Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Characteristics of Patient Cohort and Genetic Testing
2.2. HDGC Criteria
2.3. Helicobacter pylori (HP) Infection
2.4. Patients with CDH1 or CTNNA1 PV
2.4.1. Gastric Cancer
2.4.2. Breast Cancer
2.5. Patients without a Proven CDH1 or CTNNA1 PV
2.5.1. Gastric Cancer
2.5.2. Breast Cancer
2.6. Comparison of PV Carriers with Patients without a PV
2.7. Patients with a CDH1 VUS
3. Discussion
4. Materials and Methods
4.1. Study Population
4.2. Genetic Testing
4.3. Data Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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HDGC Testing Criteria from 2015 [6] | HDGC Testing Criteria from 2020 [7] |
---|---|
Established testing criteria | Family criteria |
|
|
Extended criteria (testing could be considered) | Individual criteria |
|
|
Baseline and Clinical Characteristics | CDH1/CTNNA1 PV | CDH1 VUS | No PV |
---|---|---|---|
Number of patients | 62 | 5 | 140 |
Gender | 22/62 (35%) male 40/62 (65%) female | 3/5 (60%) male 2/5 (40%) female | 41/140 (29%) male 99/140 (71%) female |
Number of families | 29 | 3 | 129 |
Age at study inclusion (range) | 42 ± 14 years (16–70) | 49 ± 8 years (39–62) | 49 ± 15 years (18–87) |
GC prevalence | 38/62 (61%) | 2/5 (40%) | 102/140 (73%) |
Age at GC diagnosis (range) | 40 ± 13 years (16–72) | 41 ± 6 years (37–45) | 44 ± 12 years (17–74) |
LBC prevalence in women | 8/40 (20%) | 0 | 10/99 (10%) |
Age at LBC diagnosis (range) | 51 ± 8 years (38–65) | – | 52 ± 7 years (45–65) |
Number of gastrectomies (PTG *) | 40 32 * | 1 0 * | 27 0 * |
Yield of GC in gastrectomies (PTG *) | 31/40 (78%) 23/32 (72%) * | 1/1 (100%) | 27/27 (100%) |
Cancer staging in gastrectomy <pT2 ≥pT2 | 23/31 (74%) 8/31 (26%) | 0/1 (0%) 1/1 (100%) | 5/27 (19%) 22/27 (81%) |
Patients with multifocal GC in gastrectomy | 11/31 (35%) | 0/1 (0%) | 0/27 (0%) |
2015 HDGC Criteria | Index Patients | Index Patients with CDH1/CTNNA1 PV | Detection Rate |
---|---|---|---|
Criterion 1 (Two cases of gastric cancer regardless of age with at least one confirmed DGC) | 97 | 20 | 21% |
Criterion 2 (One case of DGC before age 40) | 87 | 13 | 15% |
Criterion 3 (Personal or family history of DGC and LBC with one diagnosed before age 50) | 40 | 11 | 28% |
Patients fulfilling more than one criterion | 66 | 15 | 23% |
Total (index patients) | 161 | 29 | 18% |
Total (all patients) | 207 | 62 | 30% |
Variant | Reported Variant Classification | Classification with CDH1-Specific Criteria [33] | Type of Variant | Number of Family Members Included | Reported GC in Family Pedigree | Reported BC in Family Pedigree | Mean Age at Diagnosis of Manifest Cancer * |
---|---|---|---|---|---|---|---|
(Likely) pathogenic variants | |||||||
c.3G>A;p.? | pathogenic | pathogenic | start lost | 6 | 2 | 0 | 47 (46–47) |
c.48+1G>A;p.? | pathogenic | pathogenic | splice | 3 | 4 | 0 | 52 (33–75) |
c.86dupA;p.(His296Glnfs*5) | pathogenic | likely pathogenic | frameshift | 1 | 2 | 1 | 29 (26–35) |
c.521delA;p.(Asn174Thrfs*41) mosaicism | pathogenic | likely pathogenic | frameshift | 1 | 1 | 1 | 41 (41) |
c.1108G>A;p.(Asp370Asn) | likely pathogenic | VUS | missense | 5 | 4 | 0 | 48 (41–61) |
c.1137G>A;p.? | pathogenic | pathogenic | splice [34] | 1 | 4 | 0 | 47 (44–50) |
