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

Muhammad Alvi; Maurice B Loughrey; Philip Dunne; Stephen McQuaid; Richard Turkington; Marc-Aurel Fuchs; Claire McGready; Victoria Bingham; Wendy Moore; Mark Lawler; Jacqueline A James; Graeme I Murray; Richard H Wilson; Perry Maxwell; Manuel Salto-Tellez

doi:10.1038/bjc.2017.168

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

Muhammad Alvi, Maurice B Loughrey, Philip Dunne, Stephen McQuaid, Richard Turkington, Marc-Aurel Fuchs, Claire McGready, Victoria Bingham, Wendy Moore, Mark Lawler, Jacqueline A James, Graeme I Murray, Richard H Wilson, Perry Maxwell, Manuel Salto-Tellez

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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.

Original language	English
Pages (from-to)	203-209
Journal	British Journal of Cancer
Volume	117
Issue number	2
Early online date	08 Jun 2017
DOIs	https://doi.org/10.1038/bjc.2017.168 https://doi.org/10.1038/bjc.2017.168
Publication status	Published - 11 Jul 2017

Keywords

Carcinoma, Signet Ring Cell
Colorectal Neoplasms
CpG Islands
DNA Methylation
Female
Gene Expression Regulation, Neoplastic
Genomics
Genotype
Humans
Male
Microsatellite Instability
Mutation
Neoplasm Proteins
Proto-Oncogene Proteins B-raf
Transcriptome
Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/bjc.2017.168Licence: CC BY-NC-SA
10.1038/bjc.2017.168

Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies
Copyright 2017 the authors. This is an open access article published under a Creative Commons Attribution-NonCommercial-ShareAlike License (https://creativecommons.org/licenses/by-nc-sa/4.0/), which permits use, distribution and reproduction for non-commercial purposes, provided the author and source are cited and new creations are licensed under the identical terms.
Final published version, 1.39 MBLicence: CC BY-NC-SA

Manuel Salto-Tellez
- m.salto-tellezqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Clinical Professor
- Patrick G Johnston Centre for Cancer Research
Person: Academic

Cite this

Alvi, M., Loughrey, M. B., Dunne, P., McQuaid, S., Turkington, R., Fuchs, M.-A., McGready, C., Bingham, V., Moore, W., Lawler, M., James, J. A., Murray, G. I., Wilson, R. H., Maxwell, P., & Salto-Tellez, M. (2017). Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies. British Journal of Cancer, 117(2), 203-209. https://doi.org/10.1038/bjc.2017.168, https://doi.org/10.1038/bjc.2017.168

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

abstract = "BACKGROUNDSignet ring cell colorectal cancer (SRCCa) has a bleak prognosis. Employing molecular pathology techniques we investigated the potential of precision medicine in this disease.METHODSUsing 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.",

keywords = "Carcinoma, Signet Ring Cell, Colorectal Neoplasms, CpG Islands, DNA Methylation, Female, Gene Expression Regulation, Neoplastic, Genomics, Genotype, Humans, Male, Microsatellite Instability, Mutation, Neoplasm Proteins, Proto-Oncogene Proteins B-raf, Transcriptome, Journal Article",

author = "Muhammad Alvi and Loughrey, {Maurice B} and Philip Dunne and Stephen McQuaid and Richard Turkington and Marc-Aurel Fuchs and Claire McGready and Victoria Bingham and Wendy Moore and Mark Lawler and James, {Jacqueline A} and Murray, {Graeme I} and Wilson, {Richard H} and Perry Maxwell and Manuel Salto-Tellez",

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doi = "10.1038/bjc.2017.168",

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journal = "British Journal of Cancer",

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Alvi, M, Loughrey, MB, Dunne, P, McQuaid, S, Turkington, R , Fuchs, M-A, McGready, C, Bingham, V, Moore, W, Lawler, M , James, JA, Murray, GI, Wilson, RH, Maxwell, P & Salto-Tellez, M 2017, 'Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies', British Journal of Cancer, vol. 117, no. 2, pp. 203-209. https://doi.org/10.1038/bjc.2017.168, https://doi.org/10.1038/bjc.2017.168

TY - JOUR

T1 - Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies

AU - Alvi, Muhammad

AU - Loughrey, Maurice B

AU - Dunne, Philip

AU - McQuaid, Stephen

AU - Turkington, Richard

AU - Fuchs, Marc-Aurel

AU - McGready, Claire

AU - Bingham, Victoria

AU - Moore, Wendy

AU - Lawler, Mark

AU - James, Jacqueline A

AU - Murray, Graeme I

AU - Wilson, Richard H

AU - Maxwell, Perry

AU - Salto-Tellez, Manuel

PY - 2017/7/11

Y1 - 2017/7/11

N2 - BACKGROUNDSignet ring cell colorectal cancer (SRCCa) has a bleak prognosis. Employing molecular pathology techniques we investigated the potential of precision medicine in this disease.METHODSUsing 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.

AB - BACKGROUNDSignet ring cell colorectal cancer (SRCCa) has a bleak prognosis. Employing molecular pathology techniques we investigated the potential of precision medicine in this disease.METHODSUsing 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.

KW - Carcinoma, Signet Ring Cell

KW - Colorectal Neoplasms

KW - CpG Islands

KW - DNA Methylation

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Genomics

KW - Genotype

KW - Humans

KW - Male

KW - Microsatellite Instability

KW - Mutation

KW - Neoplasm Proteins

KW - Proto-Oncogene Proteins B-raf

KW - Transcriptome

KW - Journal Article

U2 - 10.1038/bjc.2017.168

DO - 10.1038/bjc.2017.168

M3 - Article

C2 - 28595259

SN - 0007-0920

VL - 117

SP - 203

EP - 209

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 2

ER -

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

Abstract

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UN SDGs

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Manuel Salto-Tellez

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