CDH1 germline mutations and hereditary lobular breast cancer

Background: CDH1 encodes the cell-cell adhesion molecule, E-cadherin, for which loss of expression facilitates the infiltrative and metastatic potential of cancers. Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer (HDGC), and in this setting female carriers have been estimated to have a 39-50% risk of lobular breast cancer (LBC) by age 80 years. Aim: To determine the frequency of CDH1 germline mutations inindividuals with early-onset LBC or those with LBC and a family history of multiple breast cancers but no gastric cancers. Methods: Germline DNA analysis of CDH1 in women with LBC, for whom germline BRCA1 and BRCA2 mutations have been excluded, who have been (1) diagnosed before the age of 45 years or (2) diagnosed at any age and have a family history of breast cancer. Results: Analysis of 194 LBC cases has thus far revealed two novel missense mutations predicted to affect protein function. Functional assays to assess their pathogenicity along with germline analyses of the remaining 200 cases are currently underway. Several unreported silent changes have also been identified and will be measured in a case- control sample to assess whether they are associated with LBC risk. Conclusion: Germline CDH1 mutations may cause a small proportion of familial and early onset LBC.

Download Full-text

89Zr-atezolizumab PET Scan and Lobular Breast Cancer

Case Medical Research ◽

10.31525/ct1-nct04222426 ◽

2020 ◽

Author(s):

Keyword(s):

Breast Cancer ◽

Pet Scan ◽

Lobular Breast Cancer

Download Full-text

Faculty Opinions recommendation of Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718311724.793492279 ◽

2014 ◽

Author(s):

Wade Clapp ◽

Grzegorz Nalepa

Keyword(s):

Breast Cancer ◽

Genetic Susceptibility ◽

Fanconi Anemia ◽

Early Onset ◽

Germline Mutations ◽

Shared Genetic

Download Full-text

Clinical spectrum and pleiotropic nature of CDH1 germline mutations

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105807 ◽

2019 ◽

Vol 56 (4) ◽

pp. 199-208 ◽

Cited By ~ 18

Author(s):

Joana Figueiredo ◽

Soraia Melo ◽

Patrícia Carneiro ◽

Ana Margarida Moreira ◽

Maria Sofia Fernandes ◽

...

Keyword(s):

Breast Cancer ◽

Gastric Cancer ◽

Genetic Alterations ◽

Tumour Suppressor Gene ◽

Diffuse Gastric Cancer ◽

Loss Of Function ◽

Lobular Breast Cancer ◽

Cancer Syndrome ◽

Risk Of Cancer ◽

E Cadherin

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

Download Full-text

The frequency of PTEN germline mutations in Chinese breast cancer patients: The PTEN gene may not be closely associated with breast cancer in the Chinese population

Gene ◽

10.1016/j.gene.2020.144630 ◽

2020 ◽

Vol 744 ◽

pp. 144630

Author(s):

Yu Wu ◽

Dabing Huang ◽

Huanhuan Zhang ◽

Xiaoling Weng ◽

Honglian Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Chinese Population ◽

Germline Mutations ◽

Pten Gene ◽

Breast Cancer Patients

Download Full-text

Extended gene panel testing in lobular breast cancer

Familial Cancer ◽

10.1007/s10689-021-00241-5 ◽

2021 ◽

Author(s):

Elke M. van Veen ◽

D. Gareth Evans ◽

Elaine F. Harkness ◽

Helen J. Byers ◽

Jamie M. Ellingford ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Detection Rate ◽

Gene Panel ◽

Lobular Breast Cancer ◽

Germline Variants ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

Download Full-text