<i>BRAF</i>-Mutated Colorectal Cancer Exhibits Distinct Clinicopathological Features from Wild-Type<i>BRAF</i>-Expressing Cancer Independent of the Microsatellite Instability Status

Jang, Min Hye; Kim, Sehun; Hwang, Dae Yong; Kim, Wook Youn; Lim, So Dug; Kim, Wan Seop; Hwang, Tea Sook; Han, Hye Seung

doi:10.3346/jkms.2017.32.1.38

Cited by 27 publications

(27 citation statements)

References 26 publications

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“…liver and lung, but negatively with metastatic spread to the peritoneum, a finding that might be clinically useful in the follow-up of patients. This could in part be due to the higher prevalence of BRAF-mutated cases in tumours with low SATB2 expression, as BRAF mutated tumours often metastasise to the peritoneum [26,27].…”

Section: Discussionmentioning

confidence: 99%

Metastatic colorectal carcinomas with high SATB2 expression are associated with better prognosis and response to chemotherapy: a population-based Scandinavian study

et al. 2019

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Background: Survival and response to therapy in patients with metastatic colorectal cancer (mCRC) are very heterogeneous. There is an unmet need for better markers of prognosis and treatment benefit for mCRC patients. The homeobox 2 gene SATB2 has a highly specific expression in colorectal tissue and is associated with better prognosis in non-metastatic CRC. Material and methods: A population-based cohort of 798 mCRC patients was analysed. From primary tumour material, protein expression was assessed by immunohistochemistry. BRAF and KRAS mutation status was also determined. Associations with clinicopathological data, overall and progression-free survival and response to first-line chemotherapy were analysed. Results: Tumour tissue and clinical data were available from 467 patients. SATB2 was strongly expressed in 58% of cases, significantly more in left-sided, low-grade and wild-type BRAF tumours. Patients with high SATB2 tumours had longer overall survival compared with low SATB2 tumours (median 13 vs 8 months respectively, p < .001). Chemotherapy was given to 282 patients (63%). Patients with high SATB2 tumours had longer OS (median 22 vs 15 months respectively, p ¼ .001) and more often responded to chemotherapy than those with low SATB2 (objective response 43% vs 29%, p ¼ .02; clinical response 83% vs 67%, p ¼ .004). Progression-free survival on first-line irinotecan chemotherapy was longer in high SATB2 cases (median 8 vs 4 months respectively, p ¼ .019). Patients with both low SATB2 expression and mutated BRAF (n ¼ 69) had particularly poor survival compared to the rest (median 8 and 12 months respectively, p ¼ .001). In multivariable analysis, the SATB2 findings were independent of known clinicopathological prognostic markers, including BRAF mutation status. Conclusion: Patients with mCRC expressing high level of SATB2 have better prognosis and response to chemotherapy than those with low SATB2 expression. Patients with both low SATB2 expression and mutated BRAF had particularly poor prognosis and could thus benefit from more aggressive therapies.

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Section: Discussionmentioning

confidence: 99%

Metastatic colorectal carcinomas with high SATB2 expression are associated with better prognosis and response to chemotherapy: a population-based Scandinavian study

et al. 2019

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“…BRAF-mutated (BRAFmt) CRCs have specific clinicopathological and molecular features [14][15][16][17][18], identifying a distinct subset with aggressive phenotype and poor outcome ( Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

et al. 2020

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Colorectal cancer (CRC) is a complex and molecularly heterogeneous disease representing one of the most frequent causes of cancer-related death worldwide. About 8-15% of CRCs harbor a mutation in BRAF gene, a proto-oncogene involved in cell proliferation, differentiation and survival through the MAPK signaling cascade. The acquisition of BRAF mutation is an early event in the "serrated" CRC carcinogenetic pathway and is associated with specific and aggressive clinico-pathological and molecular features. Despite that the presence of BRAF mutation is a well-recognized negative prognostic biomarker in metastatic CRC (mCRC), a great heterogeneity in survival outcome characterizes these patients, due to the complex, and still not completely fully elucidated, interactions between the clinical, genetic and epigenetic landscape of BRAF mutations. Because of the great aggressiveness of BRAF-mutated mCRCs, only 60% of patients can receive a second-line chemotherapy; so intensive combined and tailored first-line approach could be a potentially effective strategy, but to minimize the selective pressure of resistant clones and to reduce side effects, a better stratification of patients bearing BRAF mutations is needed.

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“…Several studies have tried to determine the genetic aetiology of mucinous adenocarcinoma of the colon and rectum, with heterogeneous outcomes. Mutations in Kirsten rat sarcoma viral oncogene ( KRAS ) and v‐Raf murine sarcoma viral oncogene homologue B ( BRAF ), inherited defects or epigenetic silencing of mismatch repair (MMR) proteins resulting in microsatellite instability (MSI), and the presence of the CpG island methylator phenotype (CIMP) are the most commonly studied genetic aberrations. The presence or absence of each of these genetic markers may have therapeutic and/or prognostic implications for patients with colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of the molecular associations of mucinous colorectal cancer

Reynolds

Furney

Kay

et al. 2019

British Journal of Surgery

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Background: Mucinous differentiation occurs in 5-15 per cent of colorectal adenocarcinomas. This subtype of colorectal cancer responds poorly to chemoradiotherapy and has a worse prognosis. The genetic aetiology underpinning this cancer subtype lacks consensus. The aim of this study was to use meta-analytical techniques to clarify the molecular associations of mucinous colorectal cancer.Methods: This study adhered to MOOSE guidelines. Databases were searched for studies comparing KRAS, BRAF, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), p53 and p27 status between patients with mucinous and non-mucinous colorectal adenocarcinoma. A random-effects model was used for analysis.Results: Data from 46 studies describing 17 746 patients were included. Mucinous colorectal adenocarcinoma was associated positively with KRAS (odds ratio (OR) 1⋅46, 95 per cent c.i. 1⋅08 to 2⋅00, P = 0⋅014) and BRAF (OR 3⋅49, 2⋅50 to 4⋅87; P < 0⋅001) mutation, MSI (OR 3⋅98, 3⋅30 to 4⋅79; P < 0⋅001) and CIMP (OR 3⋅56, 2⋅85 to 4⋅43; P < 0⋅001), and negatively with altered p53 expression (OR 0⋅46, 0⋅31 to 0⋅67; P < 0⋅001). Conclusion:The genetic origins of mucinous colorectal adenocarcinoma are predominantly associated with BRAF, MSI and CIMP pathways. This pattern of molecular alterations may in part explain the resistance to standard chemotherapy regimens seen in mucinous adenocarcinoma.

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BRAF-Mutated Colorectal Cancer Exhibits Distinct Clinicopathological Features from Wild-TypeBRAF-Expressing Cancer Independent of the Microsatellite Instability Status

Cited by 27 publications

References 26 publications

Metastatic colorectal carcinomas with high SATB2 expression are associated with better prognosis and response to chemotherapy: a population-based Scandinavian study

Metastatic colorectal carcinomas with high SATB2 expression are associated with better prognosis and response to chemotherapy: a population-based Scandinavian study

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

Meta-analysis of the molecular associations of mucinous colorectal cancer

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