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Published on: August 14, 2012
DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and
B C M Hermans1, J L Derks1, E Thunnissen2
1Department of Pulmonary Diseases, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
Objectives:
For stage IV pulmonary large cell neuroendocrine carcinoma (LCNEC), the only therapeutic option is palliative chemotherapy. DLL3 is a new therapeutic target, which seems to be often expressed in SCLC and LCNEC. It has recently been reported that DLL3 mRNA expression is particularly upregulated in the LCNEC subgroup with STK11/KEAP1 and TP53 co-mutations, in contrast to lower expression levels in RB1 and TP53 co-mutated LCNEC. Our aim was to investigate DLL3 protein expression in stage IV LCNEC and correlate data with mutational profiles (i.e.STK11/KEAP1/RB1), immunostaining results (pRb, NE markers) and clinical characteristics.
Materials And Methods:
Immunohistochemical analysis for DLL3 (SC16.65) and ASCL1 (SC72.201) was performed on 94 and 51 FFPE tissue sections, respectively, of pathologically reviewed stage IV LCNEC. DLL3 and ASCL1 were scored positive if ≥1% of the tumor cells showed cytoplasmic/membranous or dotlike (DLL3) or nuclear (ASCL1) immunostaining. Data were correlated with available sequencing (TP53, RB1, STK11, KEAP1), immunostaining (pRb, NE markers) and clinical data.
Results:
DLL3 was expressed in 70/94 (74%) LCNEC, 56 (80%) of which showed cytoplasmic/membranous staining. Median H-score was 55 (interquartile range 0-160). DLL3 staining was not different in pRb immunohistochemistry negative and positive patients (DLL3+ in 53/70 (76%) vs. 14/21 (67%), p = 0.409) or RB1 mutated and wildtype patients (DLL3+ in 27/34 (79%) vs. 23/33 (70%), p = 0.361). Nevertheless, 6/6 (100%) STK11 mutated, 10/11 (91%) KEAP1 mutated and 9/9 (100%) TP53 wildtype tumors were DLL3+ . Furthermore, DLL3 expression was associated with expression of ASCL1 and at least 2 out of 3 neuroendocrine markers.
Conclusion:
The high percentage (74%) of DLL3 expression in stage IV LCNEC denotes the potential of DLL3 targeted therapy in this patient group.
Insights
This study found that DLL3 protein is highly expressed in 74% of stage IV pulmonary large cell neuroendocrine carcinoma (LCNEC) cases. This high expression suggests DLL3 targeted therapy could be a promising option for LCNEC patients.
Area of Science:
- Oncology
- Molecular Pathology
- Translational Research
Background:
- Stage IV pulmonary large cell neuroendocrine carcinoma (LCNEC) has limited treatment options, primarily palliative chemotherapy.
- DLL3 is an emerging therapeutic target, frequently expressed in neuroendocrine tumors like SCLC and LCNEC.
- Previous research indicated DLL3 mRNA upregulation in LCNEC with STK11/KEAP1 and TP53 co-mutations.
Purpose of the Study:
- To investigate DLL3 protein expression in stage IV LCNEC.
- To correlate DLL3 protein expression with specific mutational profiles (STK11, KEAP1, RB1, TP53).
- To examine the relationship between DLL3 expression and pRb status, neuroendocrine markers, and clinical characteristics.
Main Methods:
- Immunohistochemical analysis of DLL3 protein on 94 stage IV LCNEC tissue sections.
- Scoring DLL3 positivity based on ≥1% tumor cell cytoplasmic/membranous staining.
- Correlation of DLL3 expression data with available sequencing (TP53, RB1, STK11, KEAP1) and immunostaining results (pRb, NE markers).
Main Results:
- DLL3 protein was expressed in 74% (70/94) of stage IV LCNEC cases.
- DLL3 expression was notably high in tumors with STK11 mutations (100%), KEAP1 mutations (91%), and TP53 wildtype (100%).
- DLL3 expression correlated with ASCL1 and other neuroendocrine marker expression.
Conclusions:
- The high prevalence of DLL3 protein expression in stage IV LCNEC supports its potential as a therapeutic target.
- DLL3-targeted therapies may offer a new treatment avenue for patients with stage IV LCNEC.
