Hereditary Diffuse Gastric Cancer Research Articles

Hereditary breast cancer: syndromes, tumour pathology and molecular testing.

Hereditary factors account for a significant proportion of breast cancer risk. Approximately 20% of hereditary breast cancers are attributable to pathogenic variants in the highly penetrant BRCA1 and BRCA2 genes. A proportion of the genetic risk is also explained by pathogenic variants in other breast cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C, RAD51D and BARD1, as well as genes associated with breast cancer predisposition syndromes - TP53 (Li-Fraumeni syndrome), PTEN (Cowden syndrome), CDH1 (hereditary diffuse gastric cancer), STK11 (Peutz-Jeghers syndrome) and NF1 (neurofibromatosis type 1). Polygenic risk, the cumulative risk from carrying multiple low-penetrance breast cancer susceptibility alleles, is also a well-recognised contributor to risk. This review provides an overview of the established breast cancer susceptibility genes as well as breast cancer predisposition syndromes, highlights distinct genotype-phenotype correlations associated with germline mutation status and discusses molecular testing and therapeutic implications in the context of hereditary breast cancer.

The Identification of Large Rearrangements Involving Intron 2 of the CDH1 Gene in BRCA1/2 Negative and Breast Cancer Susceptibility

E-cadherin, a CDH1 gene product, is a calcium-dependent cell-cell adhesion molecule playing a critical role in the establishment of epithelial architecture, maintenance of cell polarity, and differentiation. Germline pathogenic variants in the CDH1 gene are associated with hereditary diffuse gastric cancer (HDGC), and large rearrangements in the CDH1 gene are now being reported as well. Because CDH1 pathogenic variants could be associated with breast cancer (BC) susceptibility, CDH1 rearrangements could also impact it. The aim of our study is to identify rearrangements in the CDH1 gene in 148 BC cases with no BRCA1 and BRCA2 pathogenic variants. To do so, a zoom-in CGH array, covering the exonic, intronic, and flanking regions of the CDH1 gene, was used to screen our cohort. Intron 2 of the CDH1 gene was specifically targeted because it is largely reported to include several regulatory regions. As results, we detected one large rearrangement causing a premature stop in exon 3 of the CDH1 gene in a proband with a bilateral lobular breast carcinoma and a gastric carcinoma (GC). Two large rearrangements in the intron 2, a deletion and a duplication, were also reported only with BC cases without any familial history of GC. No germline rearrangements in the CDH1 coding region were detected in those families without GC and with a broad range of BC susceptibility. This study confirms the diversity of large rearrangements in the CDH1 gene. The rearrangements identified in intron 2 highlight the putative role of this intron in CDH1 regulation and alternative transcripts. Recurrent duplication copy number variations (CNV) are found in this region, and the deletion encompasses an alternative CDH1 transcript. Screening for large rearrangements in the CDH1 gene could be important for genetic testing of BC.

Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes

Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype-phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66-57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18-29·39], p=0·0017) and gastric cancer (7·81 [2·03-29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.

