scholarly journals Prognostic Value of Circulating KRAS2 Gene Mutations in Colorectal Cancer with Distant Metastases

2006 ◽  
Vol 21 (4) ◽  
pp. 223-228 ◽  
Author(s):  
C. Trevisiol ◽  
F. Di Fabio ◽  
R. Nascimbeni ◽  
L. Peloso ◽  
C. Salbe ◽  
...  

While tissue KRAS2 mutations have been extensively investigated, the role of circulating mutant KRAS2 gene in patients with colorectal carcinoma remains obscure. The aim of the present study was to explore the prognostic significance of circulating KRAS2 gene mutational status in subjects undergoing primary treatment for colorectal cancer. Codon 12 KRAS2 mutations were examined in DNA samples extracted from the serum of 86 patients with colorectal cancer and were compared with the KRAS2 status of their primary tumors. Tissue and serum KRAS2 status was compared with other clinicopathological variables (including CEA and CA 19-9 levels) and with cancer-related survival. KRAS2 mutations were found in tissue samples of 28 patients (33%); serum KRAS2 mutations were detected in 10 of them (36%). Serum KRAS2 status was significantly associated with Dukes' stage D (p=0.001) and with preoperative CA 19-9 levels (p=0.01). At multivariate analysis, cancer-related survival was associated with Dukes' stage (p<0.0001), CEA level (p=0.02), and mutant circulating KRAS2 (p=0.01). All 7 stage D patients with serum KRAS2 mutations died of the disease within 24 months of primary treatment; cancer-related survival was significantly better in 9 stage D patients without serum KRAS2 mutations, with 5 patients (56%) alive after 24 months and 1 patient (13%) alive after 44 months. Residual disease after surgery was evident in all 7 stage D patients with mutant circulating KRAS2, and in 5 out of 9 stage D patients without serum mutations. Serum KRAS2 status may impact substantially on the management of stage D colorectal carcinoma, since it appears to correlate with prognosis in this patient subgroup.

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10092-10092
Author(s):  
D. G. Mollevi ◽  
T. Serrano ◽  
M. M. Ginesta ◽  
J. Valls ◽  
J. Torras ◽  
...  

10092 Background: The aim of this study was to analyze the value of TP53 gene mutations as a prognostic marker to improve the selection of patients candidates to surgery in a consecutive series of liver metastases from colorectal cancer patients. Methods: 91 patients with liver metastases from colorectal carcinoma (CRC) were included. Mutational study of TP53 gene, exons 4 to 10, was assessed both in paraffin-embedded hepatic metastasis and normal liver parenchyma by SSCP (Single Strand Chain Polymorphism) followed by sequencing of abnormal electrophoretic mobility patterns. Immunostaining of P53 and P21 proteins were assessed in the same group of patients. Results: Forty-eight out 91 (50.05%) metastases showed mutation in TP53. Higher incidence of mutations was detected in exons 5–8, although exons 9 and 10 were mutated in 28.26% of metastases. Protein-truncating mutations (nonsense and frameshift) occur in 47.8% of metastasis harboring TP53 mutations. TP53 mutation was associated with poor prognosis in univariate (P=0.0062) and multivariate Cox proportional hazard model (P=0.012) analysis. Prognosis association was maintained in the group of patients undergoing radical resection, named R0 series (n=79; P=0.008). High prevalence of TP53 mutations happen in patients with >3 metastases (65.6%; P=0.034), primary tumors Duke’s C-D stages (57.4%; 63.0%; respectively; p=0.026) and patients with age <57 years at resection. Interestingly, patients with TP53 mutations in their metastases relapsed earlier after the resection of the primary tumor (P=0.026). Postoperative 5-FU-based chemotherapy showed a better survival outcome in patients with wild-type TP53 hepatic metastases (HR: 2.92; 95% CI: 1.32–6.46; P=0.006). Conclusions: TP53 mutational status seems to be an important prognostic factor in patients with hepatic metastases from CRC. No significant financial relationships to disclose.


2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 737-737 ◽  
Author(s):  
Benoist Chibaudel ◽  
Thierry Andre ◽  
Benoit Samson ◽  
Marie-Line Garcia-Larnicol ◽  
Jérôme Dauba ◽  
...  

