Tissue gene mutation profiles in patients with colorectal cancer and their clinical implications

Ye, Jun; Lin, Mei; Zhang, Chuanmeng; Zhu, Xiaowei; Li, Sumeng; Liu, Hui; Yin, Junhui; Yu, Hong; Zhu, Kuichun

doi:10.3892/br.2020.1303

Cited by 21 publications

(13 citation statements)

References 51 publications

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“…KRAS amplification in CRC is a rare event, with an overall prevalence of 0.67–2% ( 11 , 12 ). Previous studies have identified somatic mutations in KRAS as biomarkers for inherent resistance to EGFR-targeted drugs in patients with CRC ( 13 ), with a positive tissue mutation rate of 32–52.1% ( 7 ).…”

Section: Discussionmentioning

confidence: 99%

An Early-Onset Advanced Rectal Cancer Patient With Increased KRAS Gene Copy Number Showed A Primary Resistance to Cetuximab in Combination With Chemotherapy: A Case Report

et al. 2021

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Mutations in KRAS (codon 12/13), NRAS, BRAFV600E, and amplification of ERBB2 and MET account for 70–80% of anti-epidermal growth factor receptor (EGFR) monoclonal antibody primary resistance. However, the list of anti-EGFR monoclonal antibody primary resistance biomarkers is still incomplete. Herein, we report a case of wild-type RAS/BRAF metastatic colorectal cancer (CRC) with resistance to anti-EGFR monoclonal antibody and chemotherapy. Initially, mutation detection in postoperative tumor tissue by using amplification-refractory mutation system polymerase chain reaction indicated wild-type RAS/BRAF without point mutations, insertion deletions, or fusion mutations. Therefore, we recommended combined therapy of cetuximab and FOLFIRI after failure of platinum-based adjuvant chemotherapy, but the disease continued to progress. Next generation sequencing analysis of the postoperative tumor tissue revealed that KRAS copy number was increased and detected SMAD4, RNF43, and PREX2 mutations. This is the first case of advanced CRC with increased copy numbers of KRAS resistant to cetuximab and chemotherapy, which results in poor patient survival, and other mutated genes may be associated with the outcomes. Our findings indicate KRAS copy number alterations should also be examined, especially with anti-EGFR monoclonal antibody therapy in CRC, since it may be related with the primary resistance to these drugs.

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Section: Discussionmentioning

confidence: 99%

An Early-Onset Advanced Rectal Cancer Patient With Increased KRAS Gene Copy Number Showed A Primary Resistance to Cetuximab in Combination With Chemotherapy: A Case Report

et al. 2021

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“…In one of our cases, there was a mutation in the tumour suppressor gene RB1, which are present in 5.8% of all colorectal cancers (14,15). To date, no statistically significant impact of RB1 gene mutations on patient prognosis in colorectal cancer has been shown [31]. In addition to CTNNB1 and RB1, a PIK3CA mutation was found in one of the two neoplasms.…”

Section: Woischke Et Almentioning

confidence: 54%

Mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon: detailed molecular characterisation of two cases indicates a distinct colorectal cancer entity

Woischke

Jung

Kumbrink

et al. 2020

The Journal of Pathology CR

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We present two rare cases of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon. A literature search revealed only three published cases with similar histology but none of these reports provided profound molecular and mutational analyses. Our two cases exhibited a distinct, colon-like immunophenotype with strong nuclear CDX2 and β-catenin expression in more than 90% of the tumour cells of both components. We analysed the two carcinomas regarding microsatellite stability, RAS, BRAF and PD-L1 status. In addition, next-generation panel sequencing with Ion AmpliSeq™ Cancer Hotspot Panel v2 was performed. This approach revealed mutations in FBXW7, CTNNB1 and PIK3CA in the first case and FBXW7 and RB1 mutations in the second case. We looked for similar mutational patterns in three publicly available colorectal adenocarcinoma data sets, as well as in collections of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) and colorectal neuroendocrine carcinomas. This approach indicated that the FBXW7 point mutation, without being accompanied by classical adenoma-carcinoma sequence mutations, such as APC, KRAS and TP53, likely occurs at a relatively high frequency in mixed neuroendocrine and squamous cell carcinoma and therefore may be characteristic for this rare tumour type. FBXW7 codifies the substrate recognition element of an ubiquitin ligase, and inactivating FBXW7 mutations lead to an exceptional accumulation of its target β-catenin which results in overactivation of the Wnt-signalling pathway. In line with previously described hypotheses of dedifferentiation of colon cells by enhanced Wnt-signalling, our data indicate a crucial role for mutant FBXW7 in the unusual morphological switch that determines these rare neoplasms. Therefore, mixed large cell neuroendocrine and a squamous cell carcinoma can be considered as a distinct carcinoma entity in the colon, defined by morphology, immunophenotype and distinct molecular genetic alteration(s).

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“…However, a few studies have revealed that the APC gene may have a different performance, with a few detected SNPs in exon 15 of this tumor suppressor gene as a germline mutation 19,[29][30][31][32] . A most recent study on common gene mutation profile in CRCs showed point mutations in exon 16 of APC gene with a 19.7% prevalence 29,[33][34][35] . Although APC has been well-recognized as an initiator gene in colorectal cancer carcinogenesis, its prognostic role has not been well-established.…”

Section: Discussionmentioning

confidence: 99%

The APC gene rs41115 polymorphism is associated with survival in Iranian colorectal cancer patients

et al. 2020

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Introduction: The onset of colorectal cancer is a complex process caused by numerous genetic pathways. APC functions as a ``"gatekeeper" and its mutations occur at the initiation stage of the colorectal tumorigenesis. The main aim of this study was to investigate common somatic mutations of exon 15 APC genes in patients with colorectal cancer in East Azerbaijan, Iran. Methods: This study was designed and performed as a cross-sectional and case-only study. Tissue biopsies were obtained during colonoscopy and confirmed colorectal carcinoma cases were evaluated. Two hotspot regions of exon 15 for APC mutations were evaluated using PCR amplification and Sanger sequence analysis. Results: The synonymous (p.Thr1475Thr) polymorphism was observed in all patients; 35 patients (61.4%) had AG genotype and 22 patients (38.6%) had AA genotype. Also, a missense mutation and two deletions were found. Pearson's correlation test showed a significant correlation between the stage of the disease (rho = 0.23, P =< 0.05), and anatomical subsite of the tumor with rs41115 polymorphism (rho = 0.31, P =< 0.05). Overall comparison of survival function in the different genotypes of the APC gene showed significant differences between groups, and CRCs with AG genotype had 3.24-fold higher hazard of mortality than CRCs with AA genotype (HR = 3.24; 95% CI: 1.21 - 8.68, P = 0.020). Conclusion: APC mutation plays an important predictive role in overall survival. However, the pattern and type of APC gene have a diverse impact on clinical outcomes in the Asian population. Moreover, in CRC patients the APC mutations were reported to be diverse variants.

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Tissue gene mutation profiles in patients with colorectal cancer and their clinical implications

Cited by 21 publications

References 51 publications

An Early-Onset Advanced Rectal Cancer Patient With Increased KRAS Gene Copy Number Showed A Primary Resistance to Cetuximab in Combination With Chemotherapy: A Case Report

An Early-Onset Advanced Rectal Cancer Patient With Increased KRAS Gene Copy Number Showed A Primary Resistance to Cetuximab in Combination With Chemotherapy: A Case Report

Mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon: detailed molecular characterisation of two cases indicates a distinct colorectal cancer entity

The APC gene rs41115 polymorphism is associated with survival in Iranian colorectal cancer patients

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