S3703 A Case of Hereditary Diffuse Gastric Cancer

Introduction: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant disorder associated with pathogenic germline variants in the cadherin 1 (CDH1) or alpha-1 catenin (CTNNA1) genes. Carriers have an 80% risk of developing stomach cancer, at an average age of 38, and 60% lifetime risk of developing lobular breast cancer. This is a case of a middle-aged female diagnosed with CDH1+ HDGC. Case Description/Methods: An asymptomatic 50-year-old Bangladeshi female presented for surveillance colonoscopy given a strong family history of colon cancer in three siblings, mother and uncle and stomach cancer in her mother. She had a normal upper endoscopy three years earlier for indication of heartburn. She proceeded with colonoscopy which showed two tubular adenomas measuring 7-8 mm. Due to concern of a hereditary syndrome, she was referred to a genetics counselor and an Ambry Colonext Panel with RNA Analysis was conducted. Results were positive for pathogenic heterozygous c.1137G >A mutation in the CDH1 gene raising concern for HDGC. At the time, she opted for surveillance instead of prophylactic gastrectomy. A follow up upper endoscopy showed a few, minute pale regions on close inspection, but no masses, ulcerations or other features suggestive of malignancy. Per Cambridge protocol, 34 biopsies were collected and one gastric body biopsy returned positive for gastric adenocarcinoma with signet ring cell features and weak E-Cadherin expression. Cross sectional imaging was negative for metastatic disease. She met with oncology and surgery teams and underwent laparotomy with total gastrectomy and Roux-en-Y esophagojejunostomy. Gastrectomy biopsy confirmed a single microscopic focus of diffuse adenocarcinoma. Discussion: Diagnosis of HDGC-associated signet ring cancers is especially difficult because they are only visible on direct mucosal evaluation late in the disease process. Genetic testing is recommended for those meeting family or individual criteria. Prophylactic gastrectomy, as early as age 20, is recommended for pathogenic mutation carriers with an appropriate pedigree. Those denying surgery can be offered annual endoscopy with the understanding that frequent surveillance has not been proven to be effective in early gastric cancer detection in HDGC. During endoscopy, any visible lesion should be biopsied and a minimum of 30 biopsies are recommended to include all five anatomic gastric zones. H. pylori should be screened for and treated. Referral to a breast surgeon is also recommended.

S3700 Role of Immunotherapy in the Treatment of Recurrent Hereditary Diffuse Gastric Cancer

Introduction: Gastric cancer is the third leading cause of cancer related deaths worldwide. Majority of cases are sporadic although 10% demonstrate familial clustering, of which 1-3% arise from inherited cancer syndromes. Hereditary diffuse gastric cancer is a rare cancer caused by CDH1 genetic mutation, inherited in an autosomal dominant fashion. Immunotherapy has been shown to increase overall response rates in gastrointestinal cancers especially in those subgroups with DNA mismatch repair-deficient or microsatellite-instable tumors. We herein, present a case of recurrent hereditary diffuse gastric cancer with good response to chemoimmunotherapy. Case Description/Methods: This is a 41-year-old asian female with past medical history of stage IIB signet ring type gastric cancer diagnosed 12 years ago, status post subtotal gastrectomy with a block transverse colectomy followed by concurrent chemoradiation, who presented with disease recurrence after 10 years, when she was treated with neoadjuvant 5-fluorouracil based chemotherapy followed by surgical resection and adjuvant chemotherapy. Her genetic screening showed CDH1 mutation, with high risk for breast and gastric cancers. She was monitored closely with regular breast magnetic resonance imaging (MRI) and esophagogastroduodenoscopy (EGD). During one of her regular endoscopy assessments recently, she was found to have erythema of her gastric mucosa which upon biopsy confirmed recurrence of her poorly differentiated adenocarcinoma, diffuse type with signet ring features. She underwent treatment with oxaliplatin based chemotherapy combined with Nivolumab for six cycles. She responded well to chemoimmunotherapy as evidenced by positron emission tomography and computed tomography (PET CT) scan and esophagogastroduodenoscopy (EGD). She is awaiting surgical resection followed by adjuvant therapy with chemotherapy either alone or in combination with immunotherapy. Discussion: Gastrectomy and chemotherapy are the mainstay treatments for hereditary diffuse gastric cancer. Nivolumab has been shown to be effective in heavily pretreated gastric cancers. The combination therapy of nivolumab plus chemotherapy achieved a clinically meaningful overall survival benefit in the first line setting in all advanced gastric adenocarcinoma. Clinical trials and research encompassing antibody treatments, such as targeted anti-PD1 antibodies, are ongoing and could offer additional treatment options in patients with advanced gastric cancer.

Short and long-term outcomes of prophylactic total gastrectomy in 54 consecutive individuals with germline pathogenic mutations in the CDH1 gene.

