CDH1 Germline Research Articles

Lessons learned from 150 total gastrectomies for prevention of cancer.

Prophylactic total gastrectomy (PTG) is performed in carriers of CDH1 pathogenic and likely pathogenic (P/LP) variants and is becoming more frequent with broader use of germline genetic testing. There is an unmet need to standardize care and enhance outcomes in patients undergoing surgery for prevention of gastric cancer. We performed a retrospective analysis of 150 individuals with germline CDH1 P/LP variants who underwent prophylactic total gastrectomy as part of a prospective natural history study from October 2017 to May 2023. All individuals received multidisciplinary, protocolized care before and after total gastrectomy. A total of 150 asymptomatic patients with germline CDH1 P/LP variants underwent prophylactic total gastrectomy with the aid of a multidisciplinary enhanced recovery after surgery pathway. We demonstrated that acute major morbidity (Clavien-Dindo Grade ≥3) was low (11.3%, 17/150) and the most common complication was anastomotic leak (7.3%, 11/150) in the setting of a comprehensive preoperative and postoperative care pathway. Nearly all (88%, 132/150) gastrectomy specimens harbored occult signet ring cell lesions on final pathology. There were no gastric cancer recurrences or gastric cancer-related deaths during the study period with a median overall follow-up of 36 months (IQR 24-48) from gastrectomy. Prophylactic total gastrectomy can be performed with low surgical morbidity in a high-volume center. The delivery of patient-centered care by a multidisciplinary team and application of an enhanced recovery after surgery pathway may improve short-term outcomes. Interventions that can ameliorate the chronic morbidity associated with total gastrectomy, however, warrant further study.

Uncovering novel pathogenic variants and pathway mutations in triple-negative breast cancer among the endogamous mizo tribe.

The incidence of triple-negative breast cancer (TNBC) in India is higher compared to Western populations. The objective of this study is to identify novel and less reported variants in TNBC in Mizoram, a state with a high cancer incidence in India. We analysed whole exome sequencing data from triple-negative breast cancer (TNBC) patients in the Mizo population to identify key and novel variants. Moreover, we analysed reported breast cancer-related genes and pathway alterations. Somatic mutation analysis revealed that TP53 was the most frequently mutated gene and TP53, CACNA1E, IGSF3, RYR1, and FAM155A as significantly mutated driver genes. Based on the ACMG guidelines, we identified a rare pathogenic germline variant of BRCA1 (p.C1697R) in 13% and a likely pathogenic frameshift insertion in RBMX (p.P106Ffs) in 73% of the patients. We also found that the ATM, STK11, and CDKN2A genes were significantly mutated in germline TNBC samples compared to healthy samples. Moreover, we identified novel somatic variants in CHEK2 (p.K182M) and NF1 (p.C245X), and novel germline variants RB1 (p.D111G), CDH1 (p.A10Gfs), CDKN2A (p.V96G), CDKN2A (p.S12Afs*22), MAP3K1 (CAAdelins0), MSH6 (p.L1226_L1230del), and PMS2 (TTCdelins0). Pathway analysis revealed that most somatic mutations were highly associated with PI3K-Akt signalling pathway and MAPK signalling pathways in TNBC. These findings identified novel variants and key genes contributing to disease development and progression. Further analysis of less studied genes, including RBMX, MRC1, ATM, CTNNB1, and CDKN2A, in TNBC may reveal new potential genes for targeted therapeutic strategies and contribute to clinical advancements in the treatment of TNBC.

A Decreased Appetite for Prophylactic Total Gastrectomy.

Total gastrectomy should be performed less often in germline CDH1 variant carriers based on mounting clinical evidence.

Germline CDH1 Variants and Lifetime Cancer Risk

Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants. To describe gastric and breast cancer risk estimates for individuals with CDH1 variants. Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022. Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years. A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%). Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.

CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype

Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation. To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers' tumor samples, and the association of genetic profiles with clinical-pathological data and survival. This single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers. Accurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis. Of 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03). In this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.

Points to consider regarding prophylactic total gastrectomy in germline CDH1 variant carriers.

