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Colorectal poorly differentiated neuroendocrine carcinomas frequently exhibit BRAF mutations and are associated with
Dane C Olevian1, Marina N Nikiforova1, Simon Chiosea1
1Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213.
Abstract:
The molecular alterations in colorectal poorly differentiated neuroendocrine carcinoma remain incompletely characterized, particularly with respect to mutations in BRAF and KRAS. We analyzed 32 colorectal poorly differentiated neuroendocrine carcinomas and 40 colorectal poorly differentiated conventional adenocarcinomas for mutations in KRAS and BRAF and for DNA mismatch repair protein abnormalities to correlate histopathology with molecular alterations and survival. Compared with poorly differentiated conventional adenocarcinoma, poorly differentiated neuroendocrine carcinoma frequently harbored BRAF mutations (59% versus 5%; P < .001) and less frequently demonstrated KRAS codon 12 or 13 mutations (17% versus 43%; P = .03). BRAF mutations were identified in both pure poorly differentiated neuroendocrine carcinoma (60%) and poorly differentiated neuroendocrine carcinoma associated with a signet ring cell adenocarcinoma component (82%). Most (93%) poorly differentiated neuroendocrine carcinomas demonstrated proficient DNA mismatch repair by either microsatellite instability polymerase chain reaction or DNA mismatch repair immunohistochemistry. Patients with poorly differentiated neuroendocrine carcinoma had a significantly worse overall survival compared with patients with poorly differentiated conventional adenocarcinoma (P < .001). There was no significant difference in overall survival between patients with pure poorly differentiated neuroendocrine carcinoma and patients with both poorly differentiated neuroendocrine carcinoma and adenocarcinoma components (P = .5). In conclusion, colorectal poorly differentiated neuroendocrine carcinomas frequently harbor BRAF mutations and are associated with poor overall survival.
Insights
Colorectal poorly differentiated neuroendocrine carcinomas frequently have BRAF mutations, unlike conventional adenocarcinomas. These neuroendocrine tumors are linked to significantly worse survival outcomes.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Pathology
Background:
- Colorectal poorly differentiated neuroendocrine carcinoma (PDNEC) molecular landscape, especially BRAF and KRAS mutations, is not fully understood.
- Understanding these alterations is crucial for diagnosis and treatment strategies.
Purpose of the Study:
- To investigate the molecular differences, specifically BRAF and KRAS mutations and DNA mismatch repair (MMR) status, between colorectal PDNEC and conventional adenocarcinoma (PDCA).
- To correlate these molecular findings with histopathology and patient survival.
Main Methods:
- Analysis of KRAS and BRAF mutations in 32 colorectal PDNECs and 40 colorectal PDCs.
- Assessment of DNA mismatch repair protein abnormalities using microsatellite instability polymerase chain reaction and immunohistochemistry.
- Correlation of molecular alterations with histopathology and survival data.
Main Results:
- Colorectal PDNEC showed a significantly higher frequency of BRAF mutations (59% vs 5%) and a lower frequency of KRAS mutations (17% vs 43%) compared to PDCA.
- BRAF mutations were prevalent in both pure PDNEC (60%) and PDNEC with adenocarcinoma components (82%).
- Most PDNECs (93%) exhibited proficient DNA mismatch repair.
- Patients with PDNEC had significantly worse overall survival than those with PDCA (P < .001).
Conclusions:
- Colorectal PDNEC frequently harbors BRAF mutations, distinguishing it molecularly from PDCA.
- The presence of BRAF mutations and proficient DNA mismatch repair are key features of colorectal PDNEC.
- Colorectal PDNEC is associated with poor overall survival, underscoring the need for targeted therapies.
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