scholarly journals Colorectal cancer is associated with the presence of cancer driver mutations in normal colon

2021 ◽  
Author(s):  
Julia Matas ◽  
Brendan Kohrn ◽  
Jeanne Fredrickson ◽  
Kelly T Carter ◽  
Ming Yu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Molecule ◽  
Mutation Detection ◽  
Low Frequency ◽  
Driver Mutations ◽  
Normal Colon ◽  
Kras Mutations ◽  
Tp53 Mutations ◽  
Cancer Driver ◽  
Cancer Mutations

While somatic mutations in colorectal cancer (CRC) are well characterized, little is known about the accumulation of cancer mutations in the normal colon prior to cancer. Here we have developed and applied an ultra-sensitive, single-molecule mutational test based on CRISPR-DS technology, which enables mutation detection at extremely low frequency (<0.001) in normal colon from patients with and without CRC. We found oncogenic KRAS mutations in the normal colon of about one third of patients with CRC but in none of the patients without CRC. Patients with CRC also carried more TP53 mutations than patients without cancer, and these mutations were more pathogenic and formed larger clones, especially in patients with early onset CRC. Most mutations in normal colon were different from the driver mutations in tumors suggesting that the occurrence of independent clones with pathogenic KRAS and TP53 mutations is a common event in the colon of individuals that develop CRC.

VHVT: An ultra-sensitive somatic mutation detection and performance assessment program.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1588-1588 ◽  
Author(s):  
Jilong Liu ◽  
Zu Liu ◽  
Shaomin Cheng ◽  
Fengming Guo ◽  
Meihua Tan ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Mutation Detection ◽  
Low Frequency ◽  
Allelic Frequency ◽  
Driver Mutations ◽  
Clinical Samples ◽  
Sequencing Error ◽  
Sequencing Data ◽  
Standard Data ◽  
Somatic Mutation Detection

1588 Background: NGS as a high throughput technique is particular valuable for cancer given its ability to detect multiple driver mutations. While reads contain SNVs and short InDels can be mapped to the right position using gatk-like programs, a program designed for germline mutation detection, reads contain long InDels such as EGFR EX19 deletions often wrongly mapped especially when deletions near the ends of the reads. Thus, gatk would not recognize these reads, consequently underestimate the mutation allelic frequency, and even missed out InDels when supporting reads were rare. Methods: Here we present a variation hotspot validation toolkit (VHVT), a validation based method to precisely detect the ultra-low frequency somatic mutations. As far as we know, it is the first specialized somatic mutation detection software. First, reference sequences aimed at the hotspot mutations were assembled, then reads were be mapped to the new assembled reference to precisely distinguish the supporting reads. Moreover, log odds (LOD) and Poisson mathematical model were integrated to control sequencing error, as a result, VHVT can achieve a limitation of detection at 0.01% with sensitivity and specificity above 95% and 99% respectively. In addition, we developed a method to quantitatively assess the performance of variation detection program using standard reference data. By mapping to the reconstructed reference, all supporting reads will be detected in sequencing data, and comparing theses with the number of supporting reads delivered by a program we can define recognition ratio of supporting reads. Results: Our reference standard data showed that VHVT can recognize average 30% more support reads than gatk for EGFR EX19 deletions. In a total 498 NSCLC clinical samples test, VHVT detected actionable mutations in 289 samples. 243 positive mutations were verified (168 by SANGER sequencing, 75 by ddPCR) with concordance rate at 100%. Conclusions: Taken all together, our results demonstrated the robust performance of VHVT for somatic mutation detection and program assessment and thus facilitate the development of personalized cancer therapy.

