Prevalence of CDH1 germline mutations in subjects with early onset or familial lobular breast cancer, a multicenter collaboration

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11042-11042
Author(s):  
S. Masciari ◽  
K. A. Schrader ◽  
J. Senz ◽  
N. Tung ◽  
J. Balmana ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Family History ◽  
Early Onset ◽  
Direct Sequencing ◽  
Familial Cancer ◽  
Germline Mutations ◽  
Diffuse Gastric Cancer ◽  
Prophylactic Gastrectomy ◽  
History Of

11042 Background: Invasive lobular breast carcinoma (LBC) is part of the hereditary diffuse gastric cancer (HDGC) syndrome, associated with germline mutations in the E-cadherin (CDH1) gene. CDH1 mutations can be identified in 80% of families ascertained by DGC. The risk of DGC in CDH1 mutation carriers is 67% in males, and 83% in females; the estimated risk of LBC in women is 39–50% to age 80. Management of HDGC includes prophylactic gastrectomy. In this study, we estimated the prevalence of germline CDH1mutations among women with LBC who were either diagnosed at young age or had family history of breast cancer (BC). Methods: Germline DNA was collected from 383 women with LBC or mixed, lobular/ductal, BC from breast cancer programs, familial cancer clinics, and population-based cohorts. Germline BRCA1or BRCA2mutations carriers were excluded. Eligible women had (1) LBC before age 45 or (2) LBC at any age with at least two 1st or 2nd degree relatives with BC of any type. Denaturing high pressure liquid chromatography was undertaken, followed by direct sequencing of exons displaying changes. Results: At the time of submission 310 of 383 samples have been fully sequenced. One previously characterized missense mutation and four novel non-synonymous variants (1.6%) were found. Three of these women had LBC before 45 years and no family history of BC; two had BC family history. No gastric cancers were reported in these families. Functional assays to assess the pathogenicity of the variants are in process. Conclusions: These results confirm that CDH1 is responsible for a small proportion of familial and early onset LBC. Given the difficulty of identifying CDH1 mutations from BC history alone and the importance of managing the gastric cancer risk in CDH1carriers, these findings should underscore the need to obtain an accurate abdominal cancer family history from women with LBC. No significant financial relationships to disclose.

THE ASSOCIATION OF LOBULAR BREAST CANCER WITH GERMLINE MUTATIONS OF CDH1

2008 ◽  
Vol 31 (4) ◽  
pp. 22
Author(s):  
K Schrader ◽  
S Masciari ◽  
N Boyd ◽  
J Senz ◽  
P Kaurah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Early Onset ◽  
Dna Analysis ◽  
Control Sample ◽  
Germline Mutations ◽  
Diffuse Gastric Cancer ◽  
Missense Mutations ◽  
Lobular Breast Cancer ◽  
History Of

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.

scholarly journals Contribution of BRCA1 and BRCA2 germline mutations to early onset breast cancer: a series from north of Morocco

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Joaira Bakkach ◽  
Mohamed Mansouri ◽  
Touria Derkaoui ◽  
Ali Loudiyi ◽  
ElMostafa El Fahime ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Early Onset ◽  
Brca2 Gene ◽  
Germline Mutations ◽  
Genetic Alterations ◽  
Early Onset Breast Cancer ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
History Of

Abstract Background To date, the contribution of BRCA1/2 mutations in Moroccan early onset breast cancer patients remains unknown. Here we assess these genetic alterations for the first time in a cohort from North of Morocco. Methods Thirty-three patients diagnosed with breast cancer at the age of ≤40 years were recruited irrespective of breast and/or ovarian cancer family history. Coding regions and intron-exon boundaries of BRCA1 and BRCA2 genes were sequenced from peripheral blood DNA using Ion Proton (Thermo Fisher Scientific) next generation sequencing platform. Results Overall, five BRCA germline mutations were identified (15.1%). The frequency of mutations among patients with family history of breast cancer was 16.7%. Three mutations were found in BRCA1 (9%) and two within the BRCA2 gene (6%). These are three frameshift mutations (c.798_799del, c.2125_2126insA, c.5116_5119delAATA), one missense (c.116G > A) and one nonsense mutation (c.289G > T). The mutation c.5116_5119delAATA has a founder effect in North Africa. Moreover, one variant of unknown significance was identified in BRCA2 (c.4090A > G). Most BRCA mutations carriers (80%) had no family history of breast cancer. Conclusion Our data do not support the hypothesis that BRCA mutations alone explain the higher frequency of breast cancer in Moroccan young women. The young age (≤40 years) for breast cancer diagnosis seems to be strongly predictive of BRCA mutation status in Moroccan patients. These results will help in decision making with regard to genetic counseling and testing in the national scale.