Pathogenic germline CDH1 mutation confers high risk for developing diffuse gastric and lobular breast cancers in asymptomatic carriers. In these individuals, the estimated gastric cancer risk at 80 years of age is up to 70% for males and 56% for females. Due to this high-risk predisposition, prophylactic total gastrectomy is considered a unique life-saving approach in germline CDH1 carriers, as endoscopy often fails to detect early stage diffuse gastric carcinoma. However, surgical indication is controversial in some clinical contexts, with possible contraindications. This review discusses points against and in favor of a more aggressive surgical approach for consideration during the decision-making process.

OGBN P01 Outcomes of Prophylactic Total Gastrectomy in Germline CDH1 Mutation Carriers

Abstract Background Hereditary diffuse gastric cancer (HDGC) is predominantly attributed to CDH1 [E-Cadherin] germline mutation and carries a cumulative lifetime risk of diffuse gastric cancer (DGC) of up to 70%. Definitive treatment remains prophylactic total gastrectomy (PTG) with an attendant risk of morbidity and reduced quality of life. Endoscopic surveillance following the Cambridge protocol is an alternative for selected patients, however, the impact on disease stage and long-term gastric cancer prognosis is not established. This study aims to evaluate clinical and histopathological outcomes following PTG in patients with germline CDH1 mutations with or without prior surveillance at a national HDGC referral centre. Methods Retrospective review was performed of clinicopathological outcomes for germline CDH1 mutation carriers who underwent PTG at Addenbrooke’s Hospital between January 2006 and May 2023. Indication for surgery of clinical stage 1 tumours was guided by patient preference, multiple visible lesions and increasing number of signet ring cell (SRC) foci. Endoscopic surveillance was offered to cases with no concerning endoscopic lesion and low number of SRC foci. Patients with confirmed DGC (≥stage 2) at diagnosis were excluded. Standard PTG procedure was open TG with D1 lymphadenectomy and preservation of posterior vagus with D2 lymphadenectomy and truncal vagotomy in selected cases. Results 48 patients underwent open PTG with D1 (93.8%) or D2 (6.2%) lymphadenectomy. PTG was deferred in 18 patients (37.5%) with median of 3 pre-operative surveillance endoscopies over 22 months (5 to 61 months). Median post-operative length of stay was 7 days (6 to 12). Major morbidity was observed in 1 case (2.1%) with no post-operative mortalities. Final stage was pT1aN0M0 in 43 patients (89.6%) and pT0N0M0 in 5 patients (10.4%). No lymph node metastases were observed and complete gastric mucosal resection was achieved for all. The 5-year estimated overall and disease-specific survival were 100% with median follow-up of 7 years. Conclusions PTG remains a robust and effective treatment for patients with pathogenic germline CDH1 mutations who are appropriate surgical candidates. There was no increase in final stage following surveillance in a dedicated specialist service and this remains a safe alternative in selected cases. For patients choosing to proceed with PTG following comprehensive pre-operative counselling, this can be undertaken with low morbidity in a specialist centre. Further long-term data are needed to determine the impact of surgery and endoscopic surveillance on survival, functional outcomes and quality of life.

Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.

Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome. Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing. One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months. RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.

Investigation of pathogenic germline variants in gastric cancer and development of "GasCanBase" database.

Gastric cancer, which is also known as stomach cancer, can be influenced by both germline and somatic mutations. Non-synonymous Single Nucleotide Polymorphisms (nsSNPs) in germline have long been reported to play a pivotal role in cancer progression. The aim of this study is to examine the nsSNP in GC-associated genes. The study also aims to develop a database with extensive information regarding the nsSNPs in the GC-associated genes and their impacts. A total of 34,588 nsSNPs from 1,493,460 SNPs of the 40 genes were extracted from the available SNP database. Drug binding and energy minimization were examined by molecular docking and YASARA. To validate the existence of the germline CDH1 gene mutation (rs34466743) in the isolated blood DNA of gastric cancer (GC) patients, polymerase chain reaction (PCR) and DNA sequencing were performed. According to the results of the gene network analysis, 17 genes may interact with other types of cancer. A total of 11,363 nsSNPs were detected within the 40 GC genes. Among these, 474 nsSNPs were predicted to be damaging and 40 to be the most damaging. The SNPs in domain regions were thought to be strong candidates that alter protein functions. Our findings proposed that most of the selected nsSNPs were within the domains or motif regions. Free Energy Deviation calculationof protein structure pointed toward noteworthy changes in the structure of each protein that can demolish its natural function. Subsequently, drug binding confirmed the structural variation and the ineffectiveness of the drug against the mutant model in individuals with these germline variants. Furthermore, in vitro analysis of the rs34466743 germline variant from the CDH1 gene confirmed the strength and robustness of the pipeline that could expand the somatic alteration for causing cancer. In addition, a comprehensive gastric cancer polymorphism database named "GasCanBase" was developed to make data available to researchers. The findings of this study and the "GasCanBase" database may greatly contribute to our understanding of molecular epidemiology and the development of precise therapeutics for gastric cancer. GasCanBase is available at: https://www.gascanbase.com/.

