High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer

Jeantet, Marion; Tougeron, David; Tachon, Gaëlle; Cortes, Ulrich; Archambaut, Céline; Fromont, Gaëlle; Karayan‐Tapon, Lucie

doi:10.3390/ijms17122015

Cited by 37 publications

(32 citation statements)

References 40 publications

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“…In fact, nearly one third of CRC tumors demonstrate ITH by analyzing RAS mutations in multiple tumor areas. 27 Similar rates of intertumoral heterogeneity (39%) are seen between primary tumors and either lymph node or distant metastases. 27 While detection of mutations such as KRAS has helped to guide targeted molecular therapy, the extreme degree of genetic heterogeneity in CRC presents a major challenge to precision medicine.…”

Section: Discussionmentioning

confidence: 87%

“…27 Similar rates of intertumoral heterogeneity (39%) are seen between primary tumors and either lymph node or distant metastases. 27 While detection of mutations such as KRAS has helped to guide targeted molecular therapy, the extreme degree of genetic heterogeneity in CRC presents a major challenge to precision medicine. 28 Predicting which patients have disease that will respond to nCRT holds important clinical implications in rectal cancer.…”

Section: Discussionmentioning

confidence: 87%

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Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

Greenbaum

Martín

Bocklage

et al. 2019

Clinical Colorectal Cancer

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A standard therapy for locally advanced cancers includes neoadjuvant chemoradiation; however, currently there is no way of knowing which patients have disease that will respond to such therapy. We analyzed 21 pretreatment rectal cancer biopsy samples and found a positive correlation of the response to therapy with a quantitative mutant-allele tumor heterogeneity (MATH) score. This next-generation sequencing derived score may serve as a biomarker for response to therapy. Background: Neoadjuvant chemoradiotherapy (nCRT) is the standard of care for locally advanced adenocarcinoma of the rectum, but it is currently unknown which patients have disease that will respond. This study tested the correlation between response to nCRT and intratumoral heterogeneity using next-generation sequencing assays. Patients and Methods: DNA was extracted from formalin-fixed, paraffin-embedded biopsy samples from a cohort of patients with locally advanced rectal adenocarcinoma (T3/4 or N1/2 disease) who received nCRT. High read-depth sequencing of > 400 cancer-relevant genes was performed. Tumor mutations and variant allele frequencies were used to calculate mutant-allele tumor heterogeneity (MATH) scores as measures of intratumoral heterogeneity. Response to nCRT was pathologically scored after surgical resection. Results: Biopsy samples from 21 patient tumors were analyzed. Eight patients had disease noted to have complete response, 2 moderate, 4 minimal, and 7 poor. Higher MATH scores correlated with poorer response to treatment, demonstrating significantly increased tumor heterogeneity compared to complete response (P ¼ .039). Conclusion: The application of MATH scores as a measure of tumor heterogeneity may provide a useful biomarker for treatment response in locally advanced rectal cancer.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 87%

Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

Greenbaum

Martín

Bocklage

et al. 2019

Clinical Colorectal Cancer

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“…In 18 of these patients, liver resection had been performed before resection of the primary tumor. 25 The median number of metastases seen on the preoperative imaging scans was 6 (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], and the median size of the largest lesion was 3.1 cm (range, 1-16 cm).…”

Section: Clinical Patient Characteristicsmentioning

confidence: 99%

“…[5][6][7][8][9] Molecular profiling is routinely performed of the primary tumor and in single metastatic lesions, without considering the subclonal evolution, resulting in potential tumor heterogeneity. 10 The discordance rates in KRAS mutations between paired primary and metastatic tumors have been reported to range from 6% to 8%. [11][12][13] However, the variation among studies has been high, and mutated subclones in the primary tumor could remain undetected owing to the low-sensitivity mutation tests currently used in the clinic.…”

Section: Introductionmentioning

confidence: 99%

High Concordance and Negative Prognostic Impact of RAS/BRAF/PIK3CA Mutations in Multiple Resected Colorectal Liver Metastases

