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.

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.

DNA Image cytometry as a prognostic tool in stage II and stage III colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13565-13565
Author(s):  
A. Buhmeida ◽  
A. Ålgars ◽  
R. Ristamäki ◽  
Y. Collan ◽  
K. Syrjänen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Nuclear Dna Content ◽  
Image Cytometry ◽  
Stage Ii ◽  
Stage Iii ◽  
Computer Assisted ◽  
Primary Tumors ◽  
Free Survival ◽  
Wide Range ◽  
Dna Image Cytometry

13565 Background: We assessed the prognostic value of nuclear DNA content measured in the primary tumors of 123 patients with stage II or stage III colorectal cancer (CRC). Methods: Isolated nuclei from paraffin sections were stained with Feulgen and DNA was measured using a computer-assisted image analysis cytometry system (Ahrens ACAS). We applied 4 different approaches in analysis of DNA histograms: ABCDE approach, histogram range, peak evaluation, and DNA cut-off values. Results: Using the histogram range, narrow range was rare (3.7%) in patients who died of disease as compared with 16.4% among those alive (p=0.017). Modal peak evaluation was a significant predictor of disease free survival (DFS) (Kaplan-Meier log-rank p=0.0235). In the range evaluation, the first set (low-start gates) was a significant predictor of DFS (log-rank p=0.0121), where disease recurrence was closely associated the widest range (1.8c->10c) gates. Recurrence-free survival was markedly better among patients with narrow gate histograms than wide range histograms than among patients with wide range histograms (p<0.03). The first set also proved to be significant predictor of disease specific survival (DSS) (log-rank p=0.0045), being markedly better (78–90.0%) among the patients with the narrow-gate histograms. Grading of the histogram range into two categories (with 6.0c as cut-off for low and wide range), was a powerful predictor of both DSS (log-rank p= 0.0092) and 5-year DFS (p=0.0106) in the whole series, and separately in Stage III (but not Stage II) disease; p=0.0131 and p=0.0201, respectively. Conclusions: The DNA image cytometry with careful analysis of the histograms may provide valuable prognostic information in CRC, with potential clinical implications in patient management, particularly in predicting the patients at high risk for recurrence who should be considered as candidates for adjuvant therapy. No significant financial relationships to disclose.

Effect of preoperative hepatic and regional arterial chemotherapy on metachronous liver metastasis after curative colorectal cancer resection: A prospective, multicenter, randomized controlled trial.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 511-511
Author(s):  
Jianmin Xu ◽  
Jianguo Xia ◽  
Yan Gu ◽  
Jianjiang Lin ◽  
Kefeng Ding ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Adjuvant Therapy ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Stage Iii ◽  
Metachronous Liver Metastasis ◽  
Colorectal Cancer Resection ◽  
Multicenter Randomized Controlled Trial ◽  
Metastasis Rate

511 Background: To evaluate the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis for stage II and III colorectal cancer in a multicenter setting. Methods: Patients with clinical stage II or stage III colorectal cancer (CRC) were randomly assigned to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary end point was disease free survival (DFS). Second end points were incidence of metachronous liver metastasis, overall survival (OS) and safety. Results: A total of 688 patients from 5 centers of China were randomly assigned to each arm. Five-year DFS were 75% for PHRAC arm and 61% for control arm (HR 0.60; 95% CI, 0.45 to 0.80; p<0.001). Five-year liver-metastasis rate was 8% and 18% in PHRAC arm and control arm, respectively (HR 0.39; 95% CI, 0.24 to 0.64; p<0.001). Five-year OS was 81% in PHRAC arm and 72% in control arm (HR 0.59; 95% CI, 0.42 to 0.84; p=0.003). There were no significant differences in morbidity or mortality between two arms. The results of eligible patients were barely changed. Subgroup analysis shows differences of DFS, liver-metastasis rate and OS were significant in stage III patients, but not in stage II patients. Conclusions: Additional PHRAC could reduce the incidence of metachronous liver metastasis and improve DFS and OS in patients with stage III CRC, without compromising patient safety. Clinical trial information: NCT00643877.

scholarly journals Prognostic Factors of Colorectal Cancer: A Comparative Study on Patients With or Without Liver Metastasis

2021 ◽  
Vol 11 ◽  
Author(s):  
Honghua Peng ◽  
Guifeng Liu ◽  
Ying Bao ◽  
Xi Zhang ◽  
Lehong Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Risk Factor ◽  
Liver Metastasis ◽  
Adjuvant Therapy ◽  
Independent Risk Factor ◽  
Stage Iv ◽  
Genetic Alterations ◽  
Stage Ii ◽  
Independent Risk Factors

BackgroundRadical or palliative surgery with subsequent adjuvant therapy is the routine treatment for stage II/III colorectal cancer(CRC) and some stage IV CRC patients. This study aimed to clarify the prognostic clinicopathological and genetic factors for these patients.MethodsFifty-five stage II-IV CRC patients undergoing surgery and adjuvant therapy were recruited, including patients without liver metastasis(5 at stage II, 21 at stage III) and with liver metastasis(29 at stage IV). Genetic alterations of the primary cancer tissues were investigated by whole exome sequencing(WES). Patients were followed up to 1652 days(median at 788 days).ResultsThe mutational landscape of primary CRC tissue of patients with or without liver metastasis was largely similar, although the mutational frequency of TRIM77 and TCF7L2 was significantly higher in patients with liver metastasis. Several main driver gene co-mutations, such as TP53-APC, APC-KRAS, APC-FRG1, and exclusive mutations, such as TP53-CREBBP, were found in patients with liver metastasis, but not in patients without liver metastasis. No significant difference was found between the two groups in aberrant pathways. If stage II-IV patients were studied altogether, relapse status, SUPT20HL1 mutations, Amp27_21q22.3 and Del8_10q23.2 were independent risk factors(P&lt;0.05). If patients were divided into two groups by metastatic status, surgery types and Amp6_20q13.33 were independent risk factors for patients without liver metastasis(P&lt;0.05), while TRIM77 mutations were the only independent risk factor for patients with liver metastasis(P&lt;0.05).ConclusionsSurgery types and Amp6_20q13.33 were independent risk factors for CRC patients without liver metastasis, and TRIM77 mutations were the independent risk factor for CRC patients with liver metastasis.