Defining features of hereditary lobular breast cancer due to CDH1 with magnetic resonance imaging and tumor characteristics

Women with germline pathogenic variants in CDH1, which encodes E-cadherin protein, are at increased lifetime risk of invasive lobular carcinoma (ILC). The associated tumor characteristics of hereditary lobular breast carcinoma (HLBC) in this high-risk population are not well-known. A single-center prospective cohort study was conducted to determine the imaging and pathologic features of HLBC compared to population-based ILC using Surveillance, Epidemiology, and End Results (SEER) data. One hundred fifty-eight women with CDH1 variants were evaluated, of whom 48 (30%) also had an ILC diagnosis. The median age at CDH1 diagnosis was 45 years [interquartile range, IQR 34–57 years] whereas the median age at diagnosis of CDH1 with concomitant ILC (HLBC) was 53 [IQR 45–62] years. Among women with HLBC, 83% (40/48) were identified with CDH1 mutation after diagnosis of ILC. Among 76 women (48%, 76/158) undergoing surveillance for ILC with breast magnetic resonance imaging (MRI), 29% (22/76) had an abnormal MRI result with available biopsy data for comparison. MRI detected ILC in 7 out of 8 biopsy-confirmed cases, corresponding with high sensitivity (88%), specificity (75%), and negative predictive value (98%); however, false-positive and false-discovery rates were elevated also (25% and 68%, respectively). HLBC was most frequently diagnosed at age 40–49 years (44%, 21/48), significantly younger than the common age of diagnosis of ILC in SEER general population data (most frequent age range 60–69 years, 28%; p < 0.001). HLBC tumors were smaller than SEER-documented ILC tumors (median 1.40 vs. 2.00 cm; p = 0.002) and had a higher incidence of background lobular carcinoma in situ (88% vs. 1%; p < 0.001) as well as progesterone receptor positivity (95% vs. 81%, p = 0.032). These findings suggest that HLBC is often detected via conventional screening methods as an early-stage hormone receptor-positive tumor, thus the clinical benefit of intensive screening with MRI may be limited to a subset of women with germline CDH1 variants.

Factors associated with detection of hereditary diffuse gastric cancer on endoscopy in individuals with germline CDH1 mutations

Individuals with germline pathogenic CDH1 variants have a high risk of hereditary diffuse gastric cancer. The sensitivity of EGD in detecting signet ring cell carcinoma (SRCC) in this population is low. We aimed to identify endoscopic findings and biopsy practices associated with detection of SRCC. This retrospective cohort included individuals with a germline pathogenic/likely pathogenic CDH1 variant undergoing at least 1 EGD at Memorial Sloan Kettering Cancer Center between January 1, 2006, and March 25, 2022. The primary outcome was detection of SRCC on EGD. Findings on gastrectomy were also assessed. The study included periods before and after implementation of the Cambridge protocol for endoscopic surveillance, allowing for assessment of a spectrum of biopsy practices. Ninety-eight CDH1 patients underwent at least 1 EGD at our institution. SRCC was detected in 20 (20%) individuals on EGD overall and in 50 (86%) of the 58 patients undergoing gastrectomy. Most SRCC foci were detected in the gastric cardia/fundus (EGD, 50%; gastrectomy, 62%) and body/transition zone (EGD, 60%; gastrectomy, 62%). Biopsy results of gastric pale mucosal areas were associated with detection of SRCC (P< .01). The total number of biopsy samples taken on EGD was associated with increased detection of SRCC (P= .01), with 43% detected when≥40 samples were taken. Targeted biopsy sampling of gastric pale mucosal areas and increasing number of biopsy samples taken on EGD were associated with detection of SRCC. SRCC foci were mostly detected in the proximal stomach, supporting updated endoscopic surveillance guidelines. Further studies are needed to refine endoscopic protocols to improve SRCC detection in this high-risk population.

