Abstract
Purpose
To better understand the clinicopathological characteristics and molecular alterations in different intratumoral components of colorectal cancer (CRC) with heterogeneity of mismatch repair (MMR) protein expression and microsatellite instability (MSI) status.
Methods
The histopathological features, MSI status, and other molecular alterations were analyzed in separately microdissected intratumoral regions and matched metastatic lymph nodes in four cases with intratumoral heterogenous MMR expression screened from 500 CRC patients, using PCR-based MSI testing, MLH1 promoter methylation, and targeted next-generation sequencing (NGS).
Results
High microsatellite instability (MSI-H) was identified in MLH1/PMS2-deficient regions in Cases 1 to 3 and in MSH2/MSH6-deficient regions in Case 4, while microsatellite stability (MSS) was detected in all the intratumoral regions and metastatic lymph nodes with proficient MMR expression (pMMR). Intratumoral heterogeneity of MLH1 promoter methylation and/or other common driving gene mutations of CRC, such as KRAS and PIK3CA mutations, was identified in all four CRCs. Further, three cases (75%) showed heterogeneous histomorphological features in intratumoral components and metastatic lymph nodes (Cases 1, 2, and 4), and the corresponding metastatic lymph nodes showed moderate differentiation with MSS/pMMR (Cases 2 and 3).
Conclusions
Intratumoral heterogeneous MSI status is highly correlated with intratumoral histomorphological heterogeneity, which is also an important clue for the intratumoral heterogeneity of drive gene mutations in CRC. Thus, it is essential to detect MMR protein expression and other gene mutations in metastases before treatment, especially for CRCs with intratumoral heterogenous MMR protein expression or heterogenous histomorphological features.
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Acknowledgements
We acknowledge technical help from Xu Cai and Wenhua Jiang, and experimental assistance by the Clinical Molecular Pathology Laboratory of Fudan University Shanghai Cancer Center.
Funding
This research was financially supported by the National Key Research and Development Program of China (No.YFC20170110100), the Science and Technology Commission of Shanghai Municipality (No.19441904900), the Shanghai Science and Technology Development Foundation (19MC1911000), the Shanghai Municipal Key Clinical Specialty (shslczdzk01301), the Innovation Group Project of Shanghai Municipal Health Commission (No.2019CXJQ03), and the Integrated Diagnostic Pathological Study on Cancer of Unknown Primary (No.20Z11900300).
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JZ and XZ: designed and conducted the study, and wrote the manuscript. QW and YYX: collected and tested samples. QLY and DH: analyzed and interpreted of the experimental data. XLZ and WQS: performed pathology assessment and article revision. XYZ and QMB: designed and managed the study, and had final responsibility for the decision to submit for publication. All authors reviewed the manuscript.
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The study was approved by Fudan University Shanghai Cancer Center’s institutional ethics committee (approval number 1812195-3).
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Zhang, J., Zhang, X., Wang, Q. et al. Histomorphological and molecular genetic characterization of different intratumoral regions and matched metastatic lymph nodes of colorectal cancer with heterogenous mismatch repair protein expression. J Cancer Res Clin Oncol 149, 3423–3434 (2023). https://doi.org/10.1007/s00432-022-04261-1
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DOI: https://doi.org/10.1007/s00432-022-04261-1