737 Background: Primary tumor sidedness (PTS) could be a predictive maker for treatment efficacy of EGFR inhibitors monoclonal antibodies in patients with wild-type (WT) RAS metastatic colorectal cancer (MCRC), cetuximab having limited efficacy in patients with WT-RAS right-sided tumors. DREAM study demonstrated that adding erlotinib, an oral EGFR tyrosine kinase inhibitor (TKI) to bevacizumab during maintenance therapy improved clinical outcomes (RR, PFS, OS) in patients with MCRC, whatever KRAS status. The aim of this post-hoc analysis is to evaluate the clinical outcomes according to KRAS mutational status and PTS when adding erlotinib to bevacizumab maintenance therapy. Methods: PTS was retrospectively collected in patients from the DREAM phase III trial treated with bevacizumab with or without erlotinib as maintenance therapy for MCRC who have been controlled by induction therapy. The limit for the definition of PTS was splenic flexure, and rectal tumors were considered as left-sided tumors. The primary endpoint was overall survival (OS). Results: Among 452 patients who received maintenance therapy, PTS ascertainment was 84.7% (n = 383) with 265 (71.0%) patients having left-sided primary tumor and 108 (28.9%) having right-sided primary tumors (3 patients had both and tumor location was unknown in 7 patients). Median OS and treatment effect are presented in table 1. Conclusions: The greatest OS benefit of adding erlotinib to bevacizumab maintenance therapy was observed in patients with WT-KRAS and right-sided MCRC, suggesting a clinical impact of the different mechanism of action between EGFR TKI and monoclonal antibodies. Clinical trial information: NCT00265824. [Table: see text]


2021 ◽  
Author(s):  
Fumitaka Taniguchi ◽  
Akihiro Nyuya ◽  
Toshiaki Toshima ◽  
Kazuya Yasui ◽  
Yoshiko Mori ◽  
...  

Abstract Background: Acquired mutations are detected in plasma. However, still few reports examine the concordance between liquid biopsy and metastatic lesions with acquired resistance. Herein we evaluated whether a polymerase chain reaction-reverse sequence-specific oligonucleotide (PCR-rSSO) method can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance.Methods: Firstly, we examined the presence of acquired mutations in 7 chemoresistant metastatic lesions and blood samples obtained from a metastatic colorectal cancer (mCRC) patient without RAS activating mutations treated with anti-EGFR treatment. The patient (patient 1) displayed initial early tumor shrinkage and finally progressed to disease (PD). Blood samples were collected before the development of PD and after acquiring resistance. Next, we evaluated RAS and BRAF mutational status among blood samples, primary tumors, and metastatic lesions obtained from three additional mCRC patients without RAS activating mutations. Acquired mutations were examined using Sanger sequencing and the PCR-rSSO approach.Results: Of patient 1, metastatic tumor specimens harbored diverse acquired mutations in the KRAS gene in all of the 7 (100%) metastases, and the three acquired mutations were detected in blood specimens collected after acquiring resistance. Next, we analyzed primary tumors, metastatic lesions after chemotherapy, and blood samples from three additional mCRC patients but noted that none of the patients exhibited mutations in liquid biopsy except for one case with BRAF V600E mutation, which was confirmed in both primary tumor and peritoneal dissemination. Of the four cases, acquired mutations of RAS, as well as BRAF V600E mutation, was detected in the blood obtained only after confirmation of acquiring resistance by radiological examinations.Conclusions: Our results suggest liquid biopsy based on the PCR-rSSO is a successful procedure for capturing acquired mutations with precise information of mutational spectrum that may lend us to reach selective target agents for RAS mutations.


2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 504-504
Author(s):  
Jeeyun Lee ◽  
Stefanie Mortimer ◽  
Gangwu Mei ◽  
Dragan Sebisanovic ◽  
LaiMun Siew ◽  
...  

