Mutational load distribution analysis of colorectal and pancreatic carcinoma by next generation sequencing platform.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 57-57
Author(s):  
Adriana Lopez-Doriga ◽  
Daniel Azuara ◽  
Mireia Morell ◽  
Javier de Oca ◽  
Francisco Rodriguez-Moranta ◽  
...  
Keyword(s):  
Pancreatic Carcinoma ◽  
Load Distribution ◽  
Genetic Alterations ◽  
Response To Therapy ◽  
Colorectal Adenomas ◽  
Distribution Analysis ◽  
Mutational Load ◽  
Colorectal Carcinomas ◽  
Normal Pancreas ◽  
Risk Of Cancer

57 Background: It has been suggested that the sequential analysis of the mutational spectra at loci involved in the pathogenesis of tumors (mutational load distribution analysis [MLDA]) may reflect the biology of the tumor and/or the risk of cancer before the tumor emerges. Metrics derived from MLDA could assist quantifying risk, in early diagnosis, and in monitoring response to therapy. The aim of this study was to assess the efficacy of the NGS platform to obtain clinically relevant metrics derived from MLDA. Methods: Two sets of DNA samples were assessed: (i) 6 paired tumor/normal colorectal carcinomas and 8 colorectal adenomas; and (ii) 21 pancreatic carcinoma and 6 non-matched normal pancreas. Thirty amplicons from 6 genes (KRAS, BRAF, EGFR, CDKN2A, TP53, and PI3KCA) were sequenced using the Roche 454 GS FLX-TI platform. Data analysis was carried out by Variant Identification Pipeline (VIP) software and R (computing environment) commands. Total mutational load (TML) was calculated as the sum of all variants frequency for each sample. Results: In all, 18,626 variants were identified. Optimal filters applied to discard false positives were: (1) variants with an absolute frequency < 10x, (2) variants in homopolymer (HP) ≥ 6 nucleotides, (3) insertions and deletions (INDELs) in HP ≥ 5 nucleotides, and (4) INDELs in only one strand. Filtering yielded 870 variants from all samples remained as valid, 92 being unique. After discarding polymorphisms, variants classified as neutral by the Condel software and variants preferentially detected in normal tissues, 46 variants were used to compute TML. TML in colonic carcinomas and adenomas was higher than normal mucosa (0.83 vs. 0.607 vs. 0.128, p = 0.01). In pancreatic disease, TML for pancreatic carcinoma was higher than normal pancreas (0.716 vs. 0.135, p = 0.01). KRAS and TP53 analysis provide most of the information in both tumors, while PI3KCA adds information for colorectal carcinomas exclusively and CDKNA2 is informative in pancreatic samples. Conclusions: NGS provides a robust and quantitative measure of genetic alterations in tumor samples. MLDA is an effective tool for the classification of GI tumors.

Analysis of genetic alterations, classified according to their DNA ploidy pattern, in the progression of colorectal adenomas and early colorectal carcinomas

2003 ◽  
Vol 200 (2) ◽  
pp. 168-176 ◽  
Author(s):  
Tamostu Sugai ◽  
Hiroshi Takahashi ◽  
Wataru Habano ◽  
Shin-ichi Nakamura ◽  
Kimihiko Sato ◽  
...  
Keyword(s):  
Dna Ploidy ◽  
Genetic Alterations ◽  
Colorectal Adenomas ◽  
Colorectal Carcinomas ◽  
Dna Ploidy Pattern ◽  
Ploidy Pattern

scholarly journals Clinical spectrum and pleiotropic nature of CDH1 germline mutations

2019 ◽  
Vol 56 (4) ◽  
pp. 199-208 ◽  
Author(s):  
Joana Figueiredo ◽  
Soraia Melo ◽  
Patrícia Carneiro ◽  
Ana Margarida Moreira ◽  
Maria Sofia Fernandes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Genetic Alterations ◽  
Tumour Suppressor Gene ◽  
Diffuse Gastric Cancer ◽  
Loss Of Function ◽  
Lobular Breast Cancer ◽  
Cancer Syndrome ◽  
Risk Of Cancer ◽  
E Cadherin

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

scholarly journals Genetic alterations in DNA diploid, aneuploid and multiploid colorectal carcinomas identified by the crypt isolation technique

2000 ◽  
Vol 88 (4) ◽  
pp. 614-619 ◽  
Author(s):  
Tamotsu Sugai ◽  
Wataru Habano ◽  
Shin-ichi Nakamura ◽  
Hajime Sato ◽  
Noriyuki Uesugi ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Colorectal Carcinomas ◽  
Isolation Technique ◽  
Crypt Isolation

