International Gastric Cancer Linkage Consortium Research Articles

Large cohort analysis of incidental CDH1 PVs among patients undergoing MGPT.

10618 Background: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant condition caused by a heterozygous pathogenic variant (PV) in CDH1.HDGC is associated with an increased risk for DGC (33-70%) and invasive lobular breast cancer (LBC) (~64%) [1]. The National Cancer Center Network (NCCN) and International Gastric Cancer Linkage Consortium (IGCLC) recommend consideration of CDH1 germline testing based on personal and family history of DGC and LBC. However, with the advent of next generation sequencing and the inclusion of CDH1 in multigene panels (MGP), several cohort studies have identified CDH1+ patients who do not meet criteria [2,3,4,5]. Our group previously analyzed a cohort of patients with a personal or family history of BC who had CDH1 testing through MGPT and did not observe a significant association between CDH1 PVs and suspicion for HDGC (p-value=0.2066) [6]. In this expanded study, we aim to evaluate a larger cohort of patients of all cancer histories to gain a more comprehensive picture of the prevalence of incidental CDH1 PV among patients undergoing MGPT. Methods: 14,891 individuals who underwent CDH1 testing within MGPT were seen at MD Anderson’s Clinical Cancer Genetics (CCG) program between August 2013 and January 2024. This cohort was obtained from a prospectively maintained patient database within MD Anderson’s CCG program. Individuals were stratified based on CDH1 germline status (PV vs. negative or variant of uncertain significance) and meeting modified criteria for HDGC. Results: Within our expanded cohort, 1,716 individuals (11.5%) met criteria for suspicion for HDGC, while 13,715 did not meet criteria. Of the 70 individuals who tested positive for CDH1 (0.47%), 39 (0.28%) met criteria while 31 (0.23%) did not. We observed a statistically significant relationship between meeting our modified criteria for suspicion for HDGC and testing positive for a pathogenic variant in CDH1 (p-value <0.0001). Conclusions: Among patients who underwent CDH1 testing within MGPT, we observed a correlationbetween having a CDH1PV and meeting criteria for suspicion for HDGC. This contrasts with prior findings from our breast cancer cohort, potentially due to the limited number of CDH1 positive patients (n=3). These results suggest that while perhaps not robustly capturing HDGC families within a sub-population of patients undergoing MGPT, overall, NCCN and IGCLC guidelines closely reflect the clinical picture of a significant number of HDGC families. Meanwhile, the presence of incidental CDH1 PVs in this cohort portrays the variable expressivity and incomplete penetrance among patients with HDGC, including the detection of occult signet ring cell carcinomas during endoscopies or total gastrectomies [7]. We seek to expand this analysis by comparing these findings to rates of incidental CDH1 PVs in a subset of patients who meet NCCN guidelines for CDH1 testing based on suspicion for hereditary breast cancer syndromes.

Frequency of CDH1, CTNNA1 and CTNND1 Germline Variants in Families with Diffuse and Mixed Gastric Cancer.

The most well-characterized hereditary form of gastric cancer is hereditary diffuse gastric cancer (HDGC), an autosomal dominant syndrome characterized by an increased risk of diffuse gastric and lobular breast cancer. HDGC is predominantly caused by germline pathogenic variants in the CDH1 gene, and more rarely in the CTNNA1 gene. Furthermore, the International Gastric Cancer Linkage Consortium (IGCLC) guidelines do not clarify whether or not mixed gastric cancer (with a diffuse component) should be considered in the HDGC genetic testing criteria. We aimed to evaluate the contribution of CTNNA1 and CTNND1 germline variants to HDGC. Additionally, we also intended to compare the frequencies of CDH1 and CTNNA1 (and eventually CTNND1) germline variants between patients with diffuse and mixed gastric carcinomas to evaluate if genetic testing for these genes should or should not be considered in patients with the latter. We analyzed the CDH1 gene in 67 cases affected with early-onset/familial mixed gastric carcinomas and the CTNNA1 and CTNND1 genes in 208 cases with diffuse or mixed gastric cancer who had tested negative for CDH1 pathogenic germline variants. A deleterious CTNNA1 germline variant was found in 0.7% (1/141) of diffuse gastric cancer patients meeting the 2020 IGCLC criteria, as compared to the rate of 2.8% of CDH1 deleterious variants found by us in this setting. No deleterious variants were found in CTNND1, but six variants of uncertain significance were identified in this gene. We did not find any pathogenic CDH1, CTNNA1 or CTNND1 variant in index patients with early-onset/familial mixed gastric cancer, so there is no evidence that supports including this tumor type in the testing criteria for germline variants in these genes. The role of the CTNND1 gene in inherited gastric cancer predisposition is still unclear.