Brunsell

Sveen

Bjørnbeth

et al. 2020

Clinical Colorectal Cancer

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We investigated the intra-patient heterogeneity of driver gene mutations among colorectal liver metastases by sequencing 479 tumor samples from 106 patients. A near-perfect intra-patient concordance was found in the mutation status of the primary tumor and multiple metastatic lesions of KRAS/NRAS/BRAF and PIK3CA when high-sensitivity methods were applied. Mutations in KRAS alone and KRAS/NRAS/BRAF combined had a negative prognostic impact after liver resection. Background: The prevalence and clinical implications of genetic heterogeneity in patients with multiple colorectal liver metastases remain largely unknown. In a prospective series of patients undergoing resection of colorectal liver metastases, the aim was to investigate the inter-metastatic and primary-to-metastatic heterogeneity of mutations in KRAS, NRAS, BRAF, and PIK3CA and their prognostic impact. Patients and Methods: We analyzed the mutation status among 372 liver metastases and 78 primary tumors from 106 patients by methods used in clinical routine testing, by Sanger sequencing, by next-generation sequencing (NGS), and/or by droplet digital polymerase chain reaction. The 3-year cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method. Results: Although Sanger sequencing indicated inter-metastatic mutation heterogeneity in 14 of 97 patients (14%), almost all cases were refuted by high-sensitive NGS. Also, heterogeneity among metastatic deposits was concluded only for PIK3CA in 2 patients. Similarly, primary-to-metastatic heterogeneity was indicated in 8 of 78 patients (10%) using Sanger sequencing but for only 2 patients after NGS, showing the emergence of 1 KRAS and 1 PIK3CA mutation in the metastatic lesions. KRAS mutations were present in 53 of 106 patients (50%) and were associated with poorer 3-year CSS after liver resection (37% vs. 61% for KRAS wild-type; P ¼ .004). Poor prognostic associations were found also for the combination of KRAS/NRAS/BRAF mutations compared with triple wild-type (P ¼ .002). Conclusion: Intrapatient mutation heterogeneity was virtually undetected, both between the primary tumor and the liver metastases and among the metastatic deposits. KRAS mutations separately, and KRAS/NRAS/BRAF mutations combined, were associated with poor patient survival after partial liver resection.

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“…On the other hand, different molecular subtypes correlate with various discriminating morphological features [1]. Various MR imaging modules [11][12][13][14][15][16] (i.e. diffusionweighted MR imaging [DWI], magnetic resonance spectroscopy [MRS], arterial spin labelling [ASL]) and advanced analysis for routine MR imaging [17][18][19][20][21] have been introduced in the oncologic field to evaluate tumoral biological characteristics and predict KRAS status.…”

Section: Introductionmentioning

confidence: 99%

Characterizing MRI features of rectal cancers with different KRAS status

et al. 2019

BMC Cancer

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Background: To investigate whether MRI findings, including texture analysis, can differentiate KRAS mutation status in rectal cancer. Methods: Totally, 158 patients with pathologically proved rectal cancers and preoperative pelvic MRI examinations were enrolled. Patients were stratified into two groups: KRAS wild-type group (KRAS wt group) and KRAS mutation group (KRAS mt group) according to genomic DNA extraction analysis. MRI findings of rectal cancers (including texture features) and relevant clinical characteristics were statistically evaluated to identify the differences between the two groups. The independent samples t test or Mann-Whitney U test were used for continuous variables. The differences of the remaining categorical polytomous variables were analyzed using the Chi-square test or Fisher exact test. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminatory power of MRI features. The area under the ROC curve (AUC) and the optimal cutoff values were calculated using histopathology diagnosis as a reference; meanwhile, sensitivity and specificity were determined. Results: Mean values of six texture parameters (Mean, Variance, Skewness, Entropy, gray-level nonuniformity, runlength nonuniformity) were significantly higher in KRAS mt group compared to KRAS wt group (p < 0.0001, respectively). The AUC values of texture features ranged from 0.703~0.813. In addition, higher T stage and lower ADC values were observed in the KRAS mt group compared to KRAS wt group (t = 7.086, p = 0.029; t = − 2.708, p = 0.008). Conclusion: The MRI findings of rectal cancer, especially texture features, showed an encouraging value for identifying KRAS status.

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High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer

Cited by 37 publications

References 40 publications

Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

High Concordance and Negative Prognostic Impact of RAS/BRAF/PIK3CA Mutations in Multiple Resected Colorectal Liver Metastases

Characterizing MRI features of rectal cancers with different KRAS status

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