Spectrum and Frequency of Tumors, Cancer Risk and Survival in Chilean Families with Lynch Syndrome: Experience of the Implementation of a Registry
Abstract
:1. Introduction
2. Methods
2.1. Hereditary Colorectal Cancer Registry from Clinica Las Condes
2.2. Genetic Analysis
2.3. MMR Variant Nomenclature and Classification
2.4. Study Population
2.5. Statistical Analysis
3. Results
3.1. Genetic Characterization of LS Families
3.2. Clinicopathologic Features of LS Families
3.3. Spectrum and Frequency of Tumors by Gene, Gender and Age
3.4. Characterization of Path_MMR Carriers
3.5. Path_ MMR Carriers: Tumor Spectrum, Cumulative Incidence and Survival Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AMS | Amsterdam |
CRC | colorectal cancer |
HGMD | Human Gene Mutation Database |
HGVS | Human Genome Variation Society |
InSIGHT | International Society of Gastrointestinal Hereditary Tumors |
LS | Lynch syndrome |
LOVD | Leiden Open Variation Database |
MLPA | Multiplex ligation dependent-probes amplification |
MMR | mismatch-repair gene |
MSI | microsatellite instability |
NGS | Next generation sequencing |
Path_MMR | Pathogenic (disease-causing) variant of an MMR gene. |
path_MLH1 | Pathogenic (disease-causing) variant of the MLH1 gene |
path_MSH2 | Pathogenic (disease-causing) variant of the MSH2 gene |
path_MSH6 | Pathogenic (disease-causing) variant of the MSH6 gene |
path_PMS2 | Pathogenic (disease-causing) variant of the PMS2 gene |
path_EPCAM | Pathogenic (disease-causing) variant of the EPCAM gene |
UMD | Universal Mutation Database |
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Family | Criteria # | Gene | Nucleotide Change ## | Protein Change |
---|---|---|---|---|
HNPCC056 | Ams | MLH1 | Deletion exon 1 b | p.0? |
HNPCC008 | Ams | MLH1 | Deletion exon 1 b | p.0? |
HNPCC006 | Ams | MLH1 | c.503dupA a | p.N168Kfs*4 |
HNPCC002 | Ams | MLH1 | c.677 + 5G > A b | p.Q197Rfs*8/p.E53Ffs*8 |
HNPCC029 | Ams | MLH1 | c.790 + 1G > A a | p.E227_S295del |
HNPCC043 | Ams | MLH1 | c.794G > C c | p.R265P |
HNPCC009 | Ams | MLH1 | c.901C > T a | p.Q301* |
HNPCC080 | Ams | MLH1 | c.997_1000delAAGC c | p.K333Sfs*33 |
HNPCC037 | Ams | MLH1 | c.1038 + 1G > T b | p.T347Ffs*14 |
HNPCC062 | Ams | MLH1 | c.1559 − 2A > C c | p.L521Kfs*34 |
HNPCC018 | Ams | MLH1 | Deletion exons 14 and 15 b | p.V520Gfs*7 |
HNPCC001 | Ams | MLH1 | c.1731 + 3A > T a | p.S556Rfs*14 |
HNPCC073 | Ams | MLH1 | c.2041G > A a | p.A681T |
HNPCC082 | Ams | MLH1 | c.2041G > A a | p.A681T |