Germline mutation of CDH1 is rare and leads to hereditary diffuse gastric cancer (DGC). Patients (pts) with CDH1 mutation who underwent multidisciplinary counseling followed by open prophylactic total gastrectomy (PTG) by a single surgeon were reviewed. Fifty-four pts with a median age of 41 years (16-70 years) underwent PTG between 2006 and 2021. Median operative time was 161 min, and median hospital stay was 7 days (range 6-12). There were 5 complications (9.2%) within 30 days, and two complications (pulmonary embolism and pancreatitis) required readmission. There were no anastomotic leaks. The pathologic analysis of the first 10 pts included the entire gastric mucosa, revealing a median of 15 foci of DGC (range 5-136). The subsequent 44 pts with more limited analysis had a median of 2 foci (range 0-5), and two pts (3.7%) had no foci identified. Median maximum weight loss was 19%. In long-term follow-up (median 4.6 years) of 20 pts, median global QOL was 2.0 (very good), the majority had persistent difficulty with certain foods or liquids, and all stated they would again elect PTG over surveillance endoscopy. PTG can be performed safely at high-volume referral centers with very good QOL but nutritional sequelae persist.

Attitudes toward preimplantation genetic testing and quality of life among individuals with hereditary diffuse gastric cancer syndrome

BackgroundHereditary Diffuse Gastric Cancer (HDGC) syndrome is an autosomal dominant hereditary cancer predisposition associated with germline pathogenic/likely pathogenic variants in the CDH1 gene. Identifying early stage HDGC is difficult, and prophylactic measures can be effective in preventing incidence. Preimplantation Genetic Testing (PGT) can provide information about CDH1 variant status, HDGC risk, and limit familial transmission of CDH1 variants. To date, however, little is known about the attitudes of individuals with CDH1 variants towards PGT.MethodsGiven that little is known about the reproductive attitudes of individuals with HDGC, we recruited participants with CDH1 variants from a familial gastric cancer registry and administered a cross-sectional survey with open- and closed-ended response items. We assessed attitudes regarding PGT and the effect of HDGC on quality of life.ResultsParticipants (n = 21) were predominantly partnered (61.9%), had a personal cancer history (71.4%), and had biological children (71.4%). Interest in learning about PGT was high; 66.7% of participants were interested in PGT and 90.5% approved of healthcare providers discussing PGT with individuals with CDH1 variants. Attitudes regarding personal use were varied. Among all participants, 35% would not, 25% were uncertain, and 40% would use PGT. Personal philosophy and preferences for family and reproduction were key factors related to PGT attitudes. HDGC had moderate effects on participants’ quality of life, including social relationships, health behaviors, and emotional experiences including worry about cancer risk and guilt regarding familial implications.ConclusionPGT was identified by participants as acceptable for use in a variety of contexts and benefits of reproductive counseling involving PGT may extend beyond CDH1 carriers to family members’ reproductive behaviors. Dispositions towards PGT are governed by personal philosophy or belief systems. These findings can help guide providers counseling individuals with CDH1 variants.

First estimates of diffuse gastric cancer risks for carriers of CTNNA1 germline pathogenic variants

BackgroundPathogenic variants (PV) of CTNNA1 are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study...