c.1416dupC;p.(Val473Argfs*10) | pathogenic | likely pathogenic | frameshift | 1 | 1 | 0 | 48 (48) |
c.1565+1G>A;p.? | pathogenic | pathogenic | splice | 1 | 0 | 2 | 49 (38–60) |
c.1565+1G>A;p.? | pathogenic | pathogenic | splice | 2 | 4 | 0 | 47 (32–64) |
c.1565+1G>A;p.? | pathogenic | pathogenic | splice | 1 | 0 | 5 | 65 (65) |
c.1565+2dupT;p.? | likely pathogenic | pathogenic | splice | 3 | 1 | 0 | 34 (34) |
c.1565+2dupT;p.? | likely pathogenic | pathogenic | splice | 1 | 2 | 0 | 50 (50) |
c.1651G>T;p.(Glu551*) | pathogenic | likely pathogenic | nonsense | 3 | 3 | 1 | 55 (40–76) |
c.1679C>G;r.1680_1711del;p.(Tyr561Phefs*16) | pathogenic | pathogenic | splice [35] | 1 | 2 | 1 | 49 (47–50) |
c.1679C>G;r.1680_1711del;p.(Tyr561Phefs*16) | pathogenic | pathogenic | splice [35] | 1 | 3 | 0 | unknown |
c.1746_1747dup;p.(Leu583Argfs*2) | pathogenic | likely pathogenic | frameshift | 3 | 4 | 0 | unknown |
c.1746_1747dup;p.(Leu583Argfs*2) | pathogenic | likely pathogenic | frameshift | 4 | 6 | 1 | unknown |
c.1786G>T;p.(Glu596*) | pathogenic | likely pathogenic | nonsense | 1 | 2 | 0 | 46 (44–47) |
c.1792C>T;p.(Arg598*) | pathogenic | pathogenic | nonsense | 1 | 3 | 0 | 30 (23–37) |
c.1792C>T;p.(Arg598*) | pathogenic | pathogenic | nonsense | 2 | 4 | 1 | 51 (43–63) |
c.1901C>T;r.1900_1936del; p.(Ala634Profs*7) | pathogenic | pathogenic | splice [36] | 2 | 3 | 2 | 16 (16) |
c.2116C>T;p.(Gln706*) | pathogenic | likely pathogenic | nonsense | 4 | 3 | 2 | 53 (52–54) |
c.2165-2A>C;p? | pathogenic | likely pathogenic | splice | 3 | 2 | 0 | 40 (32–48) |
deletion exon 1–2 | pathogenic | pathogenic | large exonic deletion | 1 | 2 | 0 | 39 (33–45) |
deletion exon 1–2 | pathogenic | pathogenic | large exonic deletion | 1 | 4 | 0 | 43 (32–49) |
deletion exon 3–8 | pathogenic | likely pathogenic | large exonic deletion | 1 | 3 | 2 | 49 (38–58) |
deletion exon 1–16 | pathogenic | pathogenic | large exonic deletion | 1 | 2 | 0 | 47 (37–56) |
deletion exon 8–11 | pathogenic | likely pathogenic | large exonic deletion | 5 | 7 | 5 | 56 (48–72) |
CTNNA1: c.1175delA;p.(Asp392Valfs*13) | pathogenic | likely pathogenic | frameshift | 2 | 2 | 0 | 44 (44) |
Variants of uncertain significance (VUS) | |||||||
c.659T>G;p.(Leu220Arg) | VUS | VUS | missense | 2 | 2 | 0 | 47 (45–49) |
c.1466C>T;p.(Pro489Leu) | VUS | VUS | missense | 1 | 1 | 0 | 37 (37) |
c.2629G>A; p.(Gly877Arg) | VUS | VUS | missense | 2 | 2 | 0 | 43 (32–54) |
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Marwitz, T.; Hüneburg, R.; Spier, I.; Lau, J.-F.; Kristiansen, G.; Lingohr, P.; Kalff, J.C.; Aretz, S.; Nattermann, J.; Strassburg, C.P. Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status. Cancers 2020, 12, 3726. https://doi.org/10.3390/cancers12123726
Marwitz T, Hüneburg R, Spier I, Lau J-F, Kristiansen G, Lingohr P, Kalff JC, Aretz S, Nattermann J, Strassburg CP. Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status. Cancers. 2020; 12(12):3726. https://doi.org/10.3390/cancers12123726
Chicago/Turabian StyleMarwitz, Tim, Robert Hüneburg, Isabel Spier, Jan-Frederic Lau, Glen Kristiansen, Philipp Lingohr, Jörg C. Kalff, Stefan Aretz, Jacob Nattermann, and Christian P. Strassburg. 2020. "Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status" Cancers 12, no. 12: 3726. https://doi.org/10.3390/cancers12123726