Genomics study to identify novel cancer genes predictive for prognosis and 5-FU benefit in stage II/III colorectal cancer

2016 ◽  
Vol 61 ◽  
pp. S180
Author(s):  
M. Parsons ◽  
O. Sieber ◽  
D. Mouradov
Keyword(s):  
Colorectal Cancer ◽  
Stage Ii ◽  
Cancer Genes

Analysis of genomic DNA copy number alterations in chromosome arm 18q demonstrates distinct molecular categories of colorectal carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10005-10005
Author(s):  
H. Ji ◽  
M. Zhang ◽  
K. Farnam ◽  
K. Salari ◽  
R. Davis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colorectal Carcinoma ◽  
Genomic Instability ◽  
Genetic Markers ◽  
New Technologies ◽  
Stage Ii ◽  
Cancer Genes ◽  
Genomic Deletions ◽  
Chromosome Arm ◽  
Dna Copy Number Alterations

10005 Background: Genomic instability is a major feature of neoplastic development in colorectal carcinoma and other cancers. Specific genomic instability events such as genomic deletions have potential utility as biologically relevant prognostic biomarkers. Loss of heterozygosity (LOH) on chromosome arm 18q is an indicator of colorectal carcinoma behavior and potentially, prognosis. For stage II and III colorectal cancer, a number of retrospective studies have shown strong correlations between deletions in 18q and reduced survival. However, other studies have failed to identify this correlation. This discrepancy is likely the result of different sets of genetic markers and their widely disparate locations along chromosome arm 18q, often separated by megabases. New technologies are needed to overcome these issues. Methods: Using a novel genomic technology called molecular inversion probes (MIPs), we analyzed genomic deletions at exon-level resolution in primary colorectal carcinoma. Unlike microsatellite genetic markers, MIPs are not dependent on having informative alleles to discern a LOH event. This enables querying microsatellite genetic markers used in any clinical study. We designed a set of probes to interrogate several hundred individual exons of over two hundred cancer genes with an overall distribution covering all chromosome arms. Also represented were a series of over 100 probes along chromosome arm 18q representing genetic markers used in clinical studies. An analysis was carried out on primary tumor samples from patients with stage II and III disease. Results: We discovered several distinct categories of colorectal carcinomas based upon their profile of 18q genomic deletions and other allelic imbalances. Colorectal carcinoma extent of invasion showed an association with cluster designation which suggests that the multiple genomic instability events influence the invasive behavior of colorectal carcinoma. Conclusions: Colorectal cancer has distinct patterns of 18q genomic deletions, representing a potential molecular classifier. This finding has potential clinical ramifications given the application of 18q LOH events as an indicator for adjuvant treatment in stage II colorectal carcinoma. No significant financial relationships to disclose.

Stratification of patients with colorectal cancer of UICC stage II using prognostic mutations signatures obtained by deep amplicon sequencing of cancer genes.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 377-377
Author(s):  
Andre Rosenthal ◽  
Karsten Ridwelski ◽  
Frank Marusch ◽  
Matthias Pross ◽  
Rene Mantke ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Therapy ◽  
Deep Sequencing ◽  
Predictive Value ◽  
Amplicon Sequencing ◽  
Stage Ii ◽  
Rna Expression ◽  
Uicc Stage ◽  
Cancer Genes ◽  
Primary Tumors

377 Background: Assignment of patients (pts) with UICC-stage II colorectal cancer (CRC) to adjuvant therapy remains controversial. The clinical utility of histo-pathological parameters (pT4, L+, V+) as well as tumor RNA expression signatures like Oncotype Dx Colon Cancer Assay, ColoPrint, or Predictor C is low given their positive predictive value (PPV) of 0.13, 0.22, 0.19, and 0.33, respectively, when adjusted to an incidence of 10% for occurrence of metastatic disease (mets) within 3 years after diagnosis. Methods: We applied deep amplicon sequencing of 48 well-known cancer genes to DNA samples of primary tumors from 173 pts with UICC-stage II CRC using the Illumina MiSeq technology. Patients were selected from a prospective, multicenter clinical diagnostic study named MSKK. More than 6,500 patients with CRC have been recruited into this study conducted by 39 hospitals in Germany. 79 of the 173 pts had progression of disease events within 3 years after R0 resection including 40 pts with mets, 12 pts with local recurrences, and 27 pts with secondary malignancies. 94 pts remained progression-free. Results: Deep sequencing revealed a total of 2,221 sequence variations (SV) including missense, stop, InDel, noncoding, nonsense SV. 401 SV were in COSMIC, 750 SV in normal tissue. The remaining 1471 SV served as basis for development of SV-signatures (SVS) for prediction of progression events in a classical double-nested bootstrap approach in order to generate second order unbiased estimates of performance of SVS, namely sensitivity(S+), specificity (S-), PPV, and negative predictive value (NPV). The best SVS for prediction of metastases contained SV in less than 15 genes and has a S+ of 0.41, S- of 0.93, PPV of 0.40, and NPV of 0.93 (incidence of metastasis: 10%). The best SVS for prediction any progression event has a S+ of 0.33, S- of 0.93, PPV of 0.54, and NPV of 0.84 (incidence for any progression = 20.5%). Conclusions: This deep sequencing based prognostic tissue test with a PPV of 40% and a NPV of 93% represents a milestone over prognostic tests based on RNA expression. The increased PPV leads to more patients being treated correctly with adjuvant therapy.

