Pathogenic Germline Mutations of DNA Repair Pathway Components in Early-Onset Sporadic Colorectal Polyp and Cancer Patients
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. 2.3%, 4.0%, and 12.2% of Germline Mutation Rate Found in Normal, Polyp, and CRC Groups
2.2. Mutations in Early-Onset CRC and Polyp Patients Occurred Mainly in DNA Repair Pathway-Related Genes
2.3. Phenotypic Characteristics of Mutation Carriers in the Early-Onset Sporadic CRC Group
3. Discussion
4. Materials and Methods
4.1. Study Subjects and Sample Collection
4.2. Design of the 30 CRC-Susceptibility Gene Panel
4.3. Next-Generation Sequencing and Analysis Pipeline
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Features | Normal (n = 43) | Polyps (n = 50) | CRC (n = 49) | p-Value |
---|---|---|---|---|
Gender (F/M) | 25/17 | 25/25 | 24/25 | 0.635 |
Age (Mean ± SD) | 41.4 ± 6.8 | 42.2 ± 5.9 | 43.4 ± 5.6 | 0.287 |
CEA (Mean ± SD) | 1.04 ± 0.78 | 1.23 ± 1.10 | 11.47 ± 19.46 | <0.005 |
Mutation carrier no (%) | 1(2.3%) | 2 (4%) | 6 (12.2%) | 0.105 |
Involved Pathway | Mutation Gene | Mutation Type | Normal (n = 43) | Polyps (n = 50) | CRC (n = 49) |
---|---|---|---|---|---|
Mismatch Repair | MLH1 | p.Arg265Cys; p.Tyr343Ter (X 2) | 0 | 0 | 3 |
Recombinational Repair | CHEK2 | p.Ile158TyrfsTer10 (X 2) | 0 | 2 | 0 |
BRCA2 | p.Asp885ArgfsTer3 | 1 | 0 | 0 | |
BLM | p.Phe1189LeufsTer10 | 0 | 0 | 1 | |
Base-excision Repair | NTHL1 | p.Ser116ArgfsTer38 | 0 | 0 | 1 |
Combined | MLH1 and BRCA1 | p.Arg265Cys and p.Gln1577Ter | 0 | 0 | 1 |
Total mutation | 1 (2.3%) | 2 (4%) | 6 (12.2%) |
Features | All | Mutation Carriers | Non-Mutation Carrier | p Value |
---|---|---|---|---|
Patient No | 49 | 6 | 43 | |
Age | 43.4 ± 5.7 | 43.7 ± 5.3 | 43.4 ± 5.8 | 0.906 |
Gender | ||||
Female | 24 | 3 (13%) | 21 (87%) | 0.957 |
Male | 25 | 3 (12%) | 22 (88%) | |
Tumor TNM stage | ||||
1 | 8 | 0 (0%) | 8 (100%) | 0.237 |
2 | 10 | 1 (10%) | 9 (90%) | |
3 | 21 | 2 (9.5%) | 19 (90.5%) | |
4 | 10 | 3 (30%) | 7 (70%) | |
Tumor Location | ||||
Right colon | 10 | 3 (30%) | 7 (70%) | 0.055 |
Left colon and rectum | 39 | 3 (7.7%) | 36 (92.3%) | |
Tumor size | ||||
<5 cm | 32 | 2 (6.3%) | 30 (93.7%) | 0.079 |
≥5 cm | 17 | 4 (24%) | 13 (76%) | |
Tumor histology | ||||
Adenocarcinoma | 44 | 4 (9%) | 40 (91%) | 0.001 |
Mucinous | 3 | 0 (0%) | 3 (100%) | |
Signet ring cell | 2 | 2 (100%) | 0 (0%) | |
Tumor grade | ||||
Well | 7 | 0 (0%) | 7 (100%) | 0.334 |
Moderate | 34 | 4 (12%) | 30 (88%) | |
Poor | 8 | 2 (25%) | 6 (75%) | |
Pre_operation CEA | ||||
<5 ng/mL | 31 | 2 (6.5%) | 29 (93.5%) | 0.104 |
≥5 ng/mL | 18 | 4 (22%) | 14 (78%) | |
