Diagnostics of Mutations in MMR/EPCAM Genes and Their Role in the Treatment and Care of Patients with Lynch Syndrome
Abstract
:1. Introduction
1.1. LS I-Clinical Presentation
1.2. LS II-Clinical Presentation
2. Function and Mutations in Genes Responsible for DNA Repair and Involved in LS
3. Diagnostics of LS
3.1. Clinical Diagnostics
3.2. Immunohistochemistry and Microsatellite Instability Testing
3.3. Molecular Testing
4. The Care and Treatment of Patients with LS and Their Families
5. Conclusions and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Gene | Localization on Chromosome | Protein | Type of Mutations Leading to LS | Ref. |
---|---|---|---|---|
MSH2 (human mutS homolog 2), 16 exons | 2p21–p16.3 | DNA binding domain, 2 domains interacting with MSH6/MSH3 and MutL homolog | large deletions (whole exons) approx. 30%, secondary epimutation due to the loss of 3′ end of the EPCAM gene | [32,41,42,43,44] |
MLH1 (human mutL homolog 1), 19 exons | 3p22.2 | 3 domains (ATPase, MutS homologs, PMS2/MLH3/PMS1 interaction domain) | mainly missense, nonsense mutations, splicing aberrations and large rearrangements or constitutional epimutation resulting in hypermethylation of MLH1 promoter | [32,34,45,46] |
MSH6 (human mutS homolog 6), 10 exons | 2p16.3 | an ATPase domain, a conservative sequence and adenine-repeats consisting motif | mostly missense or nonsense | [29,47] |
EPCAM (epithelial cell adhesion molecule), 9 exons | 2p21.2 | intracellular domain (EpICD) regulating the expression of other genes responsible for growth, proliferation, migration, and differentiation of cell | deletion of the 3′ end resulting in the loss of termination sequence and production of EPCAM-MSH2 hybrid transcript, and eventually resulting in hypermethylation of MSH2 promoter | [29,41,44,48,49] |
Amsterdam Criteria I: |
At least three relatives with histologically verified colorectal cancer and one of which is a first-degree relative of the other two *, At least two successive generations affected, At least one of the relatives with colorectal cancer diagnosed at < 50 years of age. |
Amsterdam Criteria II: |
At least three relatives with histologically verified HNPCC-associated cancer (colorectal cancer, endometrial, stomach, ovary, ureter/renal pelvis, brain, small bowel, hepatobiliary tract and skin (sebaceous tumors) and one of which is a first-degree relative of the other two *, At least two successive generations affected, At least one of the HNPCC-associated cancers should be diagnosed at < 50 years of age. |
Revised Bethesda Guidelines: |
CRC diagnosed at < 50 years of age, Presence of synchronous or metachronous CRC or other LS-associated tumors ** regardless of age, Colorectal cancer with MSI-H histology diagnosed in a patient < 60 years of age, Colorectal cancer or LS-associated * tumor diagnosed under the age of 50 years in at least one first-degree relative, Colorectal cancer or LS-associated tumor ** diagnosed at any age in two first- or second-degree relatives |
Prediction Model | Analyzed Criteria | Models’ Function | Sensitivity [%] | Specificity [%] |
---|---|---|---|---|
MMRpredict | Sex, age of CRC diagnosis, tumor location, synchronous or metachronous CRCs, EC in first-degree relatives and age of diagnosis | Calculating risk of carrying characteristics for Lynch syndrome mutations | 69 | 90 |
MMRpro | Personal and family history of CRC and EC, age of diagnosis, if available—results of molecular testing for MMR genes | Calculating the risk of carrying germline mutations in any of the MLH1/MSH2/MSH6 genes and risk of developing LS-associated cancer | 89 | 85 |
PREMM 1, 2, 6 | Sex, personal and family history of LS-associated cancers | Calculating the risk of carrying mutations in MLH1/MSH2/MSH6 in the individual with suspected LS | 90 | 67 |
PREMM5 | Sex, age at genetic testing, personal and family cancer history | Calculating the risk of carrying mutations in MLH1/MSH2/MSH6/PMS2/EPCAM in the individual with suspected LS | 89.4 | 49 |
IHC Results | Interpretation |
---|---|
Retained MMR proteins expression | (a) When MSI-H tumor—germline mutation in MMR/EPCAM genes but possibly maintained protein expression (b) when MSI−L/MSS-sporadic cancer |
Heterogeneity of MMR protein expression | If heterogeneity is observed despite proper performance of IHC, it might be reasonable to consider further molecular testing. |
Loss of MSH2 protein expression | Germline MSH2 mutation |
Loss of MSH6 protein expression | Germline MSH6 mutation, rarely MSH2 |
Loss of MSH2 and MSH6 protein expression | Germline MSH2/EPCAM mutation, rarely MSH6 |
Loss of MLH1 and PMS2 protein expression | Sporadic cancer or germline MLH1 mutation—recommendation: further BRAF/MLH1 methylation testing |
Loss of MLH1 protein expression | Germline MLH1 mutation |
Loss of PMS2 protein expression | Germline PMS2 mutation, rarely MLH1 |
Method | The Mechanism/Application | Ref. |
---|---|---|
Single-Strand Conformation Polymorphism (SSCP) |