INVESTIGATION KRAS MUTATION IN CIRCULATION TUMOR DNA IN DIFFERENT STAGES OF COLORECTAL CANCER

2019 ◽  
Vol 65 (5) ◽  
pp. 701-707
Author(s):  
Vitaliy Shubin ◽  
Yuriy Shelygin ◽  
Sergey Achkasov ◽  
Yevgeniy Rybakov ◽  
Aleksey Ponomarenko ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasma Volume ◽  
Kras Mutation ◽  
Stage Iv ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Kras Gene ◽  
Kras Mutations ◽  
Droplet Pcr ◽  
Tumor Dna

To determine mutations in the plasma KRAS gene in patients with colorectal cancer was the aim of this study. The material was obtained from 44 patients with colorectal cancer of different stages (T1-4N0-2bM0-1c). Plasma for the presence of KRAS gene mutation in circulating tumor DNA was investigated using digital droplet polymerase chain reaction (PCR). KRAS mutations in circulating tumor DNA isolated from 1 ml of plasma were detected in 13 (30%) patients with cancer of different stages. Of these, with stage II, there were 3 patients, with III - 5 and with IV - 5. Patients who did not have mutations in 1 ml of plasma were analyzed for mutations of KRAS in circulating tumor DNA isolated from 3 ml of plasma. Five more patients with KRAS mutations were found with II and III stages. The highest concentrations of circulating tumor DNA with KRAS mutation were found in patients with stage IV. The increase in plasma volume to 3 ml did not lead to the identification of mutations in I stage. This study showed that digital droplet PCR allows identification of circulating tumor DNA with the KRAS mutations in patients with stage II-IV of colon cancer. The results can be used to determine the degree of aggressiveness of the tumor at different stages of the disease, but not the 1st, and it is recommended to use a plasma volume of at least 3 ml.

Prognostic role of aberrant mTOR activation in patients with stage II and III colorectal cancer

2020 ◽  
Vol 14 (12) ◽  
pp. 1127-1137
Author(s):  
Tong-Tong Zhang ◽  
Yi-Qing Zhu ◽  
Hong-Qing Cai ◽  
Jun-Wen Zheng ◽  
Jia-Jie Hao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Poor Prognostic Factor ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Potential Biomarker ◽  
Risk Predictor

Aim: This study aimed to develop an effective risk predictor for patients with stage II and III colorectal cancer (CRC). Materials & methods: The prognostic value of p-mTOR (Ser2448) levels was analyzed using Kaplan–Meier survival analysis and Cox regression analysis. Results: The levels of p-mTOR were increased in CRC specimens and significantly correlated with poor prognosis in patients with stage II and III CRC. Notably, the p-mTOR level was an independent poor prognostic factor for disease-free survival and overall survival in stage II CRC. Conclusion: Aberrant mTOR activation was significantly associated with the risk of recurrence or death in patients with stage II and III CRC, thus this activated proteins that may serve as a potential biomarker for high-risk CRC.

The efficacy of adjuvant chemotherapy for resected high-risk stage II and stage III colorectal cancer in frail patients

2021 ◽  
Author(s):  
Kosuke Mima ◽  
Nobutomo Miyanari ◽  
Keisuke Kosumi ◽  
Takuya Tajiri ◽  
Kosuke Kanemitsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Stage Ii ◽  
Stage Iii ◽  
Frail Patients

scholarly journals HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Mahdi Golkaram ◽  
Michael L. Salmans ◽  
Shannon Kaplan ◽  
Raakhee Vijayaraghavan ◽  
Marta Martins ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Subtype ◽  
Endogenous Retroviruses ◽  
Stage Ii ◽  
Clinicopathological Factors ◽  
Whole Exome ◽  
Potential Biomarker ◽  
Whole Transcriptome Sequencing ◽  
Next Generation Sequencing Ngs ◽  
Herv Expression

AbstractColorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC.

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