Controversies and strengths in prophylactic total gastrectomy for germline CDH1 pathogenic variant carriers.

aCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland bGastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA Received 15 March 2023 Accepted 15 March 2023. *Vivian E. Strong equally contributed to this article. Correspondence to Jeremy L. Davis, MD, 10 Center Drive, Rm 4-3742, Bethesda, MD 20892, USA Tel: +1 240 858 3731; e-mail: [email protected]

Cancer surveillance as an alternative to prophylactic total gastrectomy in hereditary diffuse gastric cancer: a prospective cohort study.

Loss of function variants in CDH1 are the most frequent cause of hereditary diffuse gastric cancer. Endoscopy is regarded as insufficient for early detection due to the infiltrative phenotype of diffuse-type cancers. Microscopic foci of invasive signet ring cells are pathognomonic of CDH1 and precede development of diffuse gastric cancer. We aimed to assess the safety and effectiveness of endoscopy for cancer interception in individuals with germline CDH1 variants, particularly in those who declined prophylactic total gastrectomy. In this prospective cohort study, we included asymptomatic patients aged 2 years or older with pathogenic or likely pathogenic germline CDH1 variants who underwent endoscopic screening and surveillance at the National Institutes of Health (Bethesda, MD, USA) as part of a natural history study of hereditary gastric cancers (NCT03030404). Endoscopy was done with non-targeted biopsies and one or more targeted biopsy and assessment of focal lesions. Endoscopy findings, pathological data, personal and family cancer history, and demographics were recorded. Procedural morbidity, gastric cancer detection by endoscopy and gastrectomy, and cancer-specific events were assessed. Screening was defined as the initial endoscopy and all subsequent endoscopies were considered surveillance; follow-up endoscopy was at 6 to 12 months. The primary aim was to determine effectiveness of endoscopic surveillance for detection of gastric signet ring cell carcinoma. Between Jan 25, 2017, and Dec 12, 2021, 270 patients (median age 46·6 years [IQR 36·5-59·8], 173 [64%] female participants, 97 [36%] male participants; 250 [93%] were non-Hispanic White, eight [3%] were multiracial, four [2%] were non-Hispanic Black, three [1%] were Hispanic, two [1%] were Asian, and one [<1%] was American Indian or Alaskan Native) with germline CDH1 variants were screened, in whom 467 endoscopies were done as of data cutoff (April 30, 2022). 213 (79%) of 270 patients had a family history of gastric cancer, and 176 (65%) reported a family history of breast cancer. Median follow-up was 31·1 months (IQR 17·1-42·1). 38 803 total gastric biopsy samples were obtained, of which 1163 (3%) were positive for invasive signet ring cell carcinoma. Signet ring cell carcinoma was detected in 76 (63%) of 120 patients who had two or more surveillance endoscopies, of whom 74 had occult cancer detected; the remaining two individuals developed focal ulcerations each corresponding to pT3N0 stage carcinoma. 98 (36%) of 270 patients proceeded to prophylactic total gastrectomy. Among patients who had a prophylactic total gastrectomy after an endoscopy with biopsy samples negative for cancer (42 [43%] of 98), multifocal stage IA gastric carcinoma was detected in 39 (93%). Two (1%) participants died during follow-up, one due to metastatic lobular breast cancer and the other due to underlying cerebrovascular disease, and no participants were diagnosed with advanced stage (III or IV) cancer during follow-up. In our cohort, endoscopic cancer surveillance was an acceptable alternative to surgery in individuals with CDH1 variants who declined total gastrectomy. The low rate of incident tumours (>T1a) suggests that surveillance might be a rational alternative to surgery in individuals with CDH1 variants. Intramural Research Program, National Institutes of Health.

Micronutrient Supplementation and Bone Health After Prophylactic Total Gastrectomy in Patients With CDH1 Variants.

