Mucinous adenocarcinoma is a pharmacogenomically distinct subtype of colorectal cancer

Reynolds, Ian S.; OʼConnell, Emer; Fichtner, Michael; McNamara, Deborah A.; Kay, Elaine W.; Prehn, Jochen H M; Furney, Simon J.; Burke, John P.

doi:10.1038/s41397-019-0137-6

Cited by 32 publications

(31 citation statements)

References 31 publications

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“…This is in line with previous studies, however, it is known that some patients with mucinous rectal cancer do respond to chemoradiotherapy (26)(27)(28)(29). Furthermore, there is evidence to suggest that some mucinous tumors might overexpress genes or have somatic mutations in genes encoding for enzymes involved in the metabolism of pyrimidine and platinum-based compounds and this may result in chemoresistance (30,31). The most frequently mutated genes in the Beaumont cohort included; APC (80%), KRAS (70%) FBXW7 (50%), TP53 (40%), and MUC16 (40%).…”

Section: Discussionsupporting

confidence: 89%

Mucinous Adenocarcinoma of the Rectum: A Whole Genome Sequencing Study

et al. 2020

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Introduction: Mucinous adenocarcinoma of the rectum is an infrequently encountered histological subtype that is associated with an impaired response to chemoradiotherapy and a worse overall prognosis. A genomic profile analysis of mucinous rectal tumors has not yet been performed. The aim of this study was to comprehensively describe the burden of somatic mutations and copy number variation as well as perform mutational signature and microbial analysis of an in-house collected cohort of mucinous adenocarcinoma of the rectum. Methods: Genomic DNA was extracted from 10 cases of mucinous rectal cancer and matched normal tissue. Whole genome sequencing (WGS) was carried out on these 10 cases and a comprehensive bioinformatic analysis was undertaken. Results: The average number of SNVs, InDels and SVs in the cohort was 16,600, 1,855, and 120, respectively. A single case was MSI-H. KRAS mutations were found in 70% of cases while TP53 was mutated in only 40% of cases. CNA gain was identified on chromosomes 7, 8, 12, 13, and 20 while CNA loss was found on chromosomes 4, 8, 17, and 18 corresponding to oncogenes and tumor suppressor genes, respectively. Overall mucinous rectal cancers are more likely to be MSI-H and to have KRAS, BRAF, and PIK3CA mutations when compared to rectal adenocarcinoma NOS. Microbial analysis demonstrated an abundance of Fusobacterium nucleatum in tumor samples compared to normal tissue. Conclusion: This study provides a detailed WGS analysis of 10 cases of mucinous rectal cancer. It demonstrates an important lesson in tumor biology in that histologically similar tumors can have extensive differences at the genomic level. This study is relevant as it raises important questions about the relationship between bacteria and malignancy.

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Section: Discussionsupporting

confidence: 89%

Mucinous Adenocarcinoma of the Rectum: A Whole Genome Sequencing Study

et al. 2020

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“…The expression of recognized drug metabolism genes was compared between 21 patients with mucinous CRC and 30 patients with non-mucinous CRC by Glasgow et al Mucinous tumors were found to significantly overexpress thymidylate synthase (TYMS) and glutathione S-transferase pi (GSTP1) genes, but no significant difference was noted between the expression of other drug related genes in the study cohort [42]. A recent analysis of The Cancer Genome Atlas (TCGA) dataset identified significant differences in the simple somatic mutation (SSM) rate and copy number variation (CNV) rate in genes with recognized roles in chemotherapy drug resistance in mucinous and non-mucinous CRC [43]. One gene associated with 5-FU resistance, thymidine phosphorylase (TYMP), was found to have an SSM rate of 5.97% in mucinous tumors compared with only 1.08% in non-mucinous tumors.…”