A novel RAS internal tandem duplication involving the switch II domain disrupts GAP-binding and activates oncogenic signaling.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15069-e15069
Author(s):  
Emil Lou ◽  
Thomas Turbyville ◽  
Dhirendra Simanshu ◽  
Rendong Yang ◽  
John Columbus ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colorectal Carcinoma ◽  
Primary Tumor ◽  
Tandem Duplication ◽  
Pathogenic Mutation ◽  
Driver Mutations ◽  
Molecular Testing ◽  
Oncogenic Signaling ◽  
Kras Mutations ◽  
Internal Tandem Duplication

e15069 Background: Recent clinical guidelines for expansion of molecular testing of oncogenic RAS mutations in colorectal carcinoma have led to increased identification of mutations in this patient population. The clinical characteristics of NRAS-mutated colorectal carcinoma have not been well established because of the lower prevalence of these mutations (< 6%) as compared to oncogenic KRAS mutations. Here, we report the discovery of a novel internal tandem duplication (ITD) mutation of NRAS, which disrupts the Switch II domain in an index case of a patient with widely disseminated colorectal cancer. Methods: Hotspot next generation sequencing of a brain metastasis using a clinical solid tumor panel identified this novel NRAS ITD and a TP53 missense mutation (p.P275F). Whole exome sequencing of the primary tumor and two metastatic lesions (lung and brain) was performed to identify other genetic factors potentially driving the disease. Results: The above approach confirmed that the NRAS ITD and TP53 mutation were conserved between the primary tumor and both metastatic tumors and identified an additional pathogenic mutation in CSMD1 (a tumor suppressor gene). No other clearly pathogenic driver mutations were identified. Structural biology and biochemical analyses demonstrated that the inserted 15 amino acids prevented binding to GAP protein, leading to sustained RAS activation and increased interaction with RAF to stimulate downstream MAPK activation. Conclusions: These genomic and biochemical studies indicate that a novel NRAS ITD was the primary driver mutation of this aggressive colorectal carcinoma. Identical or similar ITDs in NRAS and KRAS may also drive other forms of colorectal cancer and other aggressive malignancies and represent a new subset of RAS-driven drug-resistant cancers.

KRAS mutations in colorectal cancer from Tunisia: relationships with clinicopathologic variables and data on TP53 mutations and microsatellite instability

2013 ◽  
Vol 40 (11) ◽  
pp. 6107-6112 ◽  
Author(s):  
Sana Aissi ◽  
Marie-Pierre Buisine ◽  
Farid Zerimech ◽  
Nadia Kourda ◽  
Amel Moussa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Kras Mutations ◽  
Tp53 Mutations

scholarly journals Virulence genes are a signature of the microbiome in the colorectal tumor microenvironment

2014 ◽  
Author(s):  
Michael B Burns ◽  
Joshua Lynch ◽  
Timothy K Starr ◽  
Dan Knights ◽  
Ran Blekhman
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Microbial Communities ◽  
Active Role ◽  
Colorectal Tumor ◽  
Cancer Microenvironment ◽  
Normal Colon ◽  
Colon Tissue ◽  
Cancer Driver ◽  
Starting Point

Background The human gut microbiome is associated with the development of colon cancer, and recent studies have found changes in the composition of the microbial communities in cancer patients compared to healthy controls. However, host-bacteria interactions are mainly expected to occur in the cancer microenvironment, whereas current studies primarily use stool samples to survey the microbiome. Here, we highlight the major shifts in the colorectal tumor microbiome relative to that of matched normal colon tissue from the same individual, allowing us to survey the microbial communities at the tumor microenvironment, and provides intrinsic control for environmental and host genetic effects on the microbiome. Results We characterized the microbiome in 44 primary tumor and 44 patient-matched normal colon tissues. We find that tumors harbor distinct microbial communities compared to nearby healthy tissue. Our results show increased microbial diversity at the tumor microenvironment, with changes in the abundances of commensal and pathogenic bacterial taxa, including Fusobacterium and Providencia. While Fusobacteria has previously been implicated in CRC, Providencia is a novel tumor- associated agent, and has several features that make it a potential cancer driver, including a strong immunogenic LPS and an ability to damage colorectal tissue. Additionally, we identified a significant enrichment of virulence-associated genes in the colorectal cancer microenvironment. Conclusions This work identifies bacterial taxa significantly correlated with colorectal cancer, including a novel finding of an elevated abundance of Providencia in the tumor microenvironment. We also describe several metabolic pathways and enzymes differentially present in the tumor associated microbiome, and show that the bacterial genes in the tumor microenvironment are enriched for virulence associated genes from the aggregate microbial community. This virulence enrichment indicates that the microbiome likely plays an active role in colorectal cancer development and/or progression. These reuslts provide a starting point for future prognostic and therapeutic research with the potential to improve patient outcomes.