| [80,81] |
Denaturing Gradient Gel Electrophoresis (DGGE) |
| [80,81] |
Denaturing High-Pressure Liquid Chromatography (DHPLC) |
| [82,83] |
Conformation-sensitive Gel Electrophoresis (CSGE) |
| [84] |
High-Resolution Melting (HRM) |
| [85] |
Method | Advantages, Applications | Disadvantages, Limitations |
---|---|---|
Next-generation sequencing (NGS) | sensitivity and specificity >99% [77], massively parallel sequencing in several genes simultaneously, a relatively short time of analysis, detection of low input of DNA samples [86,88], detection of SNVs and small insertions/deletions [94,95] | advanced bioinformatics systems and large data storage potential [96,97], filtering and data interpretation (various variants can be found when a large number or whole genes are sequenced) [94,97], issues with detecting structural rearrangements or copy number variations (CNVs) [95] |
Multiplex Ligation-dependent Probe Amplification (MLPA) | wide diagnostic applications—copy numbers, point mutations detection, methylation profiling, also detected simultaneously, washing unbounded probes are not necessary, a simple and cost-effective method, easy analysis of the results [91,92] | does not detect balanced mutations, like balanced translocations or inversions (detects only ones which affect the probe binding sequence), probes can be designed only for known mutations—impossible to detect an unknown mutation, the heterozygous deletions analysis is reliable when tumor cells constitute 20–30% of the sample, heterozygous duplication—about 40% [91,92], does not provide precise deletion/insertion characteristics‘ [98] |
High-Resolution Melting (HRM) | simple after proper optimization, fast, high-throughput, software supporting optimization available, relatively simple and not-expensive equipment needed [98,99] | detected variants not characterized, further characterization with another method, e.g., sequencing needed [98,99] |
Sanger sequencing | the gold standard, mainly for detecting point mutations, high quality reads [98] | not cost-effective when a large number of samples and long sequences are analyzed, technically demanding method [98] |
Single-Strand Conformation Polymorphism (SSCP) | detection of point mutations, deletions, and insertions, detection of unknown variants, simple and quite fast method [81] | low sensitivity and repeatability, amplicons not longer than 200–300 bp, detected variants not characterized, further characterization with another method, e.g., sequencing needed [80] |
Conformation-sensitive Gel Electrophoresis (CSGE) | detection of single-nucleotide mutations, small insertions, and deletions, relatively high sensitivity and specificity, cost-effective [84] | detected aberrations need to be sequenced time-consuming method [84] |
Denaturing Gradient Gel Electrophoresis (DGGE) | detection of unknown variants [80], relatively cheap, reliable heteroduplexes detection [98] | technically demanding, results must be characterized by another method, e.g., sequencing [80,98], GC-rich regions can be difficult to optimize and analyze [98,100] |
Denaturing High-Pressure Liquid Chromatography (DHPLC) | sensitivity nearly 100% [82], a wide spectrum of applications: mutations and SNP detection, gene mapping, gene expression and methylation analysis [82,101], does not require modified primers or specific reagents [101], relatively cheap [81] | does not detect copy number aberrations [92], detected variants need to be characterized by sequencing, when more than one melting domain in tested amplicon-analysis of several temperatures required [82], chemical waste generation, not a high-throughput method [85] |
Southern blot | detection of large insertions/deletions [82] | not always small deletions are detected [82] time-consuming [98] |
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Sobocińska, J.; Kolenda, T.; Teresiak, A.; Badziąg-Leśniak, N.; Kopczyńska, M.; Guglas, K.; Przybyła, A.; Filas, V.; Bogajewska-Ryłko, E.; Lamperska, K.; et al. Diagnostics of Mutations in MMR/EPCAM Genes and Their Role in the Treatment and Care of Patients with Lynch Syndrome. Diagnostics 2020, 10, 786. https://doi.org/10.3390/diagnostics10100786
Sobocińska J, Kolenda T, Teresiak A, Badziąg-Leśniak N, Kopczyńska M, Guglas K, Przybyła A, Filas V, Bogajewska-Ryłko E, Lamperska K, et al. Diagnostics of Mutations in MMR/EPCAM Genes and Their Role in the Treatment and Care of Patients with Lynch Syndrome. Diagnostics. 2020; 10(10):786. https://doi.org/10.3390/diagnostics10100786
Chicago/Turabian StyleSobocińska, Joanna, Tomasz Kolenda, Anna Teresiak, Natalia Badziąg-Leśniak, Magda Kopczyńska, Kacper Guglas, Anna Przybyła, Violetta Filas, Elżbieta Bogajewska-Ryłko, Katarzyna Lamperska, and et al. 2020. "Diagnostics of Mutations in MMR/EPCAM Genes and Their Role in the Treatment and Care of Patients with Lynch Syndrome" Diagnostics 10, no. 10: 786. https://doi.org/10.3390/diagnostics10100786