Current scenario of Gastric cancer (GC): A systematic review

Gastric cancer (GC) is amongst the most difficult cancers to treat and, hence, has to be studied from the roots to be properly analysed. The disease starts as precancerous lesions which have to be observed. This includes dysplasia, atrophic gastritis and intestinal metaplasia. This is effective for detecting the prognosis of GC so that it can be resolved in early stages. This is dependent on a variety of risk factors which include blood type, gender, age, geography, gene polymorphisms, acid secretion, pernicious anemia, oxidative damage, previous gastric surgery, etc. Probably the most important, however, is infection by H. Pylori. With respect to virulence factors and host factors, both are significant players in the development of several cases of malignancies. Other genetic factors and lifestyle choices including alcohol use, tobacco usage and obesity, will also be analysed. There are also several genetic conditions that cause high risk of development into a malignancy including Menetrier’s disease, hereditary diffuse GC, Lynch syndrome, Peutz-Jeghers syndrome, Li Fraumani syndrome etc. Several diagnostic procedures such as lab tests, physical examinations and biopsy are used. The current review analysed the factors which are involved in the prognosis and causative agents in the development of GC. This is to better understand how GC can be diagnosed and confirmed. This may include molecular testing, including genes, which can be of high risk followed by modern treatment methods discussing surgery, chemotherapy, immunotherapy and radiotherapy. Chemotherapy includes discussion of several drugs and how they target the malignancy in question. By understanding the disease in detail, through causes, prognosis, detection and treatment, we can go one step closer to find the cure for GC.

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.

Frequency of Positive Familial Criteria in Patients with Adenocarcinoma of the Esophageal-Gastric Junction and Stomach: First Prospective Data in a Caucasian Cohort.

Simple SummaryIt is well known for gastric cancer patients with subtype of diffuse histology that a proportion of patients harbour an increased familial risk. Some patients and relatives even may be detected through a genetic testing. More precise studies about the frequency of hereditary criteria in a poplation with only European ancestries for adenocarcinoma of the esophagogastric junction and stomach are missing. In current guidelines regarding genetic testing criteria not all types of stomach cancer are considered as for example patients not with subtype of diffuse histology mostly have no detectable responsible gene. The aim of the current study was to register stomach cancer patients of all different types in a certain region (Berlin, Germany) and to estimate the frequency of positive familial criteria. Patients with esophageal cancer served as comparison group as familial or hereditary background, respectively, is not significant in these patients according to current knowledge. In our study, we identified positive familial criteria in about 15% of stomach cancer patients. In regard to all different types of stomach cancer, this number almost doubled. Furthermore, one third of all registered patients in this study might have a familial or hereditary background of their disease. We therefore conclude that guidelines regarding genetic testing criteria and screening examinations should be adjusted in future.Objectives: Current prospective studies investigating the frequency of hereditary criteria in a Caucasian population for adenocarcinoma of the esophagogastric junction (AEG) and stomach (GC) are missing. Genetic testing criteria (screening criteria) for hereditary diffuse gastric cancer (HDGC) were updated in 2020, but do not address patients with intestinal histology (familial intestinal gastric cancer FIGC). Thus, we prospectively screened patients residing in Berlin newly diagnosed with AEG or GC for hereditary criteria to gain insights into the frequency of HDGC. Methods: Prospective documentation of familial/clinical parameters in patients residing in Berlin with AEG or GC over three years was conducted. Besides HDGC criteria from 2015 and revised 2020, we also documented patients fulfilling these criteria but with intestinal type gastric cancer (FIGC). Statistical analysis was performed using X2-test. Results: One hundred fifty-three patients were finally included (92 GC; male: 50 (n.s.); 61 AEG; male: 47; p = 0.007). Hereditary criteria for HDGC were detected in 9/92 (9.8%) (2015 criteria) and in 14/92 (15.2%) (2020 criteria) of GC patients (AEG: 2015 criteria 3/61 (4.9%) versus 4/61 according to 2020 criteria (6.5%)). Patients fulfilling hereditary criteria but with intestinal histology (FIGC) increased from 8.7% (2015) to 14.1%, respectively (2020) (AEG: 3.2% (2015) versus 6.6% (2020)). Hereditary criteria including intestinal histology were found in 29.3% (GC) and 13.1% (AEG) (p = 0.03) according to the 2020 criteria. Conclusions: HDGC criteria were found in 15.2% of GC patients according to the 2020 criteria. Percentage increased to 29.3% including patients with intestinal histology among the GC group, and was 13.1% in cases with AEG. These data indicate that family history seems to be of utmost importance in GC to further detect potential hereditary genetic risks. This equally applies for patients with intestinal subtype GC.

