ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer

Geißler, Anna-Lena; Geissler, M; Kottmann, Daniel; Lutz, Lisa; Fichter, Christiane D.; Fritsch, Ralph; Weddeling, Britta; Makowiec, Frank; Werner, Martin; Laßmann, Silke

doi:10.18632/oncotarget.15211

Cited by 21 publications

(20 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because patients with RAS wild‐type CRC can be non‐responders to EGFR‐targeted therapy, Geibler et al analyzed cell lines and tumor specimens to identify prediction markers by NGS, EGFR methylation and expression, and E‐cadherin expression. The authors revealed ATM mutations and low E‐cadherin expression as novel supportive predictive markers . Adua et al analyzed primary tumor and liver metastasis samples from 7 KRAS wild‐type patients and compared the genotypes of 22 genes associated with anti‐EGFR before and after chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…The authors revealed ATM mutations and low E-cadherin expression as novel supportive predictive markers. 8 Adua et al analyzed primary tumor and liver metastasis samples from 7 KRAS wild-type patients and compared the genotypes of 22 genes associated with anti-EGFR before and after chemotherapy. The results showed marked genotypic differences between pre-and post-treatment samples, which were likely attributable to tumor cell clones selected by therapy.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Molecular characterization of colorectal cancer using whole‐exome sequencing in a Taiwanese population

et al. 2019

View full text Add to dashboard Cite

Next‐generation sequencing (NGS) technology is currently used to establish mutational profiles in many heterogeneous diseases. The aim of this study was to evaluate the mutational spectrum in Taiwanese patients with colorectal cancer (CRC) to help clinicians identify the best treatment method. Whole‐exome sequencing was conducted in 32 surgical tumor tissues from patients with CRC. DNA libraries were generated using the Illumina TruSeq DNA Exome, and sequencing was performed on the Illumina NextSeq 500 system. Variants were annotated and compared to those obtained from publicly available databases. The analysis revealed frequent mutations in APC (59.38%), TP53 (50%), RAS (28.13%), FBXW7 (18.75%), RAF (9.38%), PIK3CA (9.38%), SMAD4 (9.38%), and SOX9 (9.38%). A mutation in TCF7L2 was also detected, but at lower frequencies. Two or more mutations were found in 22 (68.75%) samples. The mutation rates for the WNT, P53, RTK‐RAS, TGF‐β, and PI3K pathways were 78.13%, 56.25%, 40.63%, 18.75%, and 15.63%, respectively. RTK‐RAS pathway mutations were correlated with tumor size ( P = 0.028). We also discovered 23 novel mutations in NRAS , PIK3CA , SOX9 , APC , SMAD4 , MSH3 , MSH4 , PMS1 PMS2 , AXIN2 , ERBB2 , PIK3R1 , TGFBR2 , and ATM that were not reported in the COSMIC, The Cancer Genome Atlas, and dbSNP databases. In summary, we report the mutational landscape of CRC in a Taiwanese population. NGS is a cost‐effective and time‐saving method, and we believe that NGS will help clinicians to treat CRC patients in the near future.

show abstract

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Molecular characterization of colorectal cancer using whole‐exome sequencing in a Taiwanese population

et al. 2019

View full text Add to dashboard Cite

show abstract

“…This mutation, in addition to the pathogenic variant (C>T, rs121913530, Gly12Ser) were detected in patient ID 8. Both variants were shown to discriminate conventional adenoma from CRC [25]. The remaining pathogenic KRAS variants were found in exon 3 (G>A, rs104894364, Thr58Ile patient ID 20) and in exon 4 (C>T, rs121913527, Ala146Thr patient ID 10), both are well-known pathogenic variants in CRC [26].…”

Section: Kras Pathogenic and Likely Pathogenic Variantsmentioning

confidence: 99%

“…Finally, PIK3CA, which plays important role in MAPK pathway, has got pathogenic missense variants in patient ID 4 (G>A, rs104886003, Glu545Lys) and patient ID 16 (A>G, rs121913279, His1047Arg,). Both variants are PIK3CA hotspot somatic mutations [57] with good response to cetuximab [25]. Interestingly, patient ID 4 is a very good example of a possible interplay between pathways of TP53, KRAS and PI3K.…”

Section: Tp53 Showed the Highest Percentage Of Germline Inherited Mutmentioning

confidence: 99%

Genetic Variations of Selected Genes Using Target Deep Sequencing in Colorectal Cancer Patients