Case Series of 11 CDH1 Families (47 Carriers) Including Incidental Findings, Signet Ring Cell Colon Cancer and Review of the Literature.

Germline pathogenic variants in E-cadherin (CDH1) confer high risk of developing lobular breast cancer and diffuse gastric cancer (DGC). The cumulative risk of DGC in CDH1 carriers has been recently reassessed (from 40-83% by age 80 to 25-42%) and varies according to the presence and number of gastric cancers in the family. As there is no accurate estimate of the risk of gastric cancer in families without DGC, the International Gastric Cancer Linkage Consortium recommendation is not straightforward: prophylactic gastrectomy or endoscopic surveillance should be proposed for these families. The inclusion of CDH1 in constitutional gene panels for hereditary breast and ovarian cancer and for gastrointestinal cancers, recommended by the French Genetic and Cancer Consortium in 2018 and 2020, leads to the identification of families with lobular cancer without DGC but also to incidental findings of pathogenic variants. Management of CDH1 carriers in case of incidental findings is complex and causes dilemmas for both patients and providers. We report eleven families (47 CDH1 carriers) from our oncogenetic department specialized in breast and ovarian cancer, including four incidental findings. We confirmed that six families did not have diffuse gastric cancer in their medical records. We discuss the management of the risk of diffuse gastric cancer in Hereditary Lobular Breast Cancer (HLBC) through a family of 11 CDH1 carriers where foci were identified in endoscopic surveillance. We also report a new colon signet ring cancer case in a CDH1 carrier, a rare aggressive cancer included in CDH1-related malignancies.

Combining clinical and molecular characterization of CDH1: a multidisciplinary approach to reclassification of a splicing variant.

Pathogenic germline variants (PGVs) in the CDH1 gene are associated with diffuse gastric and lobular breast cancer syndrome (DGLBC) and can increase the lifetime risk for both diffuse gastric cancer and lobular breast cancer. Given the risk for diffuse gastric cancer among individuals with CDH1 PGVs is up to 30-40%, prophylactic total gastrectomy is often recommended to affected individuals. Therefore, accurate interpretation of CDH1 variants is of the utmost importance for proper clinical decision-making. Herein we present a 45-year-old female, with lobular breast cancer and a father with gastric cancer of unknown pathology at age 48, who was identified to have an intronic variant of uncertain significance in the CDH1 gene, specifically c.833-9C > G. Although the proband did not meet the International Gastric Cancer Linkage Consortium (IGCLC) criteria for gastric surveillance, she elected to pursue an upper endoscopy where non-targeted gastric biopsies identified a focus of signet ring cell carcinoma (SRCC). The proband then underwent a total gastrectomy, revealing numerous SRCC foci, but no invasive diffuse gastric cancer. Simultaneously, a genetic testing laboratory performed RNA sequencing to further analyze the CDH1 intronic variant, identifying an abnormal transcript from a novel acceptor splice site. The RNA analysis in conjunction with the patient's gastric foci of SRCC and family history was sufficient evidence for reclassification of the variant from uncertain significance to likely pathogenic. In conclusion, we report the first case of the CDH1 c.833-9C > G intronic variant being associated with DGLBC and illustrate how collaboration among clinicians, laboratory personnel, and patients is crucial for variant resolution.