504 Background: Current approaches based on invasive biopsy genetic analysis can fail to capture an accurate picture of the real-time cancer profile due to limited spatial window of biopsy into residual disease throughout the body. Moreover, tumor rebiopsy has significant challenges to be widely used in practice for serial monitoring of disease progression or acquired resistance. Analysis of circulating tumor nucleic acids (ctDNA), on the other hand, presents a new tool for the monitoring and treatment of cancer. However, due to high-quality false positives in current NGS assays, the majority of studies on ctDNA have been limited to hotspot analyses, and typically only involve patients where ctDNA fractions are high (>1-5%). Methods: We have developed a differentiated sequencing assay, Digital Sequencing Technology (DST) that enables detection of rare genomic abnormalities with ultra high-specificity and sensitivity. Our assay is able to eliminate the error and distortion created by sample-prep and sequencing processes in standard NGS workflows and produce near-perfect representations of all rare variants. Results: We have shown that in sequencing a comprehensive cancer panel of 80kbp in 0.1% cancer cell line titration samples, standard Illumina SBS generates many high-quality false positive variant calls in the range of 0.05-5%, while our assay resulted in highly sensitive and completely error-free variant calls across the entire panel. We then profiled ctDNA and matched primary tumor samples in more than 50 plasma samples collected from metastatic colorectal cancer patients. We found mutations in ctDNA with allele frequencies in the range of 0.05-40%. We established the concordance of ctDNA mutations with different clones within primary tumors. We further investigated the potential clinical usefulness of discordant mutants based on the treatment history of each patient. Conclusions: This work indicates the remarkable potential of using our assay in deep analysis of ctDNA, thereby allowing researchers and clinicians to comprehensively and non-invasively monitor the genetic dimension of cancer throughout the body.


2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 641-641
Author(s):  
Ho Jung An ◽  
Bong-Hyeon Gye ◽  
Hyung Jin Kim ◽  
Ji Han Jung ◽  
Jong Hoon Lee ◽  
...  

641 Background: The incidence of K-ras mutation of exon 2 was reported between 30-40% in colorectal cancer, and it is well known predictive biomarker for EGFR monoclonal antibody. However, its prognostic role has not been defined so far, especially in Eastern country. Methods: From January 2007 to September 2013, patients who were diagnosed as colorectal cancer and examed K-ras exon 2 mutation in Saint Vincent’s hospital were retrospectively reviewed. Results: Among 436 patients, 343 patients with sufficient clinical information were analyzed. The median follow up period was 13.0 (0.2-94.8) months. The incidence of K-ras mutation was 37.9% (codon 12 mutation: 28.6%, codon 13 mutaiton: 9.0%, both: 0.3%). Codon 12 p.G12D was most frequent (52.3%), and codon 13 p.G13D was the next (22.3%). The presence of K-ras mutation was associated with old age (p=0.038), female gender (p=0.034), lesser nodal involvement (p<0.001), but not related to stage, tumor site, and histology. There is no significant clinical differences between codon 12 and 13 mutations. The recurrence free survival in patients who received curative resection was worse in patients with K-ras mutation (p=0.001). The prognostic role of K-ras mutation was more prominent in colon cancer, while it lost its prognostic significance in rectal cancer. Conclusions: The prognostic role of K-ras mutation was different according to primary tumor sites in colorectal cancer.


mSystems ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Zongchao Mo ◽  
Peide Huang ◽  
Chao Yang ◽  
Sihao Xiao ◽  
Guojia Zhang ◽  
...  

