Prognostic significance of KRAS and BRAF mutations in Japanese patients with colorectal cancer.

e14033 Background: Recent evidence highlights the potential prognostic and predictive value of BRAF and K-RAS gene alterations in patients with colorectal cancer. To determine whether differences exist in the molecular mechanisms driving colorectal cancer between Japanese and Western, we characterized Japanese patients with colorectal cancer by assessing genetic alterations involved in cancer progression and response to treatment. Methods: We retrospectively evaluated 254 Japanese diagnosed with colorectal cancer at our institution between 1994 and 2009. Mutations in KRAS codons 12 and 13 and BRAF codon 600 were identified by direct sequencing. Microsatellite instability (MSI) status was determined by genotyping in the 5 loci. Associations between KRAS or BRAF mutation and clinicopathological characteristics and prognosis were evaluated. Results: KRAS and BRAF mutation were detected in 33.5% and 6.7% of all patients, respectively. KRAS mutation was correlated with poor recurrence free survival (RFS) (p = 0.03), especially in stage II patients (p = 0.007). BRAF mutation was significantly correlated with the anatomical site of tumor (p < 0.001), tumor grade (p = 0.001) and high frequency of microsatellite instability (p < 0.001). BRAF mutation was also correlated with poor overall survival in all cases of patients (p = 0.009). Overall, the background of KRAS and BRAF mutation was almost similar between CRCs of Western countries and those of Japanese. However, KRAS mutation status was considered to be helpful to predict recurrence in Japanese patients with stage II CRC. Conclusions: Our findings indicate that BRAF and K-RAS mutation plays an important role in the tumorigenesis of colorectal cancer. These results indicate that molecular analysis for BRAF and K-RAS may be a useful biomarker for identifying patients with right-sided colon cancer with poor outcome who may benefit from a more individualized course of therapy.

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Overall survival based on MSI and BRAF mutation status for stage II/III colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.132 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 132-132

Author(s):

Sophiya Karki ◽

Rashna Madan ◽

Sarah Schmitt ◽

Ziyan Y. Pessetto ◽

Andrew K. Godwin ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Microsatellite Instability ◽

Median Survival ◽

Braf Mutation ◽

Prognostic Value ◽

Stage Ii ◽

Age At Diagnosis ◽

Mutation Status ◽

Braf Mutant

132 Background: Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths in the United States. Some of the poor prognostic factors for metastatic CRC (mCRC) include BRAF V600E mutation and microsatellite instability (MSI) that result from mutation or loss of mismatch-repair genes. While the prognostic value of MSI-high CRC for early-stage patients treated with resection and adjuvant chemotherapy is favorable, the prognostic value of BRAF mutation is still unclear. Furthermore, the impact of BRAF mutation with concurrent microsatellite instability on overall survival has not been well investigated. Methods: Here, we collected BRAF mutation status and MSI status of stage II/III CRC patients (n=106) treated at the University of Kansas Cancer Center between September 2009 and July 2020 and compared overall survival between 4 subtypes:MSI-H/BRAF mutant (n=16), MSS/BRAF mutant (n=4), MSI-H/BRAF WT (n=17) and MSS/BRAF WT (n=69), further stratifying patients by age at diagnosis and tumor location. Molecular data were obtained from molecular oncology laboratory as PCR or IHC-based or acquired from outside records. Subgroup analyses were done for stage II and stage III cancers. Results: Table shows the patient characteristics. From our preliminary analysis, MSI-H CRC was found to be primarily a right-sided tumor (MSI-H/BRAF mutant: 94% and MSI-H/BRAF WT 76%). On the contrary, MSS CRC had a more heterogenous localization, spanning left colon, right colon and rectum. In our patient cohort, median survival was not reached for stage II patients whereas for stage III patients, BRAF mutation was associated with poor median survival irrespective of MSI status (MSS/BRAF mutant: 27 months and MSI-H/BRAF mutant 29 months). Median overall survival was found to be 87 months, not reached, 27 months and 29 months for MSS/BRAF WT, MSI-H/BRAF WT, MSS/BRAF mutant and MSI-H/BRAF mutant, respectively. Although associated with poor survival, MSI-H/BRAF mutant displayed later age at diagnosis (mean age 73) compared to MSS/BRAF mutant (mean age 60, p-value<0.029). Conclusions: Our finding suggests that BRAF mutation has poor prognosis even at earlier stages of the disease and that MSS/BRAF mutation, in particular, has the worst prognostic features. These findings highlight the need for BRAF-targeted therapy for CRC at any stage. Due to small sample size, however, our results warrant validation in a larger cohort. [Table: see text]

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Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability, and CIMP status: Prognostic implications and response to chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.668 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 668-668

Author(s):

Oscar Murcia ◽

Miriam Juárez ◽

Eva Hernández-Illán ◽

Maria Rodriguez-Soler ◽

Mar Giner-Calabuig ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Braf Mutation ◽

Kras Mutation ◽

Cpg Island ◽

Disease Free Survival ◽

Molecular Classification ◽

Hazard Ratio ◽

Tnm Stage ◽

Response To Chemotherapy

668 Background: The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype’s response to chemotherapy. Methods: This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). Results: Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P < 0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P < 0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005). Conclusions: We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.