Section: Chemotherapy Drug Metabolism and Resistance In Mucinous Colomentioning

confidence: 99%

Resistance to Cell Death in Mucinous Colorectal Cancer—A Review

OʼConnell

Reynolds

McNamara

et al. 2021

Cancers

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Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10–15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is frequently associated with resistance to apoptosis. Inferior prognosis is observed in mucinous CRC, particularly in rectal cancer and metastatic cases. Mucins are heavily glycosylated secretory or transmembrane proteins that participate in protection of the colonic epithelium. MUC2 overexpression is a hallmark of mucinous CRCs. Mucinous CRC is associated with KRAS and BRAF mutation, microsatellite instability and the CpG island methylator phenotype. Mutations of the APC gene and p53 mutations which are characteristic non-mucinous colorectal adenocarcinoma are less common in mucinous CRC. Both physical and anti-apoptotic properties of mucin provide mechanisms for resistance to cell death. Mucin glycoproteins are associated with decreased expression of pro-apoptotic proteins, increased expression of anti-apoptotic proteins and increased cell survival signaling. The role for BCL-2 proteins, including BCL-XL, in preventing apoptosis in mucinous CRC has been explored to a limited extent. Additional mechanisms opposing cell death include altered death receptor expression and altered mutation rates in genes responsible for chemotherapy resistance. The roles of alternate cell death programs including necroptosis and pyroptosis are not well understood in mucinous CRC. While the presence of MUC2 is associated with an immunosuppressive environment, the tumor immune environment of mucinous CRC and the role of immune-mediated tumor cell death likewise require further investigation. Improved understanding of cell death mechanisms in mucinous CRC may allow modification of currently used regimens and facilitate targeted treatment.

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“…Mucinous CRC is known for a poorer response to chemotherapy and a worse prognosis than other types of CRC, owing largely to a higher rate of resistance [ 86 ]. Reynolds et al [ 87 ] recently analyzed TCGA data for 67 mucinous CRC and compared them to 456 samples of non-mucinous CRC. They looked for associations of 26 pharmacogenes with response to irinotecan, oxaliplatin and 5-fluorouracil (5-FU).…”

Section: Somatic Variants In Abcs and Cyps In Solid Tumorsmentioning

confidence: 99%

“…The mutation rate of these two genes associated with resistance to irinotecan. The mutations did not lead to a statistically significant difference in the expression of corresponding proteins; however, the authors postulated that these mutations result in overactive proteins that more effectively export irinotecan out of the cell, lowering its efficacy [ 87 ].…”

Section: Somatic Variants In Abcs and Cyps In Solid Tumorsmentioning

confidence: 99%

Pharmacogenomics to Predict Tumor Therapy Response: A Focus on ATP-Binding Cassette Transporters and Cytochromes P450

Hlaváč

Holý

Souček

2020

JPM

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Pharmacogenomics is an evolving tool of precision medicine. Recently, due to the introduction of next-generation sequencing and projects generating “Big Data”, a plethora of new genetic variants in pharmacogenes have been discovered. Cancer resistance is a major complication often preventing successful anticancer treatments. Pharmacogenomics of both somatic mutations in tumor cells and germline variants may help optimize targeted treatments and improve the response to conventional oncological therapy. In addition, integrative approaches combining copy number variations and long noncoding RNA profiling with germline and somatic variations seem to be a promising approach as well. In pharmacology, expression and enzyme activity are traditionally the more studied aspects of ATP-binding cassette transporters and cytochromes P450. In this review, we briefly introduce the field of pharmacogenomics and the advancements driven by next-generation sequencing and outline the possible roles of genetic variation in the two large pharmacogene superfamilies. Although the evidence needs further substantiation, somatic and copy number variants as well as rare variants and common polymorphisms in these genes could all affect response to cancer therapy. Regulation by long noncoding RNAs has also been shown to play a role. However, in all these areas, more comprehensive studies on larger sets of patients are needed.

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Mucinous adenocarcinoma is a pharmacogenomically distinct subtype of colorectal cancer

Cited by 32 publications

References 31 publications

Mucinous Adenocarcinoma of the Rectum: A Whole Genome Sequencing Study

Mucinous Adenocarcinoma of the Rectum: A Whole Genome Sequencing Study

Resistance to Cell Death in Mucinous Colorectal Cancer—A Review

Pharmacogenomics to Predict Tumor Therapy Response: A Focus on ATP-Binding Cassette Transporters and Cytochromes P450

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