Characterizing Metastatic HER2-Positive Gastric Cancer at the CDH1 Haplotype
Abstract
:1. Introduction
2. Results
2.1. Patient Characteristics
2.2. CDH1 Mutations
2.3. Association between CDH1 P7-Haplotype and mGC-HER2
2.4. Association between the CDH1 P7 Haplotype and the Survival of mGC-HER2 Patients
3. Discussion
4. Materials and Methods
4.1. Study Population
4.2. Genotyping Analysis
4.3. Immunohistochemistry
4.4. Statistical Analysis
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
GC | Gastric cancer |
mGC | Metastatic gastric cancer |
HER2 | Human epidermal growth factor receptor 2 |
E-cad | E-cadherin |
IHC | Immunohistochemical |
EBV | Epstein-barr virus |
EMT | Epithelial-to-mesenchymal transition |
MP | Metalloproteinase |
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CDH1 Region Gene | Reference Polymorphism | cDNA Change | Amino Acid Change | Type of Variant | Genotype | |||
---|---|---|---|---|---|---|---|---|
mGC-HER2 (n) | mGC (n) | |||||||
Promoter | rs5030625 | c.-472delA | Polymorphic variant | G/A (1) | G/A (10) | |||
Promoter | rs16260 | c.-285C>A | Polymorphic variant | A/A (4) | A/C (6) | A/A (3) | A/C (16) | |
Promoter | rs34149581 | c.-276T>C | T/C (1) | |||||
5′UTR | rs34033771 | c.-71C>G | C/G (1) | |||||
IV1 | rs3743674 | c.48+6C>T | Polymorphic variant | C/C (1) | T/C (9) | C/C (1) | ||
EXON3 | rs1801023 | c.345G>A | p.Thr115= | Synonymous variant | G/A (1) | |||
IV4 | rs33963999 | c.531+10G>C | G/C (2) | |||||
IV5 | rs189969617 | c.688-14C>T | C/T (1) | |||||
EXON7 | rs142822590 | c.892G>A | p.Ala298Thr | Missense variant | G/A (1) | |||
EXON11 | SCV000588228.1 | c.1612delG | p.Asp538Thrfs*19 | Frameshift mutation | delG (1) | |||
EXON12 | rs35187787 | c.1774G>A | p.Ala592Thr | Missense variant | G/A (1) | |||
EXON12 | rs33969373 | c.1896C>T | p.HIS632= | Synonymous variant | C/T (2) | |||
IV12 | rs2276330 | c.1937-13T>C | Polymorphic variant | C/T (2) | C/T (10) | |||
EXON13 | rs1801552 | c.2076T>C | p.Ala692= | Polymorphic synonymous variant | C/T (5) | T/T (3) | C/T (24) | T/T (5) |
IV13 | rs35686369 | c.2164+15_2164+16insA | insA (1) | insA (2) | ||||
EXON14 | rs879026401 | c.2232A>G | p.Pro744= | Synonymous variant | A/G (1) | |||
EXON14 | rs33964119 | c.2253C>T | p.Asn751= | Synonymous variant | C/T (1) | C/T (2) | ||
EXON15 | rs587782549 | c.2204G>A | p.Arg796Gln | Missense variant | G/A (1) |
Reference Polymorphism | Allele/Genotype | mGC-HER2 | Frequency | mGC | Frequency | p | OR (95% CI) |