Hereditary Diffuse Gastric Cancer-Update Based on the Current Consort Recommendations.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited cancer syndrome that has been associated with a mutation of the CDH1, and rarely the CTNNA1 gene, respectively. HDGC is characterized histologically by multifocal growth and signet ring cells in the gastric mucosa and lobular type breast cancer. In cases of a proven pathogenic CDH1 mutation, a prophylactic gastrectomy, or alternatively, an annual surveillance gastroscopy in expert centers is recommended. Additionally, MR imaging of the breast should be performed annually starting from the age of 30, to detect lobular breast cancer. In 2020, the International Gastric Cancer Linkage Consortium (IGCLC) additionally defined new clinical groups with specific recommendations: (1) the group of patients with a proven mutation in the CDH1 gene, but exclusive manifestation as lobular breast cancer, was defined as hereditary lobular breast cancer (HLBC); (2) the group, which clinically fulfills familial HDGC criteria, in the absence of a relevant mutation, was designated as HDGC-like. This update summarizes relevant aspects of hereditary gastric cancer and the current recommendation criteria of the IGCLC published in 2020.

Simplified and more sensitive criteria for identifying individuals with pathogenic CDH1 variants

BackgroundHereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome most often caused by pathogenic variants in CDH1. The International Gastric Cancer Linkage Consortium (IGCLC) recently updated its criteria for genetic...

CDH1 germline mutations in a Chinese cohort with hereditary diffuse gastric cancer

Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer (HDGC) and have been identified in multiple ethnicities. However, CDH1 germline mutations have seldom been documented in Chinese patients with HDGC, and their frequency remains unclear. Here, we aimed to examine the frequency of CDH1 germline mutations in Chinese patients with HDGC. In total, 285 patients who met the International Gastric Cancer Linkage Consortium 2015 testing criteria of HDGC for CDH1 germline mutations were recruited. All 16 CDH1 exons, including neighboring intronic sequences, were amplified using polymerase chain reaction and screened using Sanger sequencing. Variants were analyzed using Mutation Surveyor V4.0, SIFT, and PolyPhen-2 software. Three nonsense and nine missense CDH1 germline mutations were identified in 21 of 285 index cases (7.4%). Two CDH1 germline mutations, N405Y (Asn405Tyr) and W409X (Trp409Ter), were identified as new variants. In addition, up to 28.6% of CDH1 mutations in the 21 indicated patients were identified as c.1775G>C (E551Q). The frequency of CDH1 mutations was 6.5% (7/108) in HDGC and 7.9% (14/177) in early onset diffuse gastric cancer (EODGC). The mutation detection rates of CDH1 in males and females were 6.7% (4/60) and 8.5% (10/117) in EODGC and 4.6% (3/65) and 9.3% (4/43) in HDGC, respectively. These data reveal, for the first time, the type and frequency of CDH1 germline mutations in Chinese HDGC and demonstrate that germline CDH1 mutations are a noteworthy contributor to the high frequency of HDGC in Chinese.

Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review.