SATB1 and Her2 as predictive molecular and immunohistochemical markers for urothelial cell carcinoma of the bladder

2020 ◽  
pp. 1-11
Author(s):  
Samia Hussein ◽  
Anan Fathi ◽  
Nehal S. Abouhashem ◽  
Samar Amer ◽  
Mohamed Hemida ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Prognostic Significance ◽  
Immunohistochemical Analysis ◽  
Lymph Node Involvement ◽  
Genetic Alterations ◽  
Response To Therapy ◽  
Clinicopathological Parameters ◽  
Bladder Tissue ◽  
Normal Bladder ◽  
Erbb2 Mrna

Studying bladder cancer molecular biology revealed the presence of genetic alterations. So, detection of molecular biomarkers that help in monitoring the disease, evaluating the prognosis of the patients, and their response to therapy is needed. In this study, we investigated the expression and the prognostic significance of SATB-1 and ERBB2 mRNA and protein by quantitative RT-PCR and immunohistochemical analysis in urothelial bladder cancer cases and the surrounding normal bladder tissue. The correlations between the expression of both markers and the clinicopathological parameters were performed with further analysis of the correlation between the expression of SATB-1 and ERBB2. Compared to control, the expression of SATB-1 and ERBB2 mRNA and protein in cancer tissues were significantly up-regulated (p< 0.05). Also, a positive correlation between both markers was found (r= 0.53, p< 0.001). Moreover, elevated levels of both markers were significantly associated with the stage, lymph node involvement at both mRNA and protein levels (p< 0.001). In conclusion, there is a clinical significance of SATB-1 and ERBB2 as potential biomarkers for predicting bladder cancer patients of aggressive behavior and poor prognosis.

Static load distribution analysis of ball screws with nut position variation

2020 ◽  
Vol 151 ◽  
pp. 103893 ◽  
Author(s):  
Chang Liu ◽  
Chunyu Zhao ◽  
Xianli Meng ◽  
Bangchun Wen
Keyword(s):  
Load Distribution ◽  
Static Load ◽  
Distribution Analysis

scholarly journals Mutation Profiling of Premalignant Colorectal Neoplasia

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Jakub Karczmarski ◽  
Krzysztof Goryca ◽  
Jacek Pachlewski ◽  
Michalina Dabrowska ◽  
Kazimiera Pysniak ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Colorectal Neoplasia ◽  
Copy Number Variant ◽  
Genetic Alterations ◽  
Colorectal Adenomas ◽  
Colorectal Carcinogenesis ◽  
High Grade Dysplasia ◽  
Low Grade ◽  
High Grade ◽  
Allelic Variants

Accumulation of allelic variants in genes that regulate cellular proliferation, differentiation, and apoptosis may result in expansion of the aberrant intestinal epithelium, generating adenomas. Herein, we compared the mutation profiles of conventional colorectal adenomas (CNADs) across stages of progression towards early carcinoma. DNA was isolated from 17 invasive adenocarcinomas (ACs) and 58 large CNADs, including 19 with low-grade dysplasia (LGD), 21 with LGD adjacent to areas of high-grade dysplasia and/or carcinoma (LGD-H), and 28 with high-grade dysplasia (HGD). Ion AmpliSeq Comprehensive Cancer Panel libraries were prepared and sequenced on the Ion Proton. We identified 956 unique allelic variants; of these, 499 were considered nonsynonymous variants. Eleven genes (APC, KRAS, SYNE1, NOTCH4, BLNK, FBXW7, GNAS, KMT2D, TAF1L, TCF7L2, and TP53) were mutated in at least 15% of all samples. Out of frequently mutated genes, TP53 and BCL2 had a consistent trend in mutation prevalence towards malignancy, while two other genes (HNF1A and FBXW7) exhibited the opposite trend. HGD adenomas had significantly higher mutation rates than LGD adenomas, while LGD-H adenomas exhibited mutation frequencies similar to those of LGD adenomas. A significant increase in copy number variant frequency was observed from LGD through HGD to malignant samples. The profiling of advanced CNADs demonstrated variations in mutation patterns among colorectal premalignancies. Only limited numbers of genes were repeatedly mutated while the majority were altered in single cases. Most genetic alterations in adenomas can be considered early contributors to colorectal carcinogenesis.

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