---|---|---|---|---|---|---|---|
rs5030625 | |||||||
Allele | G | 23 | 0.96 | 84 | 0.89 | 0.33 | 2.738 (0.33–22.51) |
A | 1 | 0.04 | 10 | 0.11 | |||
Genotype | G/G | 11 | 0.92 | 37 | 0.79 | ||
G/A | 1 | 0.08 | 10 | 0.21 | |||
A/A | 0 | 0.00 | 0 | 0.00 | |||
Dominant model | GG/AA+AG | 11/1 | 0.92/0.08 | 37/10 | 0.79/0.21 | 0.30 | 2.973 (0.34–25.86) |
Recessive model | AA/AG+GG | 0/12 | 0.00/1.00 | 0/47 | 0.00/1.00 | nv | |
rs16260 | |||||||
Allele | A | 14 | 0.58 | 22 | 0.23 | ≤0.001 | 4.582 (1.79–11.75) |
C | 10 | 0.42 | 72 | 0.77 | |||
Genotype | A/A | 4 | 0.33 | 3 | 0.06 | ||
A/C | 6 | 0.50 | 16 | 0.34 | |||
C/C | 2 | 0.17 | 28 | 0.60 | |||
Recessive model | CC/AA+AC | 2/10 | 0.17/0.83 | 28/19 | 0.60/0.40 | ≤0.01 | 7.368 (1.45–37.46) |
Dominant model | AA/AC+CC | 4/8 | 0.33/0.67 | 3/44 | 0.06/0.94 | 0.01 | 7.333 (1.37–39.18) |
rs3743674 | |||||||
Allele | T | 22 | 0.92 | 83 | 0.88 | 0.64 | 1.457 (0.30–7.07) |
C | 2 | 0.08 | 11 | 0.12 | |||
Genotype | T/T | 11 | 0.92 | 37 | 0.79 | ||
T/C | 0 | 0.00 | 9 | 0.19 | |||
C/C | 1 | 0.08 | 1 | 0.02 | |||
Recessive model | CC/CT+TT | 1/11 | 0.08/0.92 | 1/46 | 0.02/0.98 | 0.29 | 4.182 (0.24–72.21) |
Dominant model | TT/CC+CT | 11/1 | 0.92/0.08 | 37/10 | 0.79/0.21 | 0.30 | 2.973 (0.34–25.86) |
rs2276330 | |||||||
Allele | T | 22 | 0.92 | 84 | 0.90 | 0.74 | 1.309 (0.27–6.42) |
C | 2 | 0.08 | 10 | 0.11 | |||
Genotype | T/T | 10 | 0.83 | 37 | 0.79 | ||
T/C | 2 | 0.17 | 10 | 0.21 | |||
C/C | 0 | 0.00 | 0 | 0.00 | |||
Dominant model | TT/CT+CC | 10/2 | 0.83/0.17 | 37/10 | 0.79/0.21 | 0.72 | 1.351 (0.25–7.19) |
Recessive model | CC/TT+CT | 0/12 | 0.00/1.00 | 0/47 | 0.00/1.00 | nv | |
rs1801552 | |||||||
Allele | C | 13 | 0.54 | 60 | 0.64 | 0.39 | 0.670 (0.27–1.66) |
T | 11 | 0.46 | 34 | 0.36 | |||
C/C | 4 | 0.33 | 18 | 0.38 | |||
Genotype | T/C | 5 | 0.42 | 24 | 0.51 | ||
T/T | 3 | 0.25 | 5 | 0.11 | |||
Recessive model | TT/CC+CT | 3/9 | 0.25/0.75 | 5/42 | 0.11/0.89 | 0.19 | 2.800 (0.56–13.90) |
Dominant model | CC/CT+TT | 4/8 | 0.33/0.67 | 18/29 | 0.38/0.62 | 0.75 | 1.241 (0.33–4.72) |
rs33964119 | |||||||
C | 23 | 0.96 | 92 | 0.98 | 0.58 | 0.500 (0.04–5.76) | |
Allele | T | 1 | 0.04 | 2 | 0.02 | ||
C/C | 11 | 0.92 | 45 | 0.96 | |||
Genotype | T/C | 1 | 0.08 | 2 | 0.04 | ||
T/T | 0 | 0.00 | 0 | 0.00 | |||
Recessive model | CC/CT+TT | 11/1 | 0.92/0.08 | 45/2 | 0.96/0.04 | 0.57 | 2.045 (0.17–24.66) |
Dominant model | TT/CC+CT | 0/12 | 0.00/1.00 | 0/47 | 0.00/1.00 | nv |
