Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges

2017 ◽  
pp. 1-12 ◽  
Author(s):  
Katrina Lowstuter ◽  
Carin R. Espenschied ◽  
Duveen Sturgeon ◽  
Charité Ricker ◽  
Rachid Karam ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Medical Management ◽  
Cancer Genetics ◽  
Medical Center ◽  
Academic Medical Center ◽  
Lifetime Risk ◽  
Diffuse Gastric Cancer ◽  
Mutation Carriers ◽  
Cdh1 Mutation ◽  
Testing Criteria

Purpose Mutations in the CDH1 gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for CDH1 mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected CDH1 mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of CDH1 mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management. Patients and Methods This cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate CDH1 mutation prevalence and associated clinical phenotypes. CDH1 mutation carriers were classified as IGCLC positive (met criteria), IGCLC partial phenotype, and IGCLC negative. Results In the laboratory cohort, 16 (0.06%) of 26,936 patients were identified as having a pathogenic CDH1 mutation. In the clinic cohort, four (1.26%) of 318 had a pathogenic CDH1 mutation. Overall, 65% of mutation carriers did not meet the revised testing criteria published in 2015. All three CDH1 mutation carriers who had risk-reducing gastrectomy had pathologic evidence of diffuse gastric cancer despite not having met IGCLC criteria. Conclusion The majority of CDH1 mutations identified on MGPT are unexpected and found in individuals who do not fit the accepted diagnostic testing criteria. These test results alter the medical management of CDH1-positive patients and families and provide opportunities for early detection and risk reduction.

Hereditary diffuse gastric cancer: Natural history, pathology, screening limitations, and prophylactic total gastrectomy in CDH1 mutation carriers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4500-4500 ◽  
Author(s):  
H. T. Lynch ◽  
C. Caldas ◽  
D. Wirtzfeld ◽  
C. Vaccaro ◽  
W. Rubinstein ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Genetic Counseling ◽  
Total Gastrectomy ◽  
Mutation Testing ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Mutation Carriers ◽  
Prophylactic Gastrectomy ◽  
Cdh1 Mutation ◽  
Prophylactic Total Gastrectomy

4500 Background: Hereditary diffuse gastric cancer (HDGC) is a potentially fatal disease that occurs due to mutations in the E- cadherin (CDH1) gene, as discovered in 1998. Its penetrance ranges between 70–80%. Its morbidity and mortality can be altered favorably through genetic counseling, germline mutation testing, and highly-targeted management that includes prophylactic total gastrectomy. Lobular breast cancer has been identified as an integral lesion in HDGC. Methods: This international collaborative group on HDGC is comprised of 56 mutation-positive families, which is the world’s largest resource of such families. Cancer diagnoses were verified with pathology slides/tissue block review when possible, or reports. Genetic counseling covering the pros and cons of mutation testing, screening and its limitations, and the option of prophylactic total gastrectomy was provided. Results: Findings on 56 HDGC mutation-positive families show carrier testing to have been performed on 267 individuals, of which 123 were CDH1 mutation positive. Prophylactic gastrectomies were performed on 14 families involving 50 individuals. Occult cancer was diagnosed in 31 (31/39=79.5%; results are pending on the remaining 11), based upon pathology and verbal reports. Five individuals underwent prophylactic gastrectomy prior to genetic counseling, 3 of whom later tested negative for mutations. In one of these remarkable HDGC families, 11 first cousins who tested positive for the CDH1 mutation underwent prophylactic total gastrectomy. On a post-surgery questionnaire, they each stated that the decision for the prophylactic procedure was the “right one” for them. In each case, a parent had died of HDGC sequelae, adding to the cousins’ acceptance of DNA testing and surgery. They considered their post-operative nutritional programs to have been acceptable. Conclusion: HDGC and its life-threatening sequelae were significantly ameliorated in CDH1 mutation carriers through total prophylactic gastrectomy in patients at enormous lifetime risk for HDGC. Decision for mutation testing and surgery may be more acceptable through intensive education in concert with a compassionate management team. No significant financial relationships to disclose.