ABSTRACT As research focusing on the colorectal cancer fecal microbiome using shotgun sequencing continues, increasing evidence has supported correlations between colorectal carcinomas (CRCs) and fecal microbiome dysbiosis. However, large-scale on-site and off-site (surrounding adjacent) tissue microbiome characterization of CRC was underrepresented. Here, considering each taxon as a feature, we demonstrate a machine learning-based method to investigate tissue microbial differences among CRC, colorectal adenoma (CRA), and healthy control groups using 16S rRNA data sets retrieved from 15 studies. A total of 2,099 samples were included and analyzed in case-control comparisons. Multiple methods, including differential abundance analysis, random forest classification, cooccurrence network analysis, and Dirichlet multinomial mixture analysis, were conducted to investigate the microbial signatures. We showed that the dysbiosis of the off-site tissue of colonic cancer was distinctive and predictive. The AUCs (areas under the curve) were 80.7%, 96.0%, and 95.8% for CRC versus healthy control random forest models using stool, tissue, and adjacent tissue samples and 69.9%, 91.5%, and 89.5% for the corresponding CRA models, respectively. We also found that the microbiota ecologies of the surrounding adjacent tissues of CRC and CRA were similar to their on-site counterparts according to network analysis. Furthermore, based on the enterotyping of tissue samples, the cohort-specific microbial signature might be the crux in addressing classification generalization problems. Despite cohort heterogeneity, the dysbiosis of lesion-adjacent tissues might provide us with further perspectives in demonstrating the role of the microbiota in colorectal cancer tumorigenesis. IMPORTANCE Turbulent fecal and tissue microbiome dysbiosis of colorectal carcinoma and adenoma has been identified, and some taxa have been proven to be carcinogenic. However, the microbiomes of surrounding adjacent tissues of colonic cancerous tissues were seldom investigated uniformly on a large scale. Here, we characterize the microbiome signatures and dysbiosis of various colonic cancer sample groups. We found a high correlation between colorectal carcinoma adjacent tissue microbiomes and their on-site counterparts. We also discovered that the microbiome dysbiosis in adjacent tissues could discriminate colorectal carcinomas from healthy controls effectively. These results extend our knowledge on the microbial profile of colorectal cancer tissues and highlight microbiota dysbiosis in the surrounding tissues. They also suggest that microbial feature variations of cancerous lesion-adjacent tissues might help to reveal the microbial etiology of colonic cancer and could ultimately be applied for diagnostic and screening purposes.


Oncology ◽  
2020 ◽  
pp. 1-17
Author(s):  
Reetta Peltonen ◽  
Jaana Hagström ◽  
Taina Tervahartiala ◽  
Timo Sorsa ◽  
Caj Haglund ◽  
...  

<b><i>Introduction:</i></b> The liver metastases of colorectal cancer (CRC) can be surgically treated in selected cases, with continuously improving results. Matrix metalloproteinases (MMPs) contribute to cancer invasion by degrading the extracellular matrix, and elevated levels of MMP-2, MMP-8, and MMP-9 have been detected in several malignancies. Myeloperoxidase (MPO) is a mediator of tissue damage that can oxidatively activate latent MMPs. We evaluated the prognostic value of MMP-2, MMP-8, and MMP-9 in tissue samples of primary tumors and liver metastases and the pre- and postoperative serum levels of MMP-8, MMP-9, and MPO in CRC patients undergoing liver resection. <b><i>Methods:</i></b> Tissue and serum samples were obtained from 111 patients who had primary colorectal tumors and their liver metastases surgically treated at the Helsinki University Hospital between 1988 and 2007. Tissue expression of MMP-2, MMP-8, and MMP-9 in primary tumors and liver metastases was evaluated by immunohistochemistry. Pre- and postoperative serum concentrations of MMP-8, MMP-9, and MPO were determined using a time-resolved immunofluorometric assay or commercially available enzyme-linked immunosorbent assay kits. Clinical data were retrieved from patient records and the Central Statistical Office of Finland. Associations with disease-free survival (DFS) and overall survival (OS) were estimated using Cox regression analysis and the Kaplan-Meier method. <b><i>Results:</i></b> High expression of MMP-9 in colorectal tumor tissue was associated with better DFS (<i>p</i> = 0.010), and high preoperative MPO in serum with improved DFS and OS (<i>p</i> &#x3c; 0.001 and <i>p</i> = 0.014, respectively). The prognostic significance varied according to gender, age, and the synchronicity of liver metastases. <b><i>Conclusion:</i></b> Low preoperative MPO in serum might identify patients at high risk of recurrence and death after resection of colorectal liver metastases. Elevated preoperative MPO and high expression of MMP-9 in colorectal tumor tissue indicate an improved prognosis. The use of these biomarkers should be adjusted according to clinical characteristics.


Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 1172-1183
Author(s):  
Gengming Niu ◽  
Li Deng ◽  
Xiaotian Zhang ◽  
Zhiqing Hu ◽  
Shanliang Han ◽  
...  

