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. 2020 Dec 11;12(12):3726.
doi: 10.3390/cancers12123726.

Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status

Tim Marwitz  1   2 , Robert Hüneburg  1   2 , Isabel Spier  2   3 , Jan-Frederic Lau  2   4 , Glen Kristiansen  2   4 , Philipp Lingohr  2   5 , Jörg C Kalff  2   5 , Stefan Aretz  2   3 , Jacob Nattermann  1   2 , Christian P Strassburg  1   2
Affiliations

Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status

Tim Marwitz et al. Cancers (Basel). .

Abstract

Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic CDH1 or CTNNA1 germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, CDH1 sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic CDH1 variants (PV) in 60 patients (28 families) and one CTNNA1 PV in two patients from one family. Sixty-eight percent (n = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of CDH1/CTNNA1 PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 ± 13 years vs. 44 ± 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% (n = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant.

Keywords: CDH1; CTNNA1; HDGC; gastric cancer; hereditary cancer.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Study population and gastric cancer incidence. (PV= (likely-) pathogenic variant, HDGC = hereditary diffuse gastric cancer, VUS = variant of unknown significance, DGC = diffuse gastric cancer, GC = gastric cancer).
Figure 2
Figure 2
Age at diagnosis of gastric cancer (GC) and lobular breast cancer (LBC) in patients with a CDH1/CTNNA1 pathogenic or likely pathogenic variant (PV) and without PV.
See this image and copyright information in PMC

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