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Published on: February 5, 2018
Quantification of epigenetic and genetic 2nd hits in CDH1 during hereditary diffuse gastric cancer syndrome
Carla Oliveira1, Sónia Sousa, Hugo Pinheiro
1Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Porto, Portugal. carlaol@ipatimup.pt
Background & Aims:
Hereditary diffuse gastric cancer (HDGC) families carry CDH1 heterozygous germline mutations; their tumors acquire complete CDH1 inactivation through "2nd-hit" mechanisms. Most frequently, this occurs via promoter hypermethylation (epigenetic modification), and less frequently via CDH1 mutations and loss of heterozygosity (LOH). We quantified the different 2nd hits in CDH1 occurring in neoplastic lesions from HDGC patients.
Methods:
Samples were collected from 16 primary tumors and 12 metastases from 17 patients among 15 HDGC families; CDH1 mutations, LOH, and promoter hypermethylation were analyzed. E-cadherin protein expression and localization were determined by immunohistochemistry.
Results:
Somatic CDH1 epigenetic and genetic alterations were detected in lesions from 80% of HDGC families and in 75% of all lesions analyzed (21/28). Of the 28 neoplastic lesions analyzed, promoter hypermethylation was found in 32.1%, LOH in 25%, both alterations in 17.9%, and no alterations in 25%. Half of the CDH1 2nd hits in primary tumors were epigenetic modifications, whereas a significantly greater percentage of 2nd hits in metastases were LOH (58.3%; P = .0274). Different neoplastic lesions from the same patient frequently displayed distinct 2nd-hit mechanisms. Different 2nd-hit mechanisms were also detected in the same tumor sample.
Conclusion:
The 2nd hit in CDH1 frequently occurs via epigenetic changes in HDGC primary tumors and LOH in metastases. Because of the concomitance and heterogeneity of these alterations in neoplastic lesions and the plasticity of hypermethylated promoters during tumor initiation and progression, drugs targeting only epigenetic alterations might not be effective, particularly in patients with metastatic HDGC.
Insights
In hereditary diffuse gastric cancer (HDGC), CDH1 gene inactivation often occurs through epigenetic promoter hypermethylation in primary tumors and loss of heterozygosity (LOH) in metastases. This heterogeneity impacts treatment strategies.
Area of Science:
- Oncology
- Cancer Genetics
- Epigenetics
Background:
- Hereditary diffuse gastric cancer (HDGC) is linked to germline CDH1 mutations.
- Tumorigenesis in HDGC involves a second hit to inactivate the remaining CDH1 allele.
- Common second hits include promoter hypermethylation, CDH1 mutations, and loss of heterozygosity (LOH).
Purpose of the Study:
- To quantify the frequency and types of CDH1 second hits in neoplastic lesions from HDGC patients.
- To investigate differences in CDH1 second hit mechanisms between primary tumors and metastases.
- To understand the heterogeneity of CDH1 alterations within individual patients and tumors.
Main Methods:
- Analysis of CDH1 mutations, LOH, and promoter hypermethylation in 16 primary tumors and 12 metastases from 17 HDGC patients.
- Immunohistochemistry to assess E-cadherin protein expression and localization.
- Comparison of alteration frequencies between primary tumors and metastases.
Main Results:
- CDH1 epigenetic and genetic alterations were found in 80% of HDGC families and 75% of lesions analyzed.
- Promoter hypermethylation was the most common alteration in primary tumors, while LOH predominated in metastases.
- Significant heterogeneity in CDH1 second hit mechanisms was observed within patients and even within single tumor samples.
Conclusions:
- CDH1 inactivation in HDGC primarily involves epigenetic changes in primary tumors and LOH in metastases.
- The heterogeneity and plasticity of these alterations suggest that therapies targeting only epigenetic modifications may be insufficient, especially for metastatic disease.
- Understanding these distinct mechanisms is crucial for developing effective therapeutic strategies for HDGC.