HNPCC086 | Beth | MLH1 | c.2041G > A a | p.A681T |
HNPCC011 | Beth | MLH1 | c.2041G > A a | p.A681T |
HNPCC057 | Ams | MLH1 | c.2041G > A a | p.A681T |
HNPCC019 | Beth | MLH1 | c.2092_2093delTC a | p.S698Rfs*5 |
HNPCC004 | Ams | MLH1 | Deletion exon 19 b | p.S702_X757del |
HNPCC010 | Ams | MLH1 | Deletion exon 19 b | p.S702_X757del |
HNPCC047 | Ams | MSH2 | Deletion exon 2 b | p.A72Ffs*9 |
HNPCC100 | Ams | MSH2 | c.388_389delCA c | p.Q130Vfs*2 |
HNPCC118 | Ams | MSH2 | c.942 + 3A > T c | p.V265_Q314del |
HNPCC027 | Ams | MSH2 | c.1215C > A a | p.Y405* |
HNPCC111 | Beth | MSH2 | c.1861C > T c | p.R621* |
HNPCC031 | Ams | MSH2 | c.2038C > T a | p.R680* |
HNPCC075 | Ams | MSH2 | c.2131C > T c | p.R711* |
HNPCC012 | Ams | MSH2 | c.2185_2192del7insCCCT a | p.M729_E731delinsP729_*730 |
HNPCC088 | Ams | EPCAM-MSH2 | Deletion EPCAM and exons 1–6 MSH2 c | p.? |
HNPCC094 | Ams | EPCAM | Deletion exons 6–9 c | p.? |
HNPCC106 | US | PMS2 | c.903G > T d | p.K301N (Skips exon 8) |
HNPCC084 | Beth | PMS2 | c.2016delG c | p.M672Ifs*15 |
HNPCC093 | Ams | PMS2 | Deletion exon 14 c | p.A759Gfs*8 |
HNPCC116 | US | PMS2 | Deletion exon 14 c | p.A759Gfs*8 |
Clinical Information | Group 1 | Group 2 |
---|---|---|
Gender: n (%) | ||
Female | 109 (51) | 37 (59) |
Male | 104 (49) | 27 (42) |
Total | 213 | 64 |
Neoplasms: n (%) | ||
CRC | 170/140 subjects | 88/61 subjects |
Extracolonic cancer | 138/109 subjects | 35/23 subjects |
Total | 308 | 123 |
Neoplasm by gender **: n (%) | ||
Female | 173 | 73 |
CRC | 72 (41.6) | 43 (58.9) |
Extracolonic cancer | 101 (58.4) | 30 (41.1) |
Male | 135 | 50 |
CRC | 98 (72.6) | 45 (90) |
Extracolonic cancer | 37 (27.4) | 5 (10) |
Age (years) at diagnosis: mean and range | ||
Any first cancer | 45.1 (1–89) | 40.8 (18–84) |
Female | 45.9 (1–89) | 39.5 (18–84) |
Male | 44.2 (10–84) | 42.5 (27–65) |
First CRC | 43.4 (18–89) | 41.2 (18–65) |
Female | 43.1 (18–89) | 39.6 (18–63) |
Male | 42.5 (21–73) | 43.2 (27–65) |
First extracolonic cancer | 51.0 (1–88) | 43.3 (26–84) |
Female | 50.8 (1–88) | 48.1 (26–84) |
Male | 51.5 (10–84) | 55.0 (40–66) |
Group 1 | Group 2 | |||||||
---|---|---|---|---|---|---|---|---|
Neoplasm | path_MLH1 n = 195 | path_MSH2 n = 99 | path_PMS2 n = 14 | Total n = 308 | path_MLH1 n = 77 | path_MSH2 n = 41 | path_PMS2 n = 5 | Total n = 123 |
Colorectal: n (%) | 116 (59.5) | 47 (47.5) | 7 (50) | 170 | 57 (74) | 27 (66) | 4 (80) | 88 |
Extracolonic: n (%) | 79 (40.5) | 52 (52.5) | 7 (50) | 138 | 20 (26) | 14 (34) | 1 (20) | 35 |
Gynecological cancer | ||||||||
