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Profiling immunohistochemical expression of NOTCH1-3, JAGGED1, cMET, and phospho-MAPK in 100 carcinomas of unknown
Dimitrios Krikelis1, George Pentheroudakis, Anna Goussia
1Department of Medical Oncology, Medical School, Aristotle University of Thessaloniki, Papageorgiou Hospital, Thessaloniki, Greece.
Abstract:
Cancer of unknown primary (CUP) is a heterogeneous entity, managed on the basis of "one size fits all" therapeutic concepts; insights into the molecular biology of CUP are urgently needed. We retrospectively examined the immunohistochemical (IHC) expression of Notch1, 2, 3, Jagged1, cMET, and pMAPK biomolecules in 100 CUP tumors using tissue microarrays, aiming to study their correlation to clinicopathologic characteristics and prognostic utility for patient outcome. Notch3 and pMAPK were most frequently expressed (97 and 91 %, respectively). A linear correlation of Notch3 and cMET expression was found (p = 0.001), while pMAPK emerged as the major adverse prognostic factor (median overall survival OS 9 vs. 17 months, p = 0.016), carrying also a significantly positive predictive value (p = 0.02). Our study indicated a favorable prognostic impact of cMET expression in CUP, both in univariate (median OS 15 vs. 9 months, p = 0.05) and in multivariate analysis (Relative Risk RR for death 0.48, p = 0.025). cMET and Notch3 expression were found to be statistically more frequent in squamous carcinomas (positive in 90 % of cases), associated with a unique metastatic IHC pattern (cMET-high in soft tissue/lymph node metastases, p < 0.001, Notch3-high in visceral, peritoneal/pleural and soft tissue/lymph node metastases, p < 0.001). Our study points to the MAPK and cMET axes as crucial in defining cancer progression and outcome in CUP patients and, if validated, could justify attempts at their therapeutic modulation.
Insights
This study investigated molecular markers in cancer of unknown primary (CUP). pMAPK was linked to worse outcomes, while cMET showed a favorable prognosis, suggesting therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cancer of unknown primary (CUP) presents a significant clinical challenge due to its heterogeneity and the lack of targeted therapies.
- Current management strategies for CUP often employ a "one size fits all" approach, highlighting the need for deeper molecular insights.
- Understanding the underlying molecular biology of CUP is crucial for developing personalized treatment strategies.
Purpose of the Study:
- To investigate the immunohistochemical (IHC) expression of specific biomolecules (Notch1, 2, 3, Jagged1, cMET, pMAPK) in CUP tumors.
- To correlate the expression of these biomolecules with clinicopathologic characteristics and their prognostic utility for patient outcomes.
- To identify potential therapeutic targets within the MAPK and cMET signaling pathways in CUP.
Main Methods:
- Retrospective analysis of 100 CUP tumor samples using tissue microarrays.
- Immunohistochemical (IHC) staining to assess the expression levels of Notch1, 2, 3, Jagged1, cMET, and pMAPK.
- Statistical analysis to determine correlations between biomolecular expression, clinicopathologic features, and patient survival.
Main Results:
- Notch3 (97%) and pMAPK (91%) were the most frequently expressed biomolecules.
- pMAPK was identified as a significant adverse prognostic factor, associated with reduced overall survival (OS).
- cMET expression demonstrated a favorable prognostic impact, improving median OS in both univariate and multivariate analyses.
- Specific expression patterns of cMET and Notch3 were observed in squamous carcinomas and different metastatic sites.
Conclusions:
- The MAPK and cMET signaling axes play critical roles in the progression and outcome of cancer of unknown primary.
- pMAPK expression is associated with poorer prognosis, while cMET expression suggests a better outcome in CUP patients.
- These findings warrant further validation and may support therapeutic strategies targeting the MAPK and cMET pathways in CUP.