Haplotype | mGC (N 94) | Frequency | mGC-HER2 (N 24) | Frequency | p | OR (95% CI) | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
rs5030625 | rs16260 | rs3743674 | rs2276330 | rs1801552 | rs33964119 | |||||||
P1 | G | C | T | T | C | C | 19 | 0.20 | 2 | 0.08 | 0.24 | 0.359 (0.08–1.67) |
P2 | G | A | T | T | C | C | 22 | 0.23 | 6 | 0.25 | 1.00 | 1.091 (0.39–3.09) |
P3 | G | C | T | T | T | C | 31 | 0.33 | 4 | 0.17 | 0.14 | 0.406 (0.13–1.29) |
P4 | G | C | T | C | C | C | 9 | 0.09 | 2 | 0.08 | 1.00 | 0.859 (0.17–4.26) |
P5 | A | C | C | T | C | C | 7 | 0.07 | 1 | 0.04 | 0.69 | 0.540 (0.06–4.61) |
P6 | A | C | C | C | C | C | 1 | 0.01 | 0 | 0.00 | 1.00 | |
P7 | G | A | T | T | T | C | 0 | 0.00 | 7 | 0.29 | ≤0.001 | |
P8 | G | C | C | T | T | C | 1 | 0.01 | 0 | 0.00 | 1.00 | |
P9 | A | C | C | T | T | C | 2 | 0.02 | 0 | 0.00 | 1.00 | |
P10 | G | C | T | T | C | T | 2 | 0.02 | 1 | 0.04 | 0.50 | 2.00 (0.17–23.03) |
P11 | G | A | C | T | C | C | 0 | 0.00 | 1 | 0.04 | 0.20 |
Patient Identifier | Haplotype | CDH1 Germline Mutation | |||
---|---|---|---|---|---|
EXON11 c.1612delG | EXON12 c.1774G>A | IV13 c.2164+15_2164+16insA | EXON14 c.2253C>T | ||
P287 | P5–P11 | ||||
P291 | P2–P7 | ||||
P292 | P4–P7 | ||||
P296 | P2–P7 | ||||
P297 | P3–P7 | ||||
P301 | P2–P3 | ||||
P303 | P2–P4 | ||||
P380 | P1–P2 | ||||
P391 | P2–P7 | ||||
P486 | P7–P7 | ||||
P582 | P3–P3 | ||||
P586 | P1–P10 |
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Caggiari, L.; Miolo, G.; Buonadonna, A.; Basile, D.; Santeufemia, D.A.; Cossu, A.; Palmieri, G.; De Zorzi, M.; Fornasarig, M.; Alessandrini, L.; et al. Characterizing Metastatic HER2-Positive Gastric Cancer at the CDH1 Haplotype. Int. J. Mol. Sci. 2018, 19, 47. https://doi.org/10.3390/ijms19010047
Caggiari L, Miolo G, Buonadonna A, Basile D, Santeufemia DA, Cossu A, Palmieri G, De Zorzi M, Fornasarig M, Alessandrini L, et al. Characterizing Metastatic HER2-Positive Gastric Cancer at the CDH1 Haplotype. International Journal of Molecular Sciences. 2018; 19(1):47. https://doi.org/10.3390/ijms19010047
Chicago/Turabian StyleCaggiari, Laura, Gianmaria Miolo, Angela Buonadonna, Debora Basile, Davide A. Santeufemia, Antonio Cossu, Giuseppe Palmieri, Mariangela De Zorzi, Mara Fornasarig, Lara Alessandrini, and et al. 2018. "Characterizing Metastatic HER2-Positive Gastric Cancer at the CDH1 Haplotype" International Journal of Molecular Sciences 19, no. 1: 47. https://doi.org/10.3390/ijms19010047