scholarly journals Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer

2013 ◽  
Vol 24 (5) ◽  
pp. 1267-1273 ◽  
Author(s):  
D. Tougeron ◽  
T. Lecomte ◽  
J.C. Pagès ◽  
C. Villalva ◽  
C. Collin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Low Frequency ◽  
Kras Mutations

scholarly journals Outcome of Anti-Egfr Antibody Therapy in Metastatic Colorectal Cancer with Low-Frequency Kras Mutations

2013 ◽  
Vol 24 ◽  
pp. ix53
Author(s):  
T. Hikosaka ◽  
K. Yamazaki ◽  
T. Tsushima ◽  
A. Todaka ◽  
T. Yokota ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Antibody Therapy ◽  
Low Frequency ◽  
Kras Mutations ◽  
Egfr Antibody

TP53 mutations in colorectal cancer from Tunisia: relationships with site of tumor origin, microsatellite instability and KRAS mutations

2014 ◽  
Vol 41 (3) ◽  
pp. 1807-1813 ◽  
Author(s):  
Sana Aissi ◽  
Marie-Pierre Buisine ◽  
Farid Zerimech ◽  
Nadia Kourda ◽  
Amel Moussa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Kras Mutations ◽  
Tp53 Mutations ◽  
Tumor Origin

The German quality assurance system for the molecular-pathological detection of KRAS-mutations in colorectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4018-4018 ◽  
Author(s):  
A. Jung ◽  
G. Baretton ◽  
M. Dietel ◽  
H. Gabbert ◽  
H. Kreipe ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Quality Assurance ◽  
Mutation Detection ◽  
Round Robin ◽  
Quality Assurance System ◽  
Kras Gene ◽  
Kras Mutations ◽  
Assurance System ◽  
Melting Point Analysis

4018 Background: In the beginning of 2008 the EMEA (European Medicines Agency) approved with panitumumab for the first time an EGFR (epidermal growth factor receptor) targeting therapy for patients with metastatic colorectal cancer overexpressing the EGFR and showing wildtypic sequences in the KRAS gene as a predictive biomarker. Thus, the need for assuring the quality of laboratories emerged. The German Society for Pathology in cooperation with the Federation of the German Pathologist supported by an unrestricted financial grant of Amgen Germany arranged a quality assurance system (QAS). In this context two round- robin tests were carried out which results are presented here. Methods: Collection of results from two round -robin tests and their statistical analysis applying binary classification tests. Results: Test sets of 4 histological sections from ten different cases of colorectal tumors with known mutational status of the KRAS gene were prepared for the round-robin tests. The method for the mutation detection was unrestricted. A total of 74 participants from universities (44 - 59.5 %) or other institutions (30 - 40.5 %) attended the tests. 11 participants (14.8 %) failed the test (6 universities: 13.6 %, 5 institutions: 16.6 %). For the analysis didesoxy-sequencing (DDS: 55 - 66.2 %), ARMS®-PCR (8 - 10.4 %), melting-point analysis (MPA: 7 - 9.1 %), pyrosequencing (PS: 6 - 7.8 %), hybridization (HYB: 4 - 5.2 %), or SSCP (1 - 1.3 %) were used, in which some participants (3) used more than one method. It turned out that all methods employed for the testing gave similar results when comparing the rate of correct or wrong hits or the rate of false positive detection: DDS (0.92, 0.07, 0.02), ARMS®-PCR (0.91, 0.08, 0.05), MPA (0.94, 0.06, 0.04), PS (0.95, 0.05, 0.03) or HYB (0.90, 0.10, 0.08). Conclusions: The quality of the molecular-pathological detection of KRAS mutations as precondition for an EGFR targeted therapy should be tested since about 15 % of laboratories did not meet a sufficient grade. For the mutation detection no method seemed superior. [Table: see text]

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