Simple SummaryE-cadherin (CDH1 gene) germline mutations are associated with the development of the autosomal cancer syndrome known as hereditary diffuse gastric cancer. About 30% of families fulfilling the clinical criteria established by the International Gastric Cancer Linkage Consortium have constitutional alterations of the CDH1 gene. Different patterns of CDH1 germline mutations have described as truncating, deletion, insertion, splice site, non sense, silence, and at last, missense alterations. The frequency of the different E-cadherin germline mutations in countries with different incidence rates for gastric carcinoma has reported extremely variable. In this study we aimed to assess the worldwide frequency of CDH1 germline mutations in gastric cancers coming from different geographical areas, using a systematic approach.Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by CDH1 germline mutations. Nevertheless, current CDH1 genetic screening recommendations disregard an unbalanced worldwide distribution of CDH1 variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing CDH1 variants in gastric cancer patients originating from both high- and low-prevalence countries. Selected studies were categorized as family study, series study, and unknown study, according to the implementation of HDGC clinical criteria for genetic testing. Our results indicate that CDH1 mutations are more frequently identified in gastric cancer low-incidence countries, and in the family study group that encompasses cases fulfilling criteria. Considering the type of CDH1 alterations, we verified that the relative frequency of mutation types varies within study groups and geographical areas. In the series study, the missense variant frequency is higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. However, application of variant scoring for putative relevance led to a strong reduction of CDH1 variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for CDH1 genetic screening are critical for identification of individuals carrying mutations with clinical significance. Further, we propose that future guidelines for testing should consider GC incidence across geographical regions for improved surveillance programs and early diagnosis of disease.

Hereditary diffuse gastric cancer: updated clinical practice guidelines.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.

Two independent families with strongly suspected hereditary diffuse gastric cancer based on the probands' endoscopic findings.

Hereditary diffuse gastric cancer (HDGC) is the most famous of hereditary gastric cancer syndromes with an autosomal dominant inheritance pattern, and its diagnosis can be made by identifying a pathogenic germline variant in CDH1. We report two independent families that were strongly suspected of having HDGC based on endoscopic findings (multiple tiny, pale areas) obtained in the probands; the probands were pathologically diagnosed as having signet ring cell carcinoma (SRCC) and were genetically confirmed to have a pathogenic CDH1 germline variant. Although the updated International Gastric Cancer Linkage Consortium (IGCLC)'s clinical guidelines for HDGC (2015) state that screening/surveillance endoscopy should be performed (Cambridge protocol), the endoscopic findings obtained in the two presently reported families suggest that pale areas should be suspected as indicating the presence of SRCCs, and biopsies should be performed in addition to obtaining a precise family history in cases suspected of having HDGC.

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

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).

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

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.

Germline variants and phenotypic spectrum in a Canadian cohort of individuals with diffuse gastric cancer.

CDH1 pathogenic variants (pvs) cause most cases of inherited diffuse gastric cancer (dgc), but have low detection rates and vary geographically. In the present study, we examined hereditary causes of dgc in patients in Ontario. CDH1 testing through single-site or multi-gene panels was conducted for patients with dgc meeting the 2015 International Gastric Cancer Linkage Consortium (igclc) criteria, or with isolated dgc at less than 50 years of age, or with a strong family history of cancer identified at the Zane Cohen Centre (zcc). All CDH1-positive patients at zcc, regardless of cancer history, were summarized. In 15 of 85 patients with dgc (17.6%), a pv or likely pv was identified through CDH1 single-site (n = 43) or multi-gene panel (n = 42) testing. The detection rate was 9.4% overall (8 of 85) and 11% using igclc criteria (7 of 65). No CDH1 pvs were identified in patients with isolated dgc at less than 40 years of age, but 1 pv was identified in a patient with isolated dgc at less than 50 years of age. Multi-gene panels identified 9 pvs (21.4%), including CDH1, STK11, ATM, BRCA2, MLH1, and MSH2. Review of 81 CDH1 carriers identified 10% with dgc (median age: 48 years; range: 38-59 years); 41% were unaffected (median age: 53 years; range: 26-89 years). Observed malignancies other than dgc or lobular breast cancer (lbc) included colorectal, gynecologic, kidney or bladder, prostate, testicular, and ductal breast cancers. Lobular-breast cancer was seen only in 3 families. In Ontario, the detection rate of CDH1 pvs in patients with dgc was low: no pvs were identified in patients with isolated dgc at less than 40 years of age, and 1 was identified in a patient with isolated dgc at less than 50 years of age. Isolated lbc with no dgc was observed in CDH1-positive families, as were pathology-confirmed nondgc or non-lbc malignancies, which had not previously been reported. Given a phenotype that overlaps with other hereditary conditions, multi-gene panels are recommended for all patients with dgc at less than 50 years of age and for those meeting igclc criteria.