Retrospective Analysis of Patients With Acute Invasive Fungal Rhinosinusitis in a Single Tertiary Academic Medical Center: A 10-Year Experience

2019 ◽  
Vol 34 (3) ◽  
pp. 324-330
Author(s):  
Gennadiy Vengerovich ◽  
Kristen A. Echanique ◽  
Ki Wan Park ◽  
Christine Wells ◽  
Jeffrey D. Suh ◽  
...  
Keyword(s):  
Medical Management ◽  
Medical Center ◽  
Academic Medical Center ◽  
Sinus Surgery ◽  
Open Approach ◽  
Presenting Symptoms ◽  
Fungal Rhinosinusitis ◽  
Acute Invasive Fungal Rhinosinusitis ◽  
Academic Medical ◽  
Invasive Fungal Rhinosinusitis

Background Acute invasive fungal rhinosinusitis (AIFRS) is an aggressive, potentially fatal disease that can spread rapidly to the orbit and intracranial structures causing significant mortality and morbidity. Objective In this study, we present a 10-year experience from a tertiary academic medical center of patients presenting with AIFRS. Data on presentation, mortality rate, comorbidities, surgical, and medical management were analyzed. Methods A retrospective chart review was performed in a tertiary academic medical center of patients with AIFRS from January 2009 through February 2019. Data collected included demographics, presenting symptoms, comorbidities, immunosuppression status, endoscopic and imaging findings, orbital and intracranial complications, surgical and medical management, as well as outcomes and mortality. Results A total of 34 patients were identified. In our series, mortality was noted to be 61.8%, excluding patients who were lost to follow-up. The most common presenting symptoms included facial pain, ophthalmologic complaints, headaches, and proptosis. Only 4 of the 34 patients did not undergo surgical intervention, as they were not deemed surgical candidates; they all succumbed to their disease. Twenty-six of the 30 surgical patients (86.7%) underwent endoscopic sinus surgery, 8 underwent an open approach (26.7%), while 7 patients underwent orbital exenteration (23.3%). All patients had surgical pathology consistent with AIFRS. Fungal species isolated from culture included Aspergillus, Mucor/ Rhizopus, Candida, Cunninghamella Scedosporium boydii, Paecilomyces, and Scopulariopsis. Medical therapies included intravenous amphotericin B, caspofungin, posaconazole, voriconazole, isavuconazole, and micafungin. Conclusion AIFRS was associated with 61.8% mortality in our series of 34 patients over the past 10 years. Early diagnosis, as well as rapid and aggressive surgical and medical management, is necessary for optimal outcomes in this devastating disease.

Searching for CDH1 gene mutations in early-onset diffuse gastric cancer in Chinese patients.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 23-23
Author(s):  
Xu Yanjun ◽  
Cao Wenming ◽  
Xu Qi ◽  
Guo Jianmin ◽  
Wang Xinbao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Lymph Node ◽  
Gene Mutations ◽  
Germline Mutations ◽  
Chinese Patients ◽  
Diffuse Gastric Cancer ◽  
Cdh1 Gene ◽  
Node Metastasis ◽  
Cdh1 Mutation

23 Background: CDH1 germline mutations are found to be associated with the development of hereditary diffuse gastric cancer (HDGC) and the early-onset diffuse gastric cancer (EODGC). But the impact of CDH1 gene mutations and large deletions on HDGC and EODGC has not been fully determined in Asians. Although the incidence of gastric cancer is relatively high in China, the detection rate of CDH1 germline mutations in Chinese patients with EODGC is rare compared to that in European patients. Methods: We investigated the mutation status of the CDH1 gene in 57 Chinese EODGC patients younger than 40 years old who met the clinical criteria for HDGC. Polymerase chain reaction-direct sequencing was performed, and multiplex ligation-dependent probe amplification (MLPA) was used to evaluate the patients with negative sequencing results. Associations between mutation, clinicopathologic, and overall survival data were analyzed by SPSS 19. Results: The germline mutations of CDH1gene were identified in 51 (89.5%) of the 57 EODGC patients. The nonsense mutation in exon 13 (c.2200T>C, p.Ala692*) occurred in fourty-six EODGC patients. The missense mutations were detected in twenty patients (Eighteen in exon 5: c.778G>C, p.Glu218Asp; Two in exon 12: c.2012C>G, p.Leu630Val). No deletion or duplication in any patient. Most of the patients carrying the CDH1 mutation in exon 13 had lymph node metastasis when compared with patients lacking CDH1 mutation (87.2% vs 60.0%) ( P < 0.05 ). EODGC patients, lacking germline CDH1 alterations, showed a longer median overall survival (mOS) than patients carrying CDH1 mutation in exon 13 ( P < 0.05 ). Moreover, the presence of CDH1 mutation in exon 13 was associated with the incidence of neural invasion ( P < 0.05 ). Conclusions: This study reveals novel CDH1 mutations in Chinese EODGC patients which had been poorly investigated. The presence of CDH1 mutation in EODGC patients may result in lymph node metastasis and poor prognosis. More research is needed to determine additional genetic targets that trigger EODGC.

Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening

2004 ◽  
Vol 203 (2) ◽  
pp. 681-687 ◽  
Author(s):  
Fátima Carneiro ◽  
David G Huntsman ◽  
Thomas C Smyrk ◽  
David A Owen ◽  
Raquel Seruca ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Early Development ◽  
Diffuse Gastric Cancer ◽  
Patient Screening ◽  
Mutation Carriers ◽  
E Cadherin

scholarly journals Change of natural history of hereditary diffuse gastric cancer after identification of a novel CDH1 mutation

2017 ◽  
Vol 28 ◽  
pp. v503
Author(s):  
N. Stjepanovic ◽  
S. Castro ◽  
N. Gadea ◽  
E. Carrasco ◽  
M. Codina ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Natural History ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Cdh1 Mutation ◽  
History Of

Gastroscopic surveillance with targeted biopsies compared with random biopsies in CDH1 mutation carriers

Endoscopy ◽  
2020 ◽  
Vol 52 (10) ◽  
pp. 839-846 ◽  
Author(s):  
Jolanda M. van Dieren ◽  
Liudmila L. Kodach ◽  
Peggy den Hartog ◽  
Lizet E. van der Kolk ◽  
Karolina Sikorska ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Early Adulthood ◽  
Signet Ring Cell Carcinoma ◽  
Signet Ring Cell ◽  
Endoscopic Biopsy ◽  
The Body ◽  
Mutation Carriers ◽  
Prophylactic Gastrectomy ◽  
Cdh1 Mutation ◽  
Targeted Biopsies

Abstract Background The International Gastric Cancer Linkage Consortium (IGCLC) consensus guideline advises prophylactic gastrectomy in early adulthood to prevent gastric cancer development in CDH1 germline mutation carriers; psychosocial reasons may postpone gastrectomy. We analyzed the yield of signet-ring cell carcinoma (SRCC) during surveillance gastroscopy in CDH1 mutation carriers. Methods A retrospective analysis on surveillance gastroscopies in CDH1 mutation carriers was performed. The yield of SRCC in both targeted and random biopsies was studied. Endoscopic (biopsy) results were compared with the histopathologic outcomes in gastrectomy specimens. Results 42 CDH1 mutation carriers (18 men; mean age 43, range 20–82 years) underwent 96 surveillance gastroscopies. SRCC lesions were identified on surveillance gastroscopy in 21 patients (50 %), by either targeted biopsies only (n = 11), random biopsies only (n = 3), or both random and targeted biopsies (n = 7). SRCC was detected in 41 /377 targeted biopsies (11 %), whereas random biopsies revealed SRCC in 14/1563 biopsies (0.9 %). At least one SRCC lesion was found in 26 of 30 gastrectomy specimens. In 18 of these 26 specimens (69 %), SRCC had been identified by endoscopic biopsies. Missed lesions were all small superficial SRCC foci, mainly in the body of the stomach. Conclusion In our cohort of CDH1 mutation carriers, SRCC lesions were identified by an extensive endoscopic surveillance protocol in 69 % of SRCC-positive patients who underwent a gastric resection. The low number of SRCC detected through random sampling demands a critical reappraisal of random biopsy sampling in the IGCLC guideline.

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