Deep Sequencing of Early T Stage Colorectal Cancers Reveals Disruption of Homologous Recombination Repair in Microsatellite Stable Tumours with High Mutational Burdens
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Specimens
2.2. Next Generation Sequencing
2.3. Ion AmpliSeq™ Comprehensive Cancer Panel
2.4. Retrieval of TCGA datasets
3. Results
3.1. Robust Deep Targeted Sequencing of Early T Stage Colorectal Cancer
3.2. No Stage-Related Mutational Differences between Stage IIIA vs. Stage I in TMB-Low Group
3.3. Mutational Spectrum of TMB-H and TMB-L CRC
3.4. Deficiency of Homologous Recombination Repair in TMB-H CRC
3.5. Oncogenic Pathway Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Stage I (n = 16) | Stage IIIA (n = 10) | p-Value * | |
---|---|---|---|
Year | |||
Range | 2007–2017 | 2008–2018 | |
Sex | p = 0.692 | ||
Female | 5 (31.25%) | 4 (40.00%) | |
Male | 11 (68.75%) | 6 (60.00%) | |
Age | p= 0.038 | ||
Range | 49–87 | 31–85 | |
Mean(sd) | 71.31 (11.07) | 57.40 (21.36) | |
Tumour size | p = 0.065 | ||
Range | 15–30 | 13–55 | |
Mean(sd) | 22.56 (4.91) | 30.50 (15.36) | |
Site | p = 0.806 | ||
Right | 6 (37.50%) | 3 (30.00%) | |
Left | 5 (31.25%) | 2 (20.00%) | |
Rectal | 5 (31.25%) | 5 (50.00%) | |
Total nodes | p = 0.091 | ||
Range | 13–22 | 12–49 | |
Mean(sd) | 17.31 (3.11) | 23.50 (13.66) | |
pT.7th.Ed | p< 0.001 | ||
T1 | 16 (100.00%) | 6 (60.00%) | |
T2 | 0 (0.00%) | 4 (40.00%) | |
pN.7th.Ed | |||
N0 | 16 (100.00%) | 0 (0.00%) | By definition |
N1a | 0 (0.00%) | 5 (50.00%) | |
N1b | 0 (0.00%) | 3 (30.00%) | |
N1c | 0 (0.00%) | 2 (20.00%) | |
Thin walled vessel invasion | p = 0.055 | ||
0 (Absent) | 15 (93.75%) | 6 (60.00%) | |
1 (Present) | 1 (6.25%) | 4 (40.00%) | |
Combined.BRAF.MMR.status | p = 1.000 | ||
BRAF V600E +/MSS | 1 (6.25%) | 1 (10.00%) | |
BRAF V600E −/MSH | 0 (0.00%) | 0 (0.00%) | |
BRAF V600E +/MSH | 3 (18.75%) | 1 (10.00%) | |
BRAF V600E −/MSS | 12 (75.00%) | 8 (80.00%) |
Gene Symbol | Stage IIIA (freq%) | Stage I (freq%) | Pval | Odds Ratio | Confidence Interval. Upper | Confidence Interval. Lower | AdjPval |
---|---|---|---|---|---|---|---|
KRAS | 5 (62.5%) | 1 (12.5%) | 0.12 | 9.76 | 625.22 | 0.68 | 0.24 |
TP53 | 7 (87.5%) | 4 (50%) | 0.28 | 6.16 | 391.63 | 0.42 | 0.38 |
APC | 7 (87.5%) | 7 (87.5%) | 1 | 1 | 89.51 | 0.01 | 1 |
Gene | TMB-H (n = 9) | TMB-L (n = 16) | Pval | AdjPval | TCGA COAD/READ Hypermutated (n = 10) | TCGA COAD/READ Nonhypermutated (n = 81) | Pval | AdjPval |
---|---|---|---|---|---|---|---|---|
ATM | 67% | 0% | 0.0005 | 0.0090 | 60% | 9% | 0.0004 | 0.0006 |
ALK | 56% | 0% | 0.0024 | 0.0090 | 20% | 2% | 0.0583 | 0.1486 |
NSD1 | 56% | 0% | 0.0024 | 0.0090 | 20% | 2% | 0.0583 | 0.1486 |
UBR5 | 56% | 0% | 0.0024 | 0.0090 | 30% | 0% | 0.0010 | 0.0114 |
TRRAP | 67% | 13% | 0.0099 | 0.0188 | 50% | 2% | 0.0001 | 0.0002 |
BCL9 | 56% | 6% | 0.0119 | 0.0188 | 20% | 1% | 0.0310 | 0.0850 |
CARD11 | 56% | 6% | 0.0119 | 0.0188 | 0% | 9% | 1.0000 | 1.0000 |
KDM5C | 56% | 6% | 0.0119 | 0.0188 | 10% | 1% | 0.2088 | 0.2491 |
MN1 | 56% | 6% | 0.0119 | 0.0188 | 10% | 0% | 0.1099 | 0.1513 |
PIK3CA | 56% | 6% | 0.0119 | 0.0188 | 40% | 20% | 0.2178 | 0.2341 |
PTPRT | 56% | 6% | 0.0119 | 0.0188 | 30% | 6% | 0.0405 | 0.0475 |
APC | 44% | 88% | 0.0581 | 0.0736 | 40% | 85% | 0.0035 | 0.0048 |
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Li, J.; Steffen, P.; Tse, B.C.Y.; Ahadi, M.S.; Gill, A.J.; Engel, A.F.; Molloy, M.P. Deep Sequencing of Early T Stage Colorectal Cancers Reveals Disruption of Homologous Recombination Repair in Microsatellite Stable Tumours with High Mutational Burdens. Cancers 2022, 14, 2933. https://doi.org/10.3390/cancers14122933
Li J, Steffen P, Tse BCY, Ahadi MS, Gill AJ, Engel AF, Molloy MP. Deep Sequencing of Early T Stage Colorectal Cancers Reveals Disruption of Homologous Recombination Repair in Microsatellite Stable Tumours with High Mutational Burdens. Cancers. 2022; 14(12):2933. https://doi.org/10.3390/cancers14122933
Chicago/Turabian StyleLi, Jun, Pascal Steffen, Benita C. Y. Tse, Mahsa S. Ahadi, Anthony J. Gill, Alexander F. Engel, and Mark P. Molloy. 2022. "Deep Sequencing of Early T Stage Colorectal Cancers Reveals Disruption of Homologous Recombination Repair in Microsatellite Stable Tumours with High Mutational Burdens" Cancers 14, no. 12: 2933. https://doi.org/10.3390/cancers14122933