Uterus | 21 (10.8) | 11 (11.1) | 1 (7.1) | 33 | 4 (5.2) | 2 (4.9) | 0 | 6 |
Ovary | 2 (1.0) | 5 (5.1) | 1 (7.1) | 8 | 1 (1.3) | 4 (9.8) | 0 | 5 |
Upper gastrointestinal cancer | ||||||||
Stomach | 10 (5.1) | 7 (7.1) | 0 | 17 | 1 (1.3) | 0 | 0 | 1 |
Pancreas | 6 (3.0) | 1 (1.0) | 1 (7.1) | 8 | 2 (2.6) | 0 | 0 | 2 |
Liver | 3 (1.5) | 0 | 0 | 3 | 0 | 0 | 0 | 0 |
Gallbladder | 1 (0.5) | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
Small Intestine | 0 | 1 (1.0) | 0 | 1 | 0 | 1 (2.4) | 0 | 1 |
Genitourinary tract cancer | ||||||||
Kidney | 2 (1.0) | 6 (6.1) | 1 (7.1) | 9 | 1 (1.3) | 1 (2.4)) | 0 | 2 |
Bladder | 0 | 1(1.0) | 0 | 1 | 0 | 1(2.4) | 0 | 1 |
Ureter | 3(1.5) | 0 | 0 | 3 | 0 | 0 | 0 | 0 |
Other cancers | ||||||||
Breast | 12 (6.2) | 7 (7.1) | 1 (7.1) | 20 | 4 (5.2) | 2 (4.9) | 0 | 6 |
Skin | 7 (3.6) | 6 (6.1) | 0 | 13 | 5 (6.5) | 3 (7.3) | 0 | 8 |
Brain | 2 (1.0) | 3 (3.0) | 0 | 5 | 0 | 0 | 0 | 0 |
Lung | 2 (1.0) | 2 (2.0) | 0 | 4 | 1 (1.3) | 0 | 0 | 1 |
Prostate | 5 (2.6) | 0 | 0 | 5 | 0 | 0 | 0 | 0 |
Soft tissue | 1 (0.5) | 0 | 0 | 1 | 1(1.3) | 0 | 0 | 1 |
Bone | 1 (0.5) | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
Leukemia | 1 (0.5) | 0 | 1 (7.1) | 2 | 0 | 0 | 0 | 0 |
Head and Neck | 0 | 1 (1.0) | 0 | 1 | 0 | 0 | 0 | 0 |
Thyroid | 0 | 1 (1.0) | 0 | 1 | 0 | 0 | 0 | 0 |
Cervix | 0 | 0 | 1 (7.1) | 1 | 0 | 0 | 1 (20) | 1 |
Cancer Type | Age, Year | All % | CI95 | Gender | path_MLH1 | path_MSH2 | path_PMS2 ** | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Female | CI95 | Male | CI95 | Female | CI95 | Male | CI95 | Female | CI95 | Male | CI95 | Both | CI95 | ||||
Colorectal (n = 61) | 50 | 59.5 | 46.4–69.4 | 59.5 | 49.1–72.2 | 60.1 | 38.9–74.0 | 63.5 | 39.1–78.2 | 67.9 | 39.7–83.0 | 53.5 | 9.8–76.0 | 68.0 | 9.2–88.7 | 20.5 | 0–42.3 |
60 | 75.7 | 62.3–84.4 | 76.5 | 56.2–87.4 | 74.6 | 52.9–86.3 | 80.5 | 52.1–92.0 | 78.6 | 50.1–90.8 | 82.6 | 10.4–96.6 | 84.0 | 9.3–97.2 | 36.4 | 0–63.1 | |
70 | 88.2 | 73.7–94.7 | 89.5 | 66.6–96.7 | 86.5 | 59.3–95.5 | 87.0 | 56.7–96.1 | 89.3 | 45.7–97.9 | 100.0 | - | 100.0 | - | 68.2 | 0–92.8 | |
Extracolonic (n = 22) | 50 | 18.5 | 8.6–27.3 | 31.3 | 14.4–44.9 | 2.7 | 0–7.8 | 23.2 | 4.6–38.1 | 0 | - | 64.1 | 12.8–85.2 | 10.0 | 0–26.8 | 0.0 | - |
60 | 28.0 | 14.8–39.2 | 39.6 | 19.7–54.5 | 13.5 | 0–27.2 | 36.6 | 10.2–55.2 | 15.4 | 0–32.9 | 64.1 | 12.8–85.2 | 10.0 | 0–26.8 | 0.0 | - | |
70 | 50.0 | 27.9–65.4 | 71.7 | 35.0–87.7 | 24.3 | 0–44.7 | 60.4 | 15.7–81.4 | 15.4 | 0–32.9 | 100 | - | 55.0 | 0–88.9 | 33.3 | 0–70.0 | |
