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 languageEnglish
Pages (from-to)203-209
JournalBritish Journal of Cancer
Volume117
Issue number2
Early online date08 Jun 2017
DOIs
Publication statusPublished - 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

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