AbstractLittle is known about the functional roles of gamma-aminobutyric acid type A receptor subunit delta (GABRD) in colorectal cancer (CRC). The expression of GABRD between CRCs and adjacent normal tissues (NTs), metastasis and primary tumors was compared using public transcriptomic datasets. A tissue microarray and immunohistochemical staining (IHC) were used to determine the clinical and prognostic significance of the GABRD in CRC. We used gain-of-function and loss-of-function experiments to investigate the in vitro roles of GABRD in cultured CRC cells. We characterized the potential mechanism of GABRD’s activities in CRC using a Gene Set Enrichment Analysis (GSEA) with The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) dataset. We found that the GABRD expression was significantly increased in CRCs compared to that in NTs, but was similar between metastasis and primary tumors. Overexpression of GABRD was significantly associated with later pTNM stages and unfavorable patient survival. Overexpression of GABRD accelerated while knock-down of GABRD inhibited cell growth and migration. Mechanistically, the function of GABRD might be ascribed to its influence on major oncogenic events such as epithelial–mesenchymal transition (EMT), angiogenesis, and hedgehog signaling. Collectively, GABRD could be a novel prognostic predictor for CRC that deserves further investigation.


2021 ◽  
Author(s):  
Yifan Zhang ◽  
Yi Chen ◽  
Chen Yang ◽  
Nelly Seger ◽  
Asle C. Hesla ◽  
...  

AbstractChondrosarcomas are the second most common malignant bone tumor. Activating promoter mutations in telomerase reverse transcriptase (TERT) was recently described by us and others as a frequent mutation in high-grade chondrosarcoma. In this study, we investigate the prognostic significance of TERT promoter mutations in 241 chondrosarcomas from 190 patients collected over 24 years (1994–2017). The TERT promoter was sequenced after microdissection of 135 chondrosarcomas from 106 patients in addition to data from our previous cohort. The TERT promoter mutation at −124 C > T was found in 45% of all patients and was significantly associated (p > 0,001) with higher tumor grade, shorter metastasis-free survival, and disease-specific survival. Additionally, TERT promoter-mutated tumors were associated with a more aggressive metastatic pattern. Shorter survival was observed in patients with wild-type primary tumors who developed a mutated metastasis indicative of tumor progression. Primary tumor genetic heterogeneity and altering mutational status between nonsynchronous metastatic lesions suggests that chondrosarcoma is a multiclonal disease progressing through a branching evolution. Conclusion: TERT promoter mutation seems to be a central event in chondrosarcoma progression with association to metastatic disease and disease-related mortality. As an easily analyzed marker, there is future potential to utilize TERT promoter mutation status as a prognostic marker and investigate telomerase-targeted therapy in chondrosarcomas.


2020 ◽  
Vol 10 (4) ◽  
pp. 271-276
Author(s):  
Hina Wasti ◽  
Summayyah Shawana ◽  
Beenish Hussain ◽  
Santosh Sidhwani ◽  
Rubbab Mir ◽  
...  

Objective: To determine the expression of BRAF V600E in tissue samples of colorectal carcinoma and to correlate it with various clinico-pathological parameters. Study design and setting: Cross-sectional study was conducted at department of Pathology, Pakistan Navy Station Shifa hospital Karachi from 1st March 2016 to 28th February 2019 Methodology: Total of 51 cases of colorectal cancer were analyzed for immunohistochemical staining using BRAF antibodies on representative tissue blocks. Clinical and pathological records were retrieved for data collection. The results of immunohistochemical analysis were correlated with the recorded clinico-pathological parameters. Results: In this study 51 cases of colorectal cancer were analyzed for immune expression of BRAF V600E. The age of the patients ranged from 14 to 85 years with the mean age of 60.96 years. Among the 51 cases, 37(72.5%) cases were males and 14(27.4%) were females. 37(72.5%) were localized to left side colon and 14(27.4%) were found in the right colon. For BRAF V600E, positive expression was seen in 20(39.2%) cases, whereas 31(60.7%) cases showed negative expression of BRAFV600E. No significant association was seen between BRAF V600E expression and histological variants like age, gender, tumor location and glandular carcinomas. Conclusion: BRAF V600E immunosuppression was seen in 39.2% of colorectal carcinoma in this study. No significant association was seen in BRAF V600E expression and histological variants


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