Gynecological (n = 10) | 50 | 22.1 | 7.1–34.7 | 22.1 | 7.1–34.7 | - | - | 12.1 | 0–24.2 | - | - | 60.0 | 5.7–83.0 | - | - | 0.0 | - |
60 | 30.0 | 11.8–44.4 | 30.0 | 11.8–44.4 | - | - | 24.2 | 2.1–41.2 | - | - | 60.0 | 5.7–83.0 | - | - | 0.0 | - | |
70 | 30.0 | 11.8–44.4 | 30.0 | 11.8–44.4 | - | - | 24.2 | 2.1–41.2 | - | - | 60.0 | 5.7–83.0 | - | - | 0.0 | - | |
Skin (n = 5) | 50 | 2.4 | 0–5.6 | 2.1 | 0–6.0 | 2.7 | 0–7.8 | 0.0 | - | 0.0 | - | 7.7 | 0–21.1 | 10.0 | 0–26.8 | 0.0 | - |
60 | 5.0 | 0–10.7 | 2.1 | 0–6.0 | 8.1 | 0–18.8 | 0.0 | - | 7.7 | 0–21.1 | 7.7 | 0–21.1 | 10.0 | 0–26.8 | 0.0 | - | |
70 | 14.5 | 0–27.0 | 11.0 | 0–26.5 | 18.3 | 0–37.2 | 12.5 | 0–32.7 | 7.7 | 0–21.1 | 7.7 | 0–21.1 | 55.0 | 0–88.9 | 0.0 | - | |
Upper gastrointestinal tract (n = 3) | 50 | 1.7 | 0–5.0 | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
60 | 4.3 | 0–10.1 | - | - | - | - | - | - | - | - | - | - | - | - | - | - | |
70 | 4.3 | 0–10.1 | - | - | - | - | - | - | - | - | - | - | - | - | - | - | |
Breast (n = 3) | 50 | 5.2 | 0–12.1 | 5.2 | 0–12.1 | - | - | 3.4 | 0–9.9 | - | - | 12.5 | 0–32.7 | - | - | 0.0 | - |
60 | 9.0 | 0–18.5 | 9.0 | 0–18.5 | - | - | 9.5 | 0–21.6 | - | - | 12.5 | 0–32.7 | - | - | 0.0 | - | |
70 | 9.0 | 0–18.5 | 9.0 | 0–18.5 | - | - | 9.5 | 0–21.6 | - | 12.5 | 0–32.7 | - | - | 0.0 | - |
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Álvarez, K.; Orellana, P.; De la Fuente, M.; Canales, T.; Pinto, E.; Heine, C.; Solar, B.; Hurtado, C.; Møller, P.; Kronberg, U.; et al. Spectrum and Frequency of Tumors, Cancer Risk and Survival in Chilean Families with Lynch Syndrome: Experience of the Implementation of a Registry. J. Clin. Med. 2020, 9, 1861. https://doi.org/10.3390/jcm9061861
Álvarez K, Orellana P, De la Fuente M, Canales T, Pinto E, Heine C, Solar B, Hurtado C, Møller P, Kronberg U, et al. Spectrum and Frequency of Tumors, Cancer Risk and Survival in Chilean Families with Lynch Syndrome: Experience of the Implementation of a Registry. Journal of Clinical Medicine. 2020; 9(6):1861. https://doi.org/10.3390/jcm9061861
Chicago/Turabian StyleÁlvarez, Karin, Paulina Orellana, Marjorie De la Fuente, Tamara Canales, Eliana Pinto, Claudio Heine, Benjamín Solar, Claudia Hurtado, Pål Møller, Udo Kronberg, and et al. 2020. "Spectrum and Frequency of Tumors, Cancer Risk and Survival in Chilean Families with Lynch Syndrome: Experience of the Implementation of a Registry" Journal of Clinical Medicine 9, no. 6: 1861. https://doi.org/10.3390/jcm9061861