG Islands - genetics
DNA methylation
DNA Methylation - genetics
Drug Resistance
Epidemiology
Female
Gene expression
Gene Expression Regulation, Neoplastic
Genomics
Genotype
Genotypes
Humans
Immune checkpoint inhibitors
Immunohistochemistry
Lymphoid cells
Male
Microsatellite Instability
Molecular Medicine
Mutation
Neoplasm Proteins - biosynthesis
Oncology
Precision medicine
Proto-Oncogene Proteins B-raf - genetics
Statistical analysis
Transcriptome - genetics
Translational Therapeutics
PDL1
KIT
genotype
ISSN:0007-0920, 1532-1827, 1532-1827
Online Access:Get full text
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Summary: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.
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/bjc.2017.168