Becoming and being a parent with an inherited predisposition to diffuse gastric cancer: A qualitative study of young adults with a CDH1 pathogenic variant

Purpose This study explored the experiences of young people with hereditary diffuse gastric cancer (HDGC), an inherited cancer predisposition syndrome, as they navigate becoming and being a parent. Design We used interpretive description and conducted semi-structured interviews with 13 young Australians (18–39 years) with a CDH1 pathogenic variant (PV). Data were analyzed using team-based, reflexive thematic analysis. Findings Participants’ reproductive decisions centered on the perceived manageability of HDGC, namely via gastrectomy, and timing of their genetic testing. Participants yet to have children and those with challenging gastrectomy experiences favored using reproductive technologies to prevent passing on their PV. Parents who had children before genetic testing described complicated decisions about having more children. Gastrectomy was considered a parental responsibility but recovery diminished parenting abilities. Conclusion Young people with HDGC face unique challenges navigating reproductive decision-making and parenting with gastrectomy. Findings lend credence to calls for longitudinal, developmentally sensitive genetic counseling services.

Hereditary Diffuse Gastric Cancer: Molecular Genetics, Biological Mechanisms and Current Therapeutic Approaches.

Hereditary diffuse gastric cancer is an autosomal dominant syndrome characterized by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is caused by inactivating mutations in the tumor suppressor gene CDH1. Genetic testing technologies have become more efficient over the years, also enabling the discovery of other susceptibility genes for gastric cancer, such as CTNNA1 among the most important genes. The diagnosis of pathogenic variant carriers with an increased risk of developing gastric cancer is a selection process involving a multidisciplinary team. To achieve optimal long-term results, it requires shared decision-making in risk management. In this review, we present a synopsis of the molecular changes and current therapeutic approaches in HDGC based on the current literature.

International Delphi consensus guidelines for follow-up after prophylactic total gastrectomy: the Life after Prophylactic Total Gastrectomy (LAP-TG) study.

Prophylactic total gastrectomy (PTG) remains the only means of preventing gastric cancer for people with genetic mutations predisposing to Hereditary Diffuse Gastric Cancer (HDGC), mainly in the CDH1 gene. The small but growing cohort of people undergoing PTG at a young age are expected to have a life-expectancy close to the general population, however, knowledge of the long-term effects of, and monitoring requirements after, PTG is limited. This study aims to define the standard of care for follow-up after PTG. Through a combination of literature review and two-round Delphi consensus of major HDGC/PTG units and physicians, and patient advocates, we produced a set of recommendations for follow-up after PTG. There were 42 first round, and 62 second round, responses from clinicians, allied health professionals and patient advocates. The guidelines include recommendations for timing of assessments and specialties involved in providing follow-up, micronutrient supplementation and monitoring, bone health and the provision of written information. While the evidence supporting the guidelines is limited, expert consensus provides a framework to best manage people following PTG, and could support the collection of information on the long-term effects of PTG.

Hereditary diffuse gastric cancer syndrome: medical genetic consulting, treatment strategy for family members, prophylactic total gastrectomy, and endoscopic surveillance in CDH1- and CTNNA1-mutation carriers

The purpose of the study was to summarize available data on genetic counseling for people with hereditary diffuse gastric cancer (HDGC) syndrome, treatment strategies for family members with HDGC, prophylactic gastrectomy (PGE), and surveillance of CDH1 and CTNNA1 mutation carriers. Material and methods. A literature search was conducted using Web of Science, Scopus, MedLine, Cochrane Library, and RSCI databases. Results. HDGC syndrome is an inherited genetic syndrome that leads to the increased risk for both diffuse gastric cancer (DGC) and lobular breast cancer (LBC). About 1 to 3% of all gastric cancer cases are HDGCs. A high frequency of CDH1 gene mutation was frst identifed by P. Guilford et al. in 1998 in 3 Maori families from New Zealand. The cumulative risk for HDGC in CDH1 mutation carriers is 42 to 70% for men and 33-56% for women at the age of 80 years. Due to the rarity of the disease, the main publications dealing with this problem are clinical case descriptions. Conclusion. Multicenter clinical trials are required to improve screening and management of HDGC syndrome.

