DNA mismatch repair (MMR) deficiency is a genetic abnormality that has important clinical implications related to therapeutic option, familial cancer risk assessment, and checkpoint inhibitor response. It occurs in approximately 15% of colorectal cancers (CRC). Associations between MMR protein expression, microsatellite instability (MSI), and gene mutations remain under investigation.
Thirty-one FFPE samples from primary CRC patients (pts) were collected for immunohistochemistry (IHC) assay of MMR proteins, PCR-based MSI assay if available and NGS-based panel assay. Genomic alterations including single base substitutions, short and long insertions/deletions, copy number variations, and gene rearrangement were assessed. MSI status were predicted based from NGS data.
Out of 31 sample, 12 CRC were identified as MMR deficiency (dMMR) by IHC including 5 males and 7 females (median age: 66 years), and 19 samples as MMR proficiency (pMMR) including 13 males and 6 females (Median age: 53 years). Eight of the 12 dMMR samples (67%) harbored at least one MMR gene mutations predicted as loss of functions,[u1] including nonsense mutations or truncations in MSH2, MSH6 or MLH1. No MMR gene mutation was detected in any of the 19 pMMR samples (p value<0.001). In addition, 2 BRAF and 6 KRAS hotspot mutations were detected in dMMR samples, and 8 KRAS, 1 BRAF and 1 NRAS mutations in pMMR samples. NGS panel based MSI algorithm successfully predicted the MSI status of all the 31 samples with 100% concordance with the MMR results. Neither copy number variation nor rearrangement was detected. Five pMMR samples were identified as microsatellite stability (MSS) by PCR, 6 dMMR were high level of microsatellite instability (MSI-H), and the rest were failed due to DNA contents.Table: 166P
|n||MMR gene mutations (n, %)||KRAS mutations (n, %)||NRAS mutations (n, %)||BRAF mutations (n, %)||NGS MSI-H status (n, %)|
|dMMR (IHC)||12||8 (66.7%)||6 (50%)||0 (0%)||2 (16.7%)||12 (100%)|
|pMMR (IHC)||19||0 (0%)||8 (42.1%)||1 (5.2%)||1 (5.2%)||0 (0%)|
We observed a significant association between MMR deficiency and MMR gene mutations from deep DNA sequencing. The results suggested that CRC pts with MMR gene mutations could be more likely to have dMMR status.
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D. Chen, X. Dong, J. Hu, G. Chirn, W. Shi, M. Yao: Employee: OrigiMed. All other authors have declared no conflicts of interest.