Recurrence (except TNM 4) | ||||
Yes | 8 | 0 (0%) | 8 (100%) | 0.360 |
No | 31 | 3 (10%) | 28 (90%) |
Author [Reference] (Published Year/Nation) | Number of Patients | Inclusion Criteria | % Inherited CRC | Detection Platform (Gene Contents) | Positive Rate of Pathogenic Mutations in Total Patients | Positive Rate of Pathogenic Mutations in Non-Inherited CRC Group | Mutation Gene in Non-Inherited CRC (Number of Patients) |
---|---|---|---|---|---|---|---|
Pearlman, R. et al. [12] (2017/USA) | 450 | <50 y/o | 11% (37 LS and 11 FAP) | NGS (25-gene panel) | 16% (72 of 450) | 6% (24 of 402) | Monoallelic MUTYH (7), APC c.3920T>A (3), ATM (3), BRCA2 (4), BRCA1 (2), PALB2 (2), CDKN2A (1), SMAD4 (1), ATM/CHEK2 (1), |
Yurgelun, M.B. et al. [13] (2017/USA) | 1058 | Unselected CRC (at all age, only 31.8% diagnosed before 50 y/o) | 3.9% (33 LS and 8 FAP) | NGS (25-gene panel) | 9.9% (105 of 1058) | 6.4% (65 of 1017) | Monoallelic MUTYH (18), APC c.3920T>A (14), BRCA2 (8), ATM (10), BR1P1 (3), BRCA1 (3), PALB2 (2), NBN (2) CHEK2 (2), CDKN1A (1), TP53 (1), BRAD1 (1) |
Stoffel, E.M. et al. [9] (2018/USA) | 430 | <50 y/o | 57.2% (any relatives with CRC) | NGS (154-gene panel) | 18.4% (79 of 430) | 7.2% (13 of 181) | Monoallelic MUTYH (8), SMAD4 (2), BRCA1 (1), TP53 (1), CHECK2 (1) |
Gong, R. et al. [10] (2019/China) | 618 | Unselected CRC (at all age, only 48.7% diagnosed before 50 y/o) | 44.7% (any relatives with CRC) | NGS (73-gene panel) | 18.1% (112 of 618) | 10.2% (35 of 342) | ATM (5), CHEK2(4), BLM (4), TSHR (4), FANCA/CC (4), BARD1 (3), BR1P1 (2), BRCA1/2 (2), monoallelic MUTYH (1), TP53 (1) and other 5 genes |
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Chang, P.-Y.; Chang, S.-C.; Wang, M.-C.; Chen, J.-S.; Tsai, W.-S.; You, J.-F.; Chen, C.-C.; Liu, H.-L.; Chiang, J.-M. Pathogenic Germline Mutations of DNA Repair Pathway Components in Early-Onset Sporadic Colorectal Polyp and Cancer Patients. Cancers 2020, 12, 3560. https://doi.org/10.3390/cancers12123560
Chang P-Y, Chang S-C, Wang M-C, Chen J-S, Tsai W-S, You J-F, Chen C-C, Liu H-L, Chiang J-M. Pathogenic Germline Mutations of DNA Repair Pathway Components in Early-Onset Sporadic Colorectal Polyp and Cancer Patients. Cancers. 2020; 12(12):3560. https://doi.org/10.3390/cancers12123560
Chicago/Turabian StyleChang, Pi-Yueh, Shih-Cheng Chang, Mei-Chia Wang, Jinn-Shiun Chen, Wen-Sy Tsai, Jeng-Fu You, Chia-Chun Chen, Hsiu-Ling Liu, and Jy-Ming Chiang. 2020. "Pathogenic Germline Mutations of DNA Repair Pathway Components in Early-Onset Sporadic Colorectal Polyp and Cancer Patients" Cancers 12, no. 12: 3560. https://doi.org/10.3390/cancers12123560