Patients with germline variants in CDH1 who undergo prophylactic total gastrectomy (TG) are at risk of altered nutrient and drug absorption due to modified gastrointestinal anatomy. Bone mineral density loss and micronutrient deficiencies have not been described previously in this patient population. In this study we included 94 patients with germline CDH1 variants who underwent prophylactic TG between October 2017 and February 2022. We examined pre- and post-gastrectomy bone mineral density (BMD); serum biomarkers including calcium, phosphorus, alkaline phosphatase, and 25 (OH)-vitamin D; and postoperative adherence to calcium and multivitamin supplementation. Almost all patients (92/94, 98%) lost a substantial amount of weight post-TG, with an average weight loss of 26.5% at 12 months post-surgery. Serum biomarkers of mineral metabolism, namely calcium and phosphorus, did not change significantly after TG. However, average BMD was decreased in all patients at 12 months post-TG. Nonadherence to calcium supplementation was associated with a decrease in BMD. Nonadherence to multivitamin supplementation was associated with greater percent BMD loss in the femoral neck and total hip. Appropriate micronutrient supplementation and nutritional counseling pre- and postoperatively in patients undergoing prophylactic TG are important to mitigate the long-term effects of gastrectomy on bone health.

The Gastric Cancer Registry Genome Explorer: A tool for genomic discovery.

434 Background: The Gastric Cancer Registry (GCR) collects clinical questionnaire data and biospecimens from gastric cancer (GC) patients and individuals at high risk for GC (through family history of GC or a germline CDH1 mutation). Its purpose is to facilitate research into better detection and treatment strategies for GC. In 2020, the GCR Genome Explorer (GCR-GE), a publicly accessible and interactive database of clinical and genomic data, was launched to meet this goal. Methods: We generated genomic datasets from participants when GC status and archival gastric tumor tissue were available. We processed the tumor tissue (and paired normal tissue when possible) for whole genome, whole exome, and bulk RNA sequencing. The following genomic features were identified: copy number variations, gene mutations, gene expression, microbiome composition, estimation of tumor-infiltrating immune cells, and tumor neoantigens. We populated (1) all genomic alterations identified from GCR sequencing data, and (2) demographic and pathologic data regarding the tumor that were compiled from participant questionnaires and medical records into the GCR-GE. In addition, sequencing files from the Cancer Genome Atlas (TCGA) were similarly analyzed and uploaded as external datasets. Features of the GCR-GE include cross-study comparisons, study summaries, and queries down to the individual gene, neoantigen, and patient level. Results: In total, 243 GC patients donated tumor samples. The new GCR-GE release contains genomic datasets for 214 of these tumors, as well as datasets for 443 gastric tumors and 185 esophageal tumors from TCGA. Data generation was possible thanks to 756 subjects who enrolled in the GCR from 2011-2022. Most subjects were diagnosed with GC only (N=487), but interestingly, some met multiple criteria. For instance, 10 GC patients had a family history; 10 had a germline CDH1 mutation; and 21 patients had GC, a family history, and a germline CDH1 mutation. Efforts to upload additional datasets are ongoing. All data in the GCR-GE is downloadable. Conclusions: The GCR-GE is a comprehensive resource of genomic and clinical data. Given its accessibility, ease of use, and large cohort sizes, the GCR-GE presents a highly valuable tool for accelerating GC research.

Transversal Perspectives of Integrative Oncology Care in Gastric and Lobular Breast Cancer.

The occurrence of gastric cancer has been associated with an increased risk of lobular breast tumors in a subset of patients harboring selected germline mutations. Among all, the germline alteration of the gene coding for E-Cadherin (CDH1) was associated with an increased risk of gastric cancer diffuse-histotype and lobular breast cancer. However, the risk assessment of breast neoplasms and the role of multiple prophylactic procedures in these patients has never been systematically addressed. In addition, the performance of the common screening procedures for lobular breast cancer like mammography is suboptimal. Therefore, recalling the need for a better articulation of the patient-centered strategies of surveillance for individuals with germline CDH1 and other similar alterations, to offer comprehensive approaches for prevention, early diagnosis, and treatment. Accordingly, this chapter aims to discuss the value and the role of integrated oncological care in the era of oncology sub-specializations. Additionally, it sheds light on how the harmonization across the health providers can enhance patient care in this setting.