scholarly journals Prevalence of germline TP53 mutation among early onset middle eastern breast cancer patients

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abdul Khalid Siraj ◽  
Tariq Masoodi ◽  
Rong Bu ◽  
Sandeep Kumar Parvathareddy ◽  
Kaleem Iqbal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Early Onset ◽  
Middle Eastern ◽  
Mutation Screening ◽  
Univariate Analysis ◽  
Positive Family History ◽  
Germline Mutations ◽  
Pathogenic Mutations ◽  
History Of

Abstract Background The data on prevalence and clinical relevance of TP53 germline mutations in early onset Middle-Eastern breast cancer (BC) is limited. Methods We determined TP53 germline mutations in a cohort of 464 early onset BC patients from Saudi Arabia using capture sequencing based next generation sequencing. Results Germline TP53 pathogenic mutations were found in 1.5% (7/464) of early onset Saudi BC patients. A total of six pathogenic missense mutations, one stop gain mutation and two variants of uncertain significance (VUS) were detected in our cohort. No TP53 pathogenic mutations were detected among 463 healthy controls. TP53 mutations carriers were significantly more likely to have bilateral breast cancer (p = 0.0008). At median follow-up of 41 months, TP53 mutations were an unfavorable factor for overall survival in univariate analysis. All the patients carrying TP53 mutations were negative for BRCA1 and BRCA2 mutations. Majority of patients (85.7%; 6/7) carrying TP53 mutation had no family history suggestive of Li-Fraumeni Syndrome (LFS) or personal history of multiple LFS related tumors. Only one patient had a positive family history suggestive of LFS. Conclusions TP53 germline mutation screening detects a clinically meaningful risk of early onset BC from this ethnicity and should be considered in all early onset BC regardless of the family history of cancer, especially in young patients that are negative for BRCA mutations.

A RAND/UCLA appropriateness study of the management of familial gastric cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 16-16
Author(s):  
Matthew Dixon ◽  
Rajini Seevaratnam ◽  
Debrah Wirtzfeld ◽  
Robin S. McLeod ◽  
Lucy K. Helyer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Expert Panel ◽  
Diffuse Gastric Cancer ◽  
Lobular Breast Cancer ◽  
Mutation Status ◽  
Prophylactic Gastrectomy ◽  
Cdh1 Mutation ◽  
Risk Patients ◽  
History Of

16 Background: Hereditary diffuse gastric cancer (HDGC) makes up 0.1-0.3% of all gastric cancers. Management of patients with HDGC is inconsistent and there is disagreement regarding management. Methods: A multi-disciplinary expert panel of 16 physicians from 6 countries scored 47 scenarios using the RAND/UCLA Appropriateness Methodology. Appropriateness was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores (AS) from 1-3 were considered inappropriate, 4−6 uncertain, and 7−9, appropriate. Agreement was reached when 11 of 16 panelists scored the statement similarly. If a statement was agreed to be appropriate, it was given a necessity score (NS) in the same manner. AS and NS are reported if agreement was met. Results: Gastric cancer (GC) patients with a family history of diffuse gastric cancer (DGC), lobular breast cancer or multiple family members with GC should be referred for genetics assessment and multidisciplinary decision-making (AS 8.0). It is appropriate for patients with DGC to have CDH1 mutation testing in a family with: (1) two or more cases of GC, with at least one case of DGC diagnosed before the age of 50 (AS 8.0); (2) three or more cases of GC diagnosed at any age, one or more of which is DGC (AS 8.0); (3) a patient diagnosed with DGC and lobular breast cancer (AS 8.0); or (4) a patient diagnosed with DGC under the age of 35 (AS 7.0, NS 5.0). A prophylactic total gastrectomy should be offered to CDH1 mutation carriers 20 years or older (AS 7.0). Conclusions: The Gastric Cancer Processes of Care panelists have outlined high risk patients in whom CDH1 mutation status should be determined, and cases in which a prophylactic gastrectomy is appropriate.

scholarly journals Mutation screening of germline TP53 mutations in high-risk Chinese breast cancer patients

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ava Kwong ◽  
Vivian Yvonne Shin ◽  
Cecilia Y. S. Ho ◽  
Chun Hang Au ◽  
Thomas P. Slavin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Cancer Patients ◽  
Germline Mutation ◽  
Early Onset ◽  
Mutation Screening ◽  
Germline Mutations ◽  
Breast Cancer Patients ◽  
History Of ◽  
History Of Cancer