Farghal¹,

Saied²,

Ghaith³

et al. 2017

J Cancer Sci Ther

View full text Add to dashboard Cite

Background: Colorectal carcinoma (CRC) is a burden problem in a developing country like Egypt since patients are usually admitted in late stage with bad prognosis and short overall survival. Because of genetic predisposition of CRC and introduction of advanced molecular techniques, efforts are directed to screen for potential pathogenic or disease-causing variants in CRC patients Methods: DNA was isolated from formalin fixed paraffin embedded tissue sections collected from 24 CRC confirmed diagnosed patients. TruSight CRC panel (Illumina) was used for detection of different variants in 15 genes. The generated reads were obtained from Illumina Miseq were clustered into single nucleotide polymorphism (SNPs) and small insertions/deletions (Indels). Further pathogenic variants with somatic and germline mutations were identified according to the recommended criteria. Some CRC patients were subjected to anti-EGFR target therapy.Results: Most of the variants were detected in TP53 gene 140 variants (65%); 105 short deletions none of them was pathogenic, 29 missense mutations and 6 SNPs at splicing sites. Next, ERBB2 has got 17 variants (8.8%) (missense and splicing), 8 of them were damaging disease causing variants. Besides, 16 pathogenic variants were identified in 12 patients (6 in TP53 and 7 in KRAS). Some pathogenic variants were not reported before in CRC e.g. TP53 C>A, rs121912654, Val157Phe. Additionally, patients carried different KRAS wild mutations showed variable response to anti-EGFR target therapy. Conclusion:The most affected pathway in CRC was TP53 pathway followed by ERBB2, NRAS, KRAS and PIK3CA genes. Variable response to target therapy suggested dependence on the type of pathogenic variant identified, also a possible role of ERBB2 which had a significant variant frequency.NRAS. The prevalence rate of TP53 mutation in Arab population is 52.5% compared to 47.5% in matched Western population [7]. TP53 mutations have roles in determining progression, invasiveness and also metastasis of CRC. So, CRC patients with mutant TP53 have more progressive phenotype and poorer survival than those with TP53 wild type [8]. The phosphatidylinositol 3-kinase/Akt/mammalian target of

show abstract

“…The authors described three hypermutated tumors with MSI-H or POLE mutation and ERBB2 amplified tumors (5% of cases) as well, which might benefit of anti-PD-1 or HER2-targeted therapy in absence of RAS/RAF mutations, respectively. Again, a recent study on both cell lines and tumor specimens [ 83 ] highlighted the importance of NGS in detecting genes potentially involved in the resistance to anti-EGFR therapy in KRAS wild-type patients. The authors analyzed the response of 7 CRC cell lines to cetuximab as well as primary tumors, liver and lung metastasis from 25 CRC patients treated with cetuximab or panitumumab, by evaluating NGS (Illumina) mutation profiles of 48 cancer-related genes, EGFR and E-cadherin expression.…”

Section: Ngs In Crcmentioning

confidence: 99%

Next-generation sequencing: recent applications to the analysis of colorectal cancer

et al. 2017

View full text Add to dashboard Cite

Since the establishment of the Sanger sequencing method, scientists around the world focused their efforts to progress in the field to produce the utmost technology. The introduction of next-generation sequencing (NGS) represents a revolutionary step and promises to lead to massive improvements in our understanding on the role of nucleic acids functions. Cancer research began to use this innovative and highly performing method, and interesting results started to appear in colorectal cancer (CRC) analysis. Several studies produced high-quality data in terms of mutation discovery, especially about actionable or less frequently mutated genes, epigenetics, transcriptomics. Analysis of results is unveiling relevant perspectives aiding to evaluate the response to therapies. Novel evidences have been presented also in other directions such as gut microbiota or CRC circulating tumor cells. However, despite its unquestioned potential, NGS poses some issues calling for additional studies. This review intends to offer a view of the state of the art of NGS applications to CRC through examination of the most important technologies and discussion of recent published results.

show abstract

ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer

Cited by 21 publications

References 74 publications

Molecular characterization of colorectal cancer using whole‐exome sequencing in a Taiwanese population

Molecular characterization of colorectal cancer using whole‐exome sequencing in a Taiwanese population

Genetic Variations of Selected Genes Using Target Deep Sequencing in Colorectal Cancer Patients

Next-generation sequencing: recent applications to the analysis of colorectal cancer

Contact Info

Product

Resources

About