Risk-reducing total gastrectomy in asymptomatic CDH1 carriers

Hereditary diffuse gastric cancer is an autosomal dominant cancer susceptibility syndrome characterized by increased risk for gastric cancer and lobular breast cancer and mainly caused by germline alterations in the CDH1 gene. This was an observational, retrospective, and unicentric study. Clinical data from patients with hereditary diffuse gastric cancer who had risk-reducing total gastrectomy between June 2005 and January 2018 were collected. A thorough histopathological analysis of gastrectomy specimens was performed, according to the current recommendations of the International Gastric Cancer Linkage Consortium. In 59 families fulfilling the clinical criteria for CDH1 testing, we identified the same CDH1 missense pathogenic variant in five families. Thirty-nine CDH1 carriers were identified. Four CDH1 carriers died with advanced diffuse gastric cancer, 19 chose risk-reducing total gastrectomy, and 16 opted for endoscopic surveillance, despite being duly informed of the limited utility of periodic gastric endoscopy in this context. The 19 asymptomatic CDH1 carriers undergoing surgery had an age range of 14–63 years (median, 39 years) and the median hospital stay was 6 days. Laparoscopic total gastrectomy was performed on four of 19 CDH1 carriers. There were no cases of mortality or major morbidity in this procedure. The range of weight loss in our series was 13%. Histopathological examination of the entirety of gastric mucosa revealed intramucosal gastric carcinoma foci (pT1a) in 17 of 19 (89.5%) total gastrectomy specimens. No lymph node metastases were detected (pN0). Risk-reducing total gastrectomy remains the best clinical management for patients with hereditary diffuse gastric cancer harboring a germline, pathogenic CDH1 variant. In our series, intramucosal carcinoma foci were found in the great majority (89.5%) of CDH1 carriers.

Abstract 3323: The feasibility for detecting hereditary genetic findings of familial gastric cancer

Abstract Background: Multiplex gene panel tests using next-generation sequencing has currently been clinically available for various cancer patients including gastric cancer in Japan. The original purpose of the Multiplex gene panel tests is to find actionable genetic alterations which might correlate with promising therapeutic antitumor drugs. Accordingly, secondary genetic findings as germline mutation which is associated with hereditary disease may also be detectable by the Multiplex gene panel tests. It has been reported that familial cancers represent around 5%–10% of all cancer patients. Gastric cancer is one of popular cancers in Japan. The prediction of patients with familial gastric cancer (FGC) before the multiplex gene panel tests might be important for the gene consultation for the patients and their family. Objective: The aim of study is to clarify the characteristic clinico-pathologic features of FGC to predict the possibility of hereditary gastric cancer. Patients and Methods: A total of 2301 gastric cancer patients who received gastrectomy at our department was enrolled in this study. We classified FGCs into 2 categories by modification of International Gastric Cancer Linkage Consortium (IGCLC) which excluded pathogenic types, as follows, group A: gastric cancer in an individual under the age of 40; group B: two gastric cancer cases in a family regardless of age. In contrast, the most gastric cancers were sporadic, which was classified as group C. The clinicopathological factors including E-cadherin and p53 expression by immunostaining, was retrospectively compared among 3 groups. Results: One hundred and fifty-two cases (6.6%) of 2301 patients were classified as FGCs (group A: 71 cases; group B: 81 cases), whereas the remaining 2149 patients were classified as group C (93.4%). Female (43.4%) and diffuse-type gastric cancer (57.2%) was significantly (p<0.001) more frequent in FGCs than that (30.5% and 42.5%) in group C. The significant difference (p<0.05) of clinicopathological variables between group A (n=71) and B (n=81) was found in the rates of female (52.1% vs 35.8%), diffuse-type (83.1% vs 34.5%), and T4 status (38.0% vs 17.3%), respectively. There was also significant difference (p<0.05) in the rates of female (52.1% vs 30.5%), diffuse-type (83.1% vs 42.5%) and Borrmann type 4 (15.5% vs 6.8%) between group A and C. No significant difference was found in clinicopathological variables between group B and C. No statistical correlation of E-cadherin loss between 3 groups. In this study, 2 cases were found in which p53 expression was positive for all cells. Conclusion: Young age (<40 years) and female patients with diffuse-type gastric cancer might have a high risk for FGC. It is necessary to take into consideration of hereditary gastric cancer when the multiplex gene panel test is performed for the young female gastric cancer patients with diffuse-type cancer. Citation Format: Sadaaki Nishimura. The feasibility for detecting hereditary genetic findings of familial gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3323.