Abstract 5899: CDH1 and CTNNA1 variants with incomplete penetrance in hereditary gastric cancer Chilean families

Abstract The purpose of this study is to describe two Chilean families having Hereditary Gastric Cancer (GC). Both families present variants of uncertain significance (VUS), that could be pathogenic, but show incomplete penetrance. GC is the leading cause of cancer-related death in Chile. Worldwide, about ten percent of gastric cancer have a familial aggregation and in Hereditary Diffuse Gastric Cancer (HDGC), E-Cadherine 1 gene (CDH1) and alpha-E-catenin gene (CTNNA1) are the most commonly mutated genes. To our knowledge, only one HDGC Chilean family with a pathogenic CDH1 mutation has been reported, suggesting a low frequency of CDH1 mutations in this population. The index patient of the first family had a diffuse GC at age 59-y. His father and paternal grandfather also died of GC. A CDH1 germline variant c.88C>A in (p.Pro30Thr, rs139866691) was found previously in the index patient by Sanger sequencing. Variant genotyping in available family members showed that two non-affected sisters were carriers. In the second family, there were eleven members affected with GC and two with breast cancer. The index patient was diagnosed with a tubular/intestinal gastric tumor at 51y of age and had a brother who died of GC at 38y. Cancer gene panel sequencing was performed in index patient DNA and cascade genotyping in family members was performed using Kompetitive allele-specific PCR. A germline variant c.293G>A (p.R98Q, rs746832629) in the CTNNA1 gene was found in the index patient. We searched the variant in other members of the family and carried out a co-segregation analysis, that indicates an incomplete penetrance of the variant because two non-affected brothers do have it. Additionally, one affected sister did not carry the variant, but her tumor sample´s histology is papillary, the most frequent type in sporadic CG and her age of onset was 60-y. Both rs139866691 and rs746832629 are located in conserved structures of their coding proteins. rs139866691 maps to a conserved loop in the E-Cadherin 1 preprotein domain and rs746832629 maps to the first alpha-helix of alpha-E-catenin corresponding to the beta-catenin binding domain. Based on our data, we believe that both variants are likely pathogenic and causative of the hereditary GC observed in these families but show incomplete penetrance. To search for additional candidate pathogenic variants, we recently completed whole-exome sequencing in the index cases from the two available affected cases of the second family and we found other candidate genes reported in breast cancer and related with nitroso compound metabolism. We are searching for the second hit in the second family index patient´s tumor sample and performing isogenic models and functional analysis of rs139866691 and rs746832629 to clarify their pathogenicity. Citation Format: Graciela Molina, Carol Parra, Nicole B Halmai, Ana P Estrada, Alma Poceros, Paul Lott, Rasika Venkatesh, Enrique Norero, Osvaldo Torres, Alejandro Corvalán, Luis Carvajal-Carmona. CDH1 and CTNNA1 variants with incomplete penetrance in hereditary gastric cancer Chilean families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5899.

Chromoendoscopy in Combination with Random Biopsies for Patients with Pathogenic CDH1 Mutations Undergoing Endoscopic Surveillance.