Abstract Background Germline TP53 mutations are associated with Li-Fraumeni syndrome, a severe and rare hereditary cancer syndrome. Despite the rarity of germline TP53 mutations, the clinical implication for mutation carriers and their families is significant. The risk management of TP53 germline mutation carriers is more stringent than BRCA carriers, and radiotherapy should be avoided when possible. Methods TP53 gene mutation screening was performed in 2538 Chinese breast cancer patients who tested negative for BRCA mutations. Results Twenty TP53 mutations were identified with high next-generation sequencing concerning for germline mutations in Chinese breast cancer families. The majorities of the TP53 carriers had early-onset, hormone receptor-positive breast cancer, and had strong family history of cancer. Among all, 11 patients carried a germline mutation and 6 of which were likely de novo germline mutations. In addition, 1 case was suspected to be induced by chemotherapy or radiation, as this patient had no significant family history of cancer and aberrant clonal expansion can commonly include TP53 mutations. Furthermore, we have identified one mosaic LFS case. Two novel mutations (c.524_547dup and c.529_546del) were identified in patients with early-onset. Conclusions In view of the high lifetime risk of malignancy, identification of patients with germline TP53 mutations are important for clinicians to aid in accurate risk assessment and offer surveillance for patients and their families.

scholarly journals Hereditary Gastric and Breast Cancer Syndromes Related to CDH1 Germline Mutation: A Multidisciplinary Clinical Review

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1598 ◽  
Author(s):  
Giovanni Corso ◽  
Giacomo Montagna ◽  
Joana Figueiredo ◽  
Carlo La Vecchia ◽  
Uberto Fumagalli Romario ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Family History ◽  
Incidental Finding ◽  
Positive Family History ◽  
Diffuse Gastric Cancer ◽  
Clinical Approach ◽  
Clinical Criteria ◽  
History Of ◽  
E Cadherin

E-cadherin (CDH1 gene) germline mutations are associated with the development of diffuse gastric cancer in the context of the so-called hereditary diffuse gastric syndrome, and with an inherited predisposition of lobular breast carcinoma. In 2019, the international gastric cancer linkage consortium revised the clinical criteria and established guidelines for the genetic screening of CDH1 germline syndromes. Nevertheless, the introduction of multigene panel testing in clinical practice has led to an increased identification of E-cadherin mutations in individuals without a positive family history of gastric or breast cancers. This observation motivated us to review and present a novel multidisciplinary clinical approach (nutritional, surgical, and image screening) for single subjects who present germline CDH1 mutations but do not fulfil the classic clinical criteria, namely those identified as—(1) incidental finding and (2) individuals with lobular breast cancer without family history of gastric cancer (GC).

Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect

2018 ◽  
Vol 55 (7) ◽  
pp. 431-441 ◽  
Author(s):  
Giovanni Corso ◽  
Joana Figueiredo ◽  
Carlo La Vecchia ◽  
Paolo Veronesi ◽  
Gabriella Pravettoni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Age At Onset ◽  
Genetic Defect ◽  
Prophylactic Surgery ◽  
Current Evidence ◽  
Diffuse Gastric Cancer ◽  
Lobular Breast Cancer ◽  
Clinicopathological Findings ◽  
History Of

Recent studies have reported germline CDH1 mutations in cases of lobular breast cancer (LBC) not associated with the classical hereditary diffuse gastric cancer syndrome. A multidisciplinary workgroup discussed genetic susceptibility, pathophysiology and clinical management of hereditary LBC (HLBC). The team has established the clinical criteria for CDH1 screening and results’ interpretation, and created consensus guidelines regarding genetic counselling, breast surveillance and imaging techniques, clinicopathological findings, psychological and decisional support, as well as prophylactic surgery and plastic reconstruction. Based on a review of current evidence for the identification of HLBC cases/families, CDH1 genetic testing is recommended in patients fulfilling the following criteria: (A) bilateral LBC with or without family history of LBC, with age at onset <50 years, and (B) unilateral LBC with family history of LBC, with age at onset <45 years. In CDH1 asymptomatic mutant carriers, breast surveillance with clinical examination, yearly mammography, contrast-enhanced breast MRI and breast ultrasonography (US) with 6-month interval between the US and the MRI should be implemented as a first approach. In selected cases with personal history, family history of LBC and CDH1 mutations, prophylactic mastectomy could be discussed with an integrative group of clinical experts. Psychodecisional support also plays a pivotal role in the management of individuals with or without CDH1 germline alterations. Ultimately, the definition of a specific protocol for CDH1 genetic screening and ongoing coordinated management of patients with HLBC is crucial for the effective surveillance and early detection of LBC.

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