Association of CDH1 Germline Variants and Colon Polyp Phenotypes in Patients with Hereditary Diffuse Gastric Cancer.

Germline CDH1 variants resulting in E-cadherin loss of function result in an increased risk of diffuse type gastric cancer and lobular type breast cancer. However, the risk of developing other epithelial neoplasms, specifically colorectal cancer, is unknown. Patients enrolled in a prospective natural history study of hereditary gastric cancer who underwent at least one colonoscopy were evaluated. Out of 300 patients with CDH1 pathogenic or likely pathogenic variants, 85 underwent colonoscopy. More than half of patients (56%, 48/85) had at least one colorectal polyp. Most of those patients (83%, 40/48) had at least one precancerous polyp (adenoma or sessile serrated lesion). More than half (56%) of patients younger than age 45 had a colorectal polyp. Of those with polyps, the most frequent CDH1 variant type was canonical splice site (27%, 13/48) followed by nonsense (21%, 10/48). There was no association between CDH1 variant type and increased likelihood of colorectal polyps. In summary, a majority of CDH1 variant carriers who underwent colonoscopy had colorectal polyps detected, and most subjects were less than 45 years old. This study of colorectal cancer risk based on the prevalence of colorectal polyps in the CDH1 population requires further investigation to appropriately counsel patients on colorectal cancer screening. Clinical trial registry website: https://clinicaltrials.gov/. Clinical trial number: NCT03030404.

Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines

BackgroundGermline pathogenic variants in CDH1 are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation...

Frequent cleft lip and palate in families with pathogenic germline CDH1 variants.

Pathogenic and likely pathogenic (P/LP) germline variants in the tumor suppressor gene CDH1 (E-cadherin) result in increased lifetime risk of diffuse-type gastric cancer and lobular breast cancer. CDH1 variants are also associated with hereditary cleft lip and palate (CLP), the mechanism of which is not well understood. We sought to determine the prevalence of CLP in families who carry P/LP CDH1 variants. Patients with P/LP CDH1 variants who were enrolled in a prospective clinical trial were reviewed (NCT03030404). The cohort included 299 individuals from 153 families that had 80 unique P/LP variants in CDH1. The rate of CLP was 19% (29/153) in families reporting CLP in at least one family member, and 2.7% (8/299) among individuals with confirmed germline CDH1 P/LP variants. There were 22 unique variants in CDH1 among the 29 families that reported CLP, or a CLP rate of 27.5% per variant (22/80). 10 of the variants were not previously reported to be associated with CLP. We observed that 24% (7/29) of CLP-associated gene variants involved large-scale (≥1 exon) deletions. Among families with CLP, 69% (20/29) had a member diagnosed with gastric cancer, and 79% (23/29) had a member with breast cancer, which were similar to rates observed in non-CLP families (p >0.3 for both). Our analysis suggests that the prevalence of CLP in families with germline CDH1 P/LP variants was high in this large cohort, and there was no genotype-phenotype pattern. Genetic testing for CDH1 variants should be considered in families with CLP and history of either diffuse-type gastric or lobular breast cancer.

CDH1 mutations recurrence and global clustering in genetically tested families with hereditary diffuse gastric cancer syndrome: results from a systematic study.

The global distribution of germline CDH1 mutations in hereditary diffuse gastric cancer families, is highly heterogenous. The aim of this study was to determine if there is any geographic clustering of CDH1 mutations in families with the hereditary diffuse gastric cancer syndrome. Data from 1998 to 2021 were collected systematically according to the PRISMA guidelines. 571 germline CDH1 mutations were recorded worldwide, with 387 (67.8%) of them reported in 108 families. The largest clusters of CDH1 mutations were identified in central Europe, north America, northern Europe, New Zealand (Māori), and south America. A high penetrance risk for GC development was observed for c.1008G > T in New Zealand (Māori), c.1565 + 2insT in northern Europe, c.1901C > T in Portugal, and c.1003C > T in the USA. Our observations are consistent with a specific local clustering of some recurrent CDH1 mutations within specific countries.