Core Concepts
Pathogenic variants in the CDH1 gene are associated with a new form of hereditary lobular breast cancer (HLBC) that is distinct from the better-known breast-ovarian syndrome linked to BRCA1 and BRCA2 alterations.
Abstract
This study investigated the frequency of germline CDH1 variants in women with lobular breast cancer (LBC) who met the clinical criteria for HLBC. The researchers analyzed a single-center cohort of nearly 5,500 primary lobular breast tumors, of which 34.4% presented the hereditary phenotype.
Key findings:
- Germline testing identified 15 CDH1 variants in 15 unrelated families. No germline variants of BRCA1 and BRCA2 were found in CDH1 variant carriers.
- The overall frequency of CDH1 germline variants was approximately 4%, with 1.5% being pathogenic or likely pathogenic.
- CDH1 variants were associated with an age ≤ 45 years at lobular tumor diagnosis and a positive family history of breast cancer.
- Somatic analysis showed structural alterations of the second CDH1 allele as the main mechanism of HLBC tumorigenesis, suggesting potential for new therapeutic biomarkers.
- The authors emphasize the importance of considering CDH1 testing in young women, those with bilateral lobular cancer, or those with a positive family history of breast cancer, and starting gastroscopy screening programs for these individuals due to the risk of gastric cancer.
Stats
34.4% of 5,500 primary lobular breast tumors presented the hereditary phenotype.
15 germline CDH1 variants were identified in 15 unrelated families.
The overall frequency of CDH1 germline variants was approximately 4%, with 1.5% being pathogenic or likely pathogenic.
CDH1 variants were associated with an age ≤ 45 years at lobular tumor diagnosis and a positive family history of breast cancer.
Quotes
"Pathogenic or likely pathogenic germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer in the so-called hereditary diffuse gastric cancer [HDGC] syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation."
"Forty percent of CDH1 variants were pathogenic or probably pathogenic. Another 40% were represented by variants of unknown significance, which may be reclassified over time, and the rest were benign."