Germline mutations in the CDH1-gene are identified as the cause of 30-40% of cases of hereditary diffuse gastric cancer, an autosomal-dominant inherited cancer predisposition syndrome. Given this high risk of developing diffuse gastric cancer, carriers of a pathogenic CDH1 germline mutation are advised to undergo prophylactic gastrectomy. For patients preferring conservative management, endoscopic surveillance is recommended. The detection of diffuse gastric cancer using white light endoscopy, however, remains challenging. Patients with pathogenic CDH1 mutation underwent (chromo)endoscopic surveillance or endoscopy prior to surgery. Biopsies were taken at suspicious sites identified by chromoendoscopy. In addition, endoscopically normal areas were assessed with mapping biopsies. Detection rates from endoscopic biopsies (mapping vs. targeted) and gastrectomy specimen were then compared. Between 11/2015 and 12/2020, ten patients from four families with a known CDH1 germline mutation had a total of n = 24 endoscopies with n = 518 total biopsies being examined. Three patients were diagnosed with GC during the study period. These patients all had suspicious chromoendoscopic lesions (= detection rate 100%). In two of three patients who had suspicious chromoendoscopic lesions, signet cell carcinoma was also detected in mapping biopsies and multiple additional cancer foci were identified in the gastrectomy specimen. Chromoendoscopy facilitated detection of gastric carcinoma foci in CDH1 mutation carriers. Chromoendoscopy identified all patients with gastric cancer, but not all cancer foci present in these patients. We conclude that for patients opting against prophylactic total gastrectomy, the addition of chromoendoscopy to white light could be used to enhance diagnostic reliability of endoscopic surveillance.

\u201cI have always lived with the disease in the family\u201d: family adaptation to hereditary cancer-risk

BackgroundHereditary cancer syndromes have been conceptualized as a family level process. The present study explores the complexity and challenges of family adaptation to the hereditary cancer syndrome, in the context of genetic counseling and long-term cancer risk management and follow-up surveillance.MethodsWe performed semi-structured interviews with 13 participants with one of the following hereditary cancer syndromes: Lynch Syndrome, Hereditary Diffuse Gastric Cancer Syndrome, Hereditary Breast and Ovarian Cancer Syndrome, or Familial Adenomatous Polyposis. The interview was developed through a participatory approach with the involvement of healthcare professionals and individuals with first-hand experience of living with the hereditary cancer syndromes.ResultsThe family is the main source of information and emotional support to deal with hereditary cancer syndromes. Multiple individual adaptation processes and communal coping networks interact, influencing the emotional and health-related behavior of family members. This is affected and affects the family’s communication and its’ members reactions to disclosure, with consequent changes in relationships.ConclusionsThe systemic interdependent dynamics of family adaptation calls for family-centered care of genetic cancer syndromes.

Hereditary Gynecologic Cancer Syndromes - A Narrative Review.

Hereditary cancer syndromes are defined as syndromes, where the genetics of cancer are the result of low penetrant polymorphisms or of a single gene disorder inherited in a mendelian fashion. During the last decade, compelling evidence has accumulated that approximately 5–10% of all cancers could be attributed to hereditary cancer syndromes. A tremendous progress has been made over the last decade in the evaluation and management of these syndromes. However, hereditary syndromes associated with gynecologic malignancies still present significant challenge for oncogynecologists. Oncogynecologists tend to pay more attention to staging, histological type and treatment options of gynecological cancers than thinking of inherited cancers and taking a detailed family history. Moreover, physicians should also be familiar with screening strategies in patients with inherited gynecological cancers. Lynch syndrome and hereditary breast-ovarian cancer syndrome are the most common and widely discussed syndromes in medical literature. The aim of the present review article is to delineate and emphasize the majority of hereditary gynecological cancer syndromes, even these, which are rarely reported in oncogynecology. The following inherited cancers are briefly discussed: Lynch syndrome; “site-specific” ovarian cancer and hereditary breast–ovarian cancer syndrome; Cowden syndrome; Li-Fraumeni syndrome; Peutz-Jeghers syndrome; ataxia-telangiectasia; DICER1- syndrome; gonadal dysgenesis; tuberous sclerosis; multiple endocrine neoplasia type I, II; hereditary small cell carcinoma of the ovary, hypercalcemic type and hereditary undifferentiated uterine sarcoma; hereditary diffuse gastric cancer and MUTYH-associated polyposis. Epidemiology, pathogenesis, diagnosis, pathology and screening of these syndromes are discussed. General treatment recommendations are beyond the scope of this review.

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.