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Prognostic Significance of Microsatellite Instability in Turkish Patients with Stage II and III Colorectal Cancer

Eurasian Journal of Medical Investigation ◽

10.14744/ejmi.2021.19999 ◽

2021 ◽

Author(s):

Adem Deligonul

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Prognostic Significance ◽

Stage Ii ◽

Turkish Patients

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Prognostic Significance of Microsatellite Instability and Ki-ras Mutation Type in Stage II Colorectal Cancer

Oncology ◽

10.1159/000069311 ◽

2003 ◽

Vol 64 (3) ◽

pp. 259-265 ◽

Cited By ~ 47

Author(s):

Cathy Wang ◽

Marius van Rijnsoever ◽

Fabienne Grieu ◽

Sean Bydder ◽

Hany Elsaleh ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Prognostic Significance ◽

Stage Ii ◽

Stage Ii Colorectal Cancer ◽

Mutation Type

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Low Level of Microsatellite Instability Correlates with Poor Clinical Prognosis in Stage II Colorectal Cancer Patients

Journal of Oncology ◽

10.1155/2016/2196703 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 10

Author(s):

Ehsan Nazemalhosseini Mojarad ◽

Seyed Mohammad Hossein Kashfi ◽

Hanieh Mirtalebi ◽

Mohammad Yaghoob Taleghani ◽

Pedram Azimzadeh ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Prognostic Significance ◽

Tumor Stage ◽

Cross Sectional Study ◽

Stage Ii ◽

Curative Surgery ◽

Cross Sectional ◽

Clinical Prognosis ◽

Distinct Subgroup

The influence of microsatellite instability (MSI) on the prognosis of colorectal cancer (CRC) requires more investigation. We assessed the role of MSI status in survival of individuals diagnosed with primary colorectal cancer. In this retrospective cross-sectional study the MSI status was determined in 158 formalin-fixed paraffin-embedded tumors and their matched normal tissues from patients who underwent curative surgery. Cox proportional hazard modeling was performed to assess the clinical prognostic significance. In this study we found that MSI-H tumors were predominantly located in the colon versus rectum (p=0.03), associated with poorer differentiation (p=0.003) and TNM stage II/III of tumors (p=0.02). In CRC patients with stage II, MSI-L cases showed significantly poorer survival compared with patients who had MSI-H or MSS tumors (p=0.04). This study indicates that MSI-L tumors correlate with poorer clinical outcome in patients with stage II tumors (p=0.04) or in tumors located in the colon (p=0.02). MSI-L characterizes a distinct subgroup of CRC patients who have a poorer outcome. This study suggests that MSI status in CRC, as a clinical prognostic marker, is dependent on other factors, such as tumor stage and location.

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Clinical implications of microsatellite instability in mucinous colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.657 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 657-657

Author(s):

Fergus Keane ◽

Darrell Martin ◽

Gregory D. Leonard ◽

Sean Hynes ◽

Margaret Sheehan

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Who Classification ◽

Prognostic Significance ◽

Stage Ii ◽

Stage Iii ◽

Low Grade ◽

Tumor Type ◽

Response To Chemotherapy ◽

Microsatellite Stability

657 Background: Colorectal Cancer(CRC) is becoming increasingly recognised as a heterogeneous tumor type. Mucinous histological subtype is identified in 10-15% of CRCs, most commonly those with microsatellite instability (MSI), and has traditionally been associated with unfavorable outcomes and poor response to chemotherapy. In contrast, MSI is associated with relatively favourable pathological features and better outcomes, compared with CRCs with microsatellite stability (MSS), such that under the 2010 WHO classification, MSI mucinous CRC is considered low grade, while MSS mucinous CRC is classified as high grade. The aim of this study is to establish the significance of microsatellite stability status in non-metastatic mucinous colorectal cancer. Methods: Between 2010 and 2017, 69 patients with stage II or stage III mucinous colorectal cancer were identified. Microsatellite status was tested in all patients (MSS or MSI), and histological and clinical data, as well as recurrence rates, were assessed in both groups. MSI status was established using polymerase chain reaction(PCR) technique. Results: Sixty-nine patients with mucinous CRC were identified. The median age for the entire group was 73 years (range 32-87), no difference in gender was identified. 63%(n=43) and 37%(n=26) were stage II and stage III respectively at diagnosis. The majority of mucinous CRCs were right-sided (72%). 33% (n=23) were identified as microsatellite unstable (MSI). MSI status was associated with right sided tumours (78% right-sided vs 22% left-sided, p<0.05), older age at diagnosis (mean 76 years vs 68 years, p=0.01), and lower TNM staging at diagnosis (83% vs 52% diagnosed stage 2, p=0.007) compared with the MSS group. A lower disease recurrence rate was identified in the MSI group (4.3% vs 13% in MSS group) at median follow-up time of 33 months (range 8-93 months). Conclusions: In patients with mucinous colorectal cancer, MSI status is a useful marker of favourable histological and clinical features, and is associated with better outcomes. Our study supports the current 2010 WHO classification, and highlights the clinical and prognostic significance of MSI status in this patient cohort.

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

Problems in oncology ◽

10.37469/0507-3758-2019-65-5-701-707 ◽

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.

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