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Next-Generation Sequencing of Multivergent Morphologies in Colorectal Carcinomas Identifies Unique Targetable
Brent K Larson1, Elias Makhoul1, Alexandra Gangi2
1Department of Pathology and Laboratory Medicine.
Abstract:
Typically, colorectal carcinoma (CRC) is morphologically relatively homogeneous. Uncommon morphologic patterns may be enriched for rare molecular drivers. This study examined the clinicopathologic characteristics of CRC with multivergent morphology (defined as 2 discrete nonconventional morphologic cytoarchitectural patterns) and whether potentially targetable molecular alterations could be identified by interrogating 2 distinct morphologic areas. Evaluation of representative sections from 213 consecutive CRC resections identified 11 with multivergent morphology. Next-generation sequencing (NGS) was performed on 2 morphologically discrete areas from multivergent cases. Compared with the remaining 202 CRCs, multivergent CRCs were larger (mean: 6.4 vs. 4.4 cm; P=0.038), had a higher T stage (100% vs. 78.2% ≥T3; P=5.0×10-4), a higher N stage (90.9% vs. 42.1% ≥N1, P=7.0×10-4), and more frequently had distant metastasis (36.4% vs. 10.9%; P=0.041). Multivergent CRCs were more likely to be mismatch repair (MMR)-deficient (45.5% vs. 15.8%; P=0.034) and to have an atypical MMR pattern (27.3% vs. 0.5%; P=1.7×10-7). Both areas of multivergent CRC often harbored molecular alterations associated with eligibility for Food and Drug Administration (FDA)-approved therapies (63.6%; 7/11) and clinical trials (72.7%; 8/11). Not uncommonly, a molecular alteration associated with eligibility for FDA-approved therapy (45.5%; 5/11) and clinical trials (72.7%; 8/11) was isolated to only one of the sequenced areas. Multivergent CRC is rare but associated with targetable molecular alterations. NGS of multiple areas with different morphologies may help identify potential therapeutic targets. While most cases have recognizable driver alterations, the less common, targetable alterations identified in these cases could open additional trial options for salvage therapy.
Insights
Rare multivergent colorectal carcinoma (CRC) exhibits distinct morphologic patterns and is linked to targetable molecular alterations. Analyzing multiple areas using next-generation sequencing (NGS) can identify potential therapies for advanced CRC.
Area of Science:
- Oncology
- Pathology
- Molecular Biology
Background:
- Colorectal carcinoma (CRC) typically presents with homogeneous morphology.
- Uncommon morphologic patterns in CRC may harbor distinct molecular drivers.
- Multivergent morphology, defined by two discrete nonconventional patterns, is a rare presentation.
Purpose of the Study:
- To investigate the clinicopathologic features of multivergent CRC.
- To determine if targetable molecular alterations can be identified by analyzing distinct morphologic areas within multivergent CRC.
- To assess the potential for personalized therapy based on molecular profiling of diverse CRC morphologies.
Main Methods:
- Evaluation of 213 consecutive CRC resections to identify cases with multivergent morphology.
- Next-generation sequencing (NGS) performed on two distinct morphologic areas from identified multivergent CRC cases.
- Comparison of clinicopathologic characteristics between multivergent and conventional CRC cases.
Main Results:
- Multivergent CRC cases were larger, with higher T and N stages, and more frequent distant metastasis compared to conventional CRC.
- A significant proportion of multivergent CRCs were mismatch repair (MMR)-deficient or showed atypical MMR patterns.
- Targetable molecular alterations, including those for FDA-approved therapies and clinical trials, were frequently identified in both morphologic areas, sometimes exclusively in one area.
Conclusions:
- Multivergent CRC is a rare subtype associated with aggressive clinicopathologic features.
- Targetable molecular alterations are common in multivergent CRC, offering potential therapeutic opportunities.
- NGS analysis of multiple distinct morphologic areas in multivergent CRC is crucial for identifying actionable molecular targets and expanding treatment options.