Comparison of CDH1 Penetrance Estimates in Clinically Ascertained Families vs Families Ascertained for Multiple Gastric Cancers

CDH1 pathogenic variants have been estimated to confer a 40% to 70% and 56% to 83% lifetime risk for gastric cancer in men and women, respectively. These are likely to be overestimates owing to ascertainment of families with multiple cases of gastric cancer. To our knowledge, there are no penetrance estimates for CDH1 without this ascertainment bias. To estimate CDH1 penetrance in a patient cohort not exclusively ascertained based on strict hereditary diffuse gastric cancer (HDGC) criteria. Retrospective review of 75 families found to have pathogenic variants in CDH1 through clinical ascertainment and multigene panel testing at a large commercial diagnostic laboratory from August 5, 2013, to June 30, 2018. CDH1 pathogenic variants were identified in 238 individuals from 75 families. Pedigrees from those families included cancer status for 1679 relatives. Penetrance estimates are based on 41 families for which completed pedigrees were available. Gastric cancer standardized incidence ratio estimates relative to Surveillance, Epidemiology, and End Results (SEER) Program incidence for pathogenic CDH1 variants from families ascertained without regard to HDGC criteria. Among the 238 individuals with a CDH1 pathogenic variant, mean (SD) age was 49.3 (18.1) years and 63.4% were female. Ethnicity was reported for 67 of 75 (89%) families; of these 67 families, 51 (76%) reported European ancestry, whereas Asian, African, Latino, and 2 or more ancestries were reported for 4 families (6%) each. Standardized incidence ratios for gastric and breast cancer were significantly elevated above SEER incidence. Extrapolated cumulative incidence of gastric cancer at age 80 years was 42% (95% CI, 30%-56%) for men and 33% (95% CI, 21%-43%) for women with pathogenic variants in CDH1, whereas cumulative incidence of female breast cancer was estimated at 55% (95% CI, 39%-68%). International Gastric Cancer Linkage Consortium criteria were met in 25 of the 75 (33%) families; however, dispensing with the requirement of confirmation of HDGC histologic subtype, 43 (57%) would meet criteria. The cumulative incidence of gastric cancer for individuals with pathogenic variants in CDH1 is significantly lower than previously described. Because prophylactic gastrectomy can have bearing upon both physical and psychological health, further discussion is warranted to assess whether this surgical recommendation is appropriate for all individuals with pathogenic variants in CDH1.

CDH1 Gene and Hereditary Diffuse Gastric Cancer Syndrome: Molecular and Histological Alterations and Implications for Diagnosis And Treatment.