Expression and methylation profiles associated with recurrent mutations in stage II colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14613-e14613
Author(s):  
Laia Pare-Brunet ◽  
Rebeca Sanz-Pamplona ◽  
Adriana Lopez-Doriga ◽  
Antoni Berenguer-Llergo ◽  
Susanna Ausso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Molecular Subtypes ◽  
Expression Patterns ◽  
Stage Ii ◽  
Molecular Heterogeneity ◽  
Rna Expression ◽  
Gene Methylation ◽  
Recurrent Mutations ◽  
Combining Data

e14613 Background: Aberration of normal genetic and epigenetic patterns occurs at early stages of colorectal cancer (CRC) and accumulates throughout cancer progression. To characterize pre-metastatic tumors, a series of stage II, microsatellite stable, colon tumors and their paired mucosa were profiled on RNA expression and DNA methylation microarrays ( www.colonomics.org ). Our aim is to define molecular subtypes based on recurrent gene mutations, methylation and expression profiles, and explore if these molecular subtypes are associated to patients’ prognosis. Methods: We have sequenced exomes (Illumina Genome Analyzer) of a subset of 42 COLONOMICS normal-tumor paired samples (21 good and 21 bad prognosis). Variants identified in normal tissue were used to filter SNPs. DNA methylation (Infinium Human Methylation 450k) and RNA expression (Affymetrix U219) data from those samples were used in this analysis. Correlation was used to assess the association between tumor mutations and differentially expressed/methylated genes. Significant genes were subsequently used to perform tumor clustering. Results: Exome analysis revealed a mean of 150 somatic mutations per sample. From these, 12 variants were recurrently mutated (KRAS, TP53, etc) in more than 3 tumors that were used to define tumor subtypes based on gene methylation/expression patterns. We obtained 12 profiles that clearly identified the cluster of mutated samples. For some profiles, the cluster only includes those tumors with the mutation. Interestingly, some clusters included the mutated samples and additional tumors showing the same phenotype despite not having the mutation. For each mutation, the overlapping between the differently methylated/expressed genes ranged from 14 to 200 common genes. When combining data from the three platforms two main CRC molecular subtypes emerge; each of which shows molecular heterogeneity but no association with prognosis. Conclusions: Mutational status is associated with gene methylation and expression patterns in CRC patients. Although none of these clusters was associated with prognosis, different groups of tumors could be related to distinctive pathways, which may reveal useful as therapeutic targets.

SMAD4 loss in colorectal cancer: Correlation with recurrence, chemoresistance, and immune infiltrate.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 587-587 ◽  
Author(s):  
Isaac Wasserman ◽  
Lik Hang Lee ◽  
Jinru Shia ◽  
Chao Wu ◽  
Xi Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Tissue Microarrays ◽  
Stage Ii ◽  
Rank Test ◽  
Immune Infiltrate ◽  
Entire Cohort ◽  
Pathologic Features ◽  
Mmr Proteins

587 Background: Few markers reliably identify colorectal cancer (CRC) patients at risk of recurrence and death. SMAD4 loss occurs in 10-20% of cases and has shown promise in identifying high-risk stage II/III patients. We examined SMAD4 status and association with clinical/pathologic features in 446 stage I-IV CRC patients at Memorial Sloan Kettering (MSK). Methods: Patients undergoing curative resection were included (1981-2010). Familial polyposis syndrome patients and those with inadequate tissue were excluded. Tissue microarrays were constructed (n=364). Immunohistochemistry for SMAD4 and mismatch repair (MMR) proteins was completed. SMAD4 nuclear stain intensity was scored (scale=0-3; 0=loss). On whole sections, MMR proteins (present or absent), tumor-infiltrating lymphocytes (TILs) and peritumoral lymphocyte aggregates (PLAs) were scored (scale=0-3). Associations between clinical/pathologic features and SMAD4 loss vs. retention were analyzed. Kaplan-Meier estimates and log-rank test were used for recurrence-free and overall survival analyses (RFS and OS). Results: SMAD4 loss was noted in 13%. Median age at diagnosis was 53 years, and 51% were male. The cohort consisted of 61% hindgut tumors and 62% stage II/III patients. With up to 33 years of follow-up, the mean was 6 years. SMAD4 loss correlated with higher tumor and nodal stage, adjuvant therapy use, and lower TIL and PLA scores (p<0.04 for all). Unlike prior studies, no significant differences in OS based on SMAD4 status across the entire cohort were noted; however, older patients (>median) were noted to have worse OS with SMAD4 loss (p<0.01). SMAD4 loss did correlate with worse RFS (p=0.02), persisting even when excluding MMR-deficient patients. Additionally, SMAD4 loss was associated with worse RFS in both the adjuvant chemotherapy group (median RFS=3.8 vs. 13 years; p=0.06) and the resection-only group (median RFS=4.2 years vs. not yet reached; p< 0.01). Conclusions: SMAD4 loss correlates with worse RFS and resistance to adjuvant therapy. SMAD4 loss also correlates with lower TIL and PLA scores. Future work will address chemoresistance mechanisms, relevance to adjuvant therapy use, and loss of immune infiltrate in SMAD4-null tumors.

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