Dataset Information

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.

SUBMITTER: Alvi MA

PROVIDER: S-EPMC5520517 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Alvi Muhammad A MA Loughrey Maurice B MB Dunne Philip P McQuaid Stephen S Turkington Richard R Fuchs Marc-Aurel MA McGready Claire C Bingham Victoria V Pang Brendan B Moore Wendy W Maxwell Perry P Lawler Mark M James Jacqueline A JA Murray Graeme I GI Wilson Richard H RH Salto-Tellez Manuel M

British journal of cancer 20170608 2

<h4>Background</h4>Signet ring cell colorectal cancer (SRCCa) has a bleak prognosis. Employing molecular pathology techniques we investigated the potential of precision medicine in this disease.<h4>Methods</h4>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.<h4> ...[more]

PMID: 28595259

Similar Datasets

Project description:BackgroundWe performed a retrospective study to assess the clinicopathological characters, molecular alterations and multigene mutation profiles in colorectal cancer patients with signet-ring cell component.MethodsBetween November 2008 and January 2015, 61 consecutive primary colorectal carcinomas with signet-ring cell component were available for pathological confirmation. RAS/BRAF status was performed by direct sequencing. 14 genes associated with hereditary cancer syndromes were analyzed by targeted gene sequencing.ResultsA slight male predominance was detected in these patients (59.0%). Colorectal carcinomas with signet-ring cell component were well distributed along the large intestine. A frequently higher TNM stage at the time of diagnosis was observed, compared with the conventional adenocarcinoma. Family history of malignant tumor was remarkable with 49.2% in 61 cases. The median OS time of stage IV patients in our study was 14 months. RAS mutations were detected in 22.2% (12/54) cases with KRAS mutations in 16.7% (9/54) cases and Nras mutations in 5.4%(3/54) cases. BRAF V600E mutation was detected in 3.7% (2/54) cases. As an exploration, we analyzed 14 genes by targeted gene sequencing. These genes were selected based on their biological role in association with hereditary cancer syndromes. 79.6% cases carried at least one pathogenic mutation. Finally, the patients were classified by the percentage of signet-ring cell. 39 (63.9%) cases were composed of ≥50% signet-ring cells; 22 (36.1%) cases were composed of <50% signet-ring cells. We compared clinical parameters, molecular and genetic alterations between the two groups and found no significant differences.ConclusionsColorectal adenocarcinoma with signet-ring cell component is characterized by advanced stage at diagnosis with remarkable family history of malignant tumor. It is likely a negative prognostic factor and tends to affect male patients with low rates of RAS /BRAF mutation. Colorectal patients with any component of signet-ring cells, regardless of the extent, shared similar clinicopathological characteristics, molecular alterations and genetic profiles.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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