In a study reported in The Lancet Oncology, Garcia-Pelaez and colleagues found that presence of germline truncating pathogenic variants or likely pathogenic variants of CDH1 were associated with hereditary diffuse gastric cancer (HDGC) tumor risk syndrome–related cancer phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), with no apparent association of these phenotypes with CDH1 missense variants of unknown significance (VUS). Expansion of criteria for the lobular breast cancer phenotype was proposed to account for cases associated with CDH1 PV/LPVs that did not meet the 2020 clinical criteria for HDGC.
Study Details
The genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1,021 relatives, irrespective of HDGC clinical criteria, from institutions in 10 member-countries of the European Reference Network on Genetic Tumour Risk Syndromes. Families were categorized according to whether they fulfilled the 2015 and 2020 HDGC clinical criteria.
Key Findings
From a total of 1,971 phenotypes among 854 probands and 1,021 relatives, 460 had gastric and breast cancer histology available. CDH1 truncating pathogenic variants or likely pathogenic variants occurred in 176 (21%) of 854 families and missense variants of unknown significance occurred in 169 (20%) families.
CDH1 pathogenic variants or likely pathogenic variants were present in 224 (89%) vs CDH1 missense variants of unknown significance in 28 (11%) of 252 individuals with diffuse gastric cancer, 125 (89%) vs 16 (11%) of 141 with gastric cancer, and 62 (93%) vs 5 (7%) of 67 with lobular breast cancer. On multivariate analysis, lobular breast cancer had the greatest positive association with the presence of pathogenic variants or likely pathogenic variants (odds ratio [OR] = 12.39, 95% confidence interval [CI] = 2.66–57.74, P = .0014), followed by diffuse gastric cancer (OR = 8.00, 95% CI = 2.18–29.39, P = .0017), and gastric cancer (OR = 7.81, 95% CI = 2.03–29.96, P = .0027).
Overall, 136 (77%) of 176 families carrying pathogenic variants or likely pathogenic variants fulfilled the 2015 HDGC clinical criteria. Of the remaining 40 families (23%), 11 fulfilled the 2020 HDGC criteria and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer but did not meet the 2020 criteria. No specific CDH1 pathogenic variant or likely pathogenic variant was found to be associated specifically with lobular breast cancer; however, lobular breast cancer only was found in 12 (7%) of 176 pathogenic variant or likely pathogenic variant carrier families.
Analysis to address the finding that CDH1 pathogenic variants or likely pathogenic variants often occurred in families with lobular breast cancer who did not meet the 2020 HDGC criteria indicated that three new lobular breast cancer–centered criteria should be added to the 2020 HDGC criteria. The three criteria were: at least two cases of breast cancer, one case of confirmed lobular breast cancer; history of gastric cancer and breast cancer, one confirmed lobular breast cancer regardless of age; and isolated lobular breast cancer in individuals aged < 55 years. The addition of these criteria to the 2020 HDGC criteria improved the receiver operating characteristic area under the curve from 0.88 to 0.92 (P = .0004).
The investigators concluded: “CDH1 [pathogenic variants or likely pathogenic variants] were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 [pathogenic variants or likely pathogenic variants] occurred often in families with lobular breast cancer who did not fulfill the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria.”
Carla Oliveira, PhD, of Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was supported by the European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), and others. For full disclosures of the study authors, visit thelancet.com.