Gastric cancer, a group of common malignancies, results in the most cancer mortality worldwide after only lung and colorectal cancer. Although familial gastric cancers have long been recognized, it was not until recently that they were discovered to be associated with mutations of specific genes. Mutations of CDH1, the gene encoding E-cadherin, are the most common germline mutations detected in gastric cancer and underlie hereditary diffuse gastric cancer (HDGC) syndrome. All reported HDGCs are the pure diffuse type by Lauren classification and are associated with dismal prognosis once the tumor invades the submucosa. Because CDH1 germline mutations are inherited in an autosomal-dominant fashion and have high penetrance, the International Gastric Cancer Linkage Consortium (IGCLC) developed criteria to facilitate the screening of CDH1 mutation carriers; these criteria have been proven to have excellent sensitivity and specificity. Recent histologic studies suggest that HDGC progresses through several stages. Even when the tumor becomes “invasive” in lamina propria, it may stay indolent for a long time. However, the molecular mechanisms that induce the transitions between stages and determine the length of the indolent phase remain to be determined. Although the standard management for CDH1 mutation carriers is prophylactic total gastrectomy, many questions must be answered before the surgery can be done. These include the optimal surveillance strategy, the best strategy to choose surgical candidates, and the ideal time to perform surgery. In addition to increasing the risk of gastric cancer, CDH1 germline mutations also increase the risk of invasive lobular carcinoma of the breast, and possibly colorectal adenocarcinoma, and are associated with blepharocheilodontic syndrome (a congenital development disorder). However, the optimal management of these conditions is less established owing to insufficient data regarding the risk of cancer development. This review focuses on molecular and histological findings in HDGC, as opposed to sporadic diffuse gastric cancer, and their implications for the management of CDH1 mutation carriers and the diagnosis and treatment of HDGC. Other conditions associated with CDH1 germline mutations and future research directions are also discussed.

Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges.

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. 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. 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. 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: One Familyʼs Story

Hereditary Diffuse Gastric Cancer (HDGC) is a multi-generational inherited form of diffuse gastric cancer, that represents 2% of gastric cancers, and carries a poor prognosis. The majority of HDGCs are caused by an autosomal dominant genetic mutation in the CDH1 gene, which encodes the cellular adhesion protein, E-cadherin. The presence of the CDH1 gene mutation causes an 80% lifetime risk of gastric cancer in both men and women and also a 60% lifetime risk of lobular breast cancer. The gastric cancer present in HDGC is located as discrete foci below an intact gastric mucosa, making endoscopic surveillance an exceedingly unreliable means of early detection. As such, prophylactic gastrectomy is recommended for individuals above age 20 with the CDH1 gene mutation. It is therefore imperative that a diagnosis of HDGC prompt genetic testing in family members so that life-saving prophylactic measures can be taken. We describe the case of a Caucasian male of Polish descent with recurrent diffuse gastric cancer, who was ultimately found to carry the CDH1 gene mutation and was diagnosed with HDGC. We also describe the patient's pedigree, including the results of his family members' genetic testing, of which fourteen members tested positive for the CDH1 gene mutation.Table 1: CDH1 Related Cancer Risks and International Gastric Cancer Linkage Consortium Management RecommendationsFigure 1

E-cadherin germline mutation carriers: clinical management and genetic implications.

Hereditary diffuse gastric cancer is an autosomic dominant syndrome associated with E-cadherin protein (CDH1) gene germline mutations. Clinical criteria for genetic screening were revised in 2010 by the International Gastric Cancer Linkage Consortium at the Cambridge meeting. About 40 % of families fulfilling clinical criteria for this inherited disease present deleterious CDH1 germline mutations. Lobular breast cancer is a neoplastic condition associated with hereditary diffuse gastric cancer syndrome. E-cadherin constitutional mutations have been described in both settings, in gastric and breast cancers. The management of CDH1 asymptomatic mutation carriers requires a multidisciplinary approach; the only life-saving procedure is the prophylactic total gastrectomy after thorough genetic counselling. Several prophylactic gastrectomies have been performed to date; conversely, no prophylactic mastectomies have been described in CDH1 mutant carriers. However, the recent discovery of novel germline alterations in pedigree clustering only for lobular breast cancer opens up a new debate in the management of these individuals. In this critical review, we describe the clinical management of CDH1 germline mutant carriers providing specific recommendations for genetic counselling, clinical criteria, surveillance and/ or prophylactic surgery.