Clinical characteristics.

Diffuse gastric and lobular breast cancer syndrome (DGLBCS) is associated with an increased risk, in males and females, of diffuse gastric cancer (DGC), a poorly differentiated adenocarcinoma (also referred to as signet ring cell carcinoma or isolated cell-type carcinoma) that infiltrates into the stomach wall, causing thickening of the wall (linitis plastica) without forming a distinct mass. In females with CDH1-related DGLBCS, but not in males, there is also an increased risk for lobular breast cancer (LBC), characterized by small, non-cohesive cells dispersed in the stroma or arranged in single-file infiltrating patterns. Cleft lip with or without cleft palate has also been reported in some individuals with CDH1-related DGLBCS.

Diagnosis/testing.

The diagnosis of DGLBCS can be established in an individual with suggestive findings and a germline heterozygous pathogenic variant in CDH1 or a germline heterozygous truncating pathogenic variant in CTNNA1 identified by molecular genetic testing. Affected individuals from families that meet consensus genetic testing criteria for DGLBCS who do not have an identified pathogenic variant in CDH1 or CTNNA1 have suspected DGLBCS of unknown genetic cause (also referred to as hereditary diffuse gastric cancer [HDGC]-like).

Management.

Targeted therapy: Prophylactic gastrectomy for diffuse gastric cancer is an option from early adulthood in individuals with normal endoscopy / gastric biopsies and a DGLBCS-related CDH1 pathogenic variant regardless of family history or a DGLBCS-related CTNNA1 pathogenic variant and a family history of DGC and/or LBC.

Supportive care: Management of DGLBCS requires a multidisciplinary team. Standard treatment to eradicate H pylori infection; total gastrectomy for early or advanced DGC; perioperative and/or adjuvant therapy for advanced DGC; surgery, hormonal therapy, and perioperative and/or adjuvant chemotherapy for LBC; consider risk-reducing contralateral mastectomy; standard treatments for cleft correction by craniofacial specialists.

Surveillance: For individuals with CDH1- or CTNNA1-related DGLBCS, referral to a high-risk gastric screening program with a thorough ≥30-minute upper endoscopy with multiple targeted and random biopsies every six to 12 months beginning in early adulthood or five to ten years prior to the earliest gastric cancer diagnosis in the family.

For females with CDH1-related DGLBCS or CTNNA1-related DGLBCS and personal or family history of breast cancer, referral to a high-risk breast cancer screening program with monthly self-breast exams beginning at age 20 years; annual clinical breast examinations, education on clinical features of breast cancer, and bilateral breast MRI with contrast from age 30 years; annual mammography between MRI screens from age 30-40 years; if MRI is unavailable, breast ultrasound should be combined with mammogram.

In individuals with CDH1-related cleft lip/palate, annual audiology and speech evaluation throughout childhood.

In individuals with suspected DGLBCS of unknown cause (also referred to as HDGC-like), referral to a high-risk gastric screening program with a thorough ≥30-minute upper endoscopy with multiple targeted and random biopsies annually beginning at age 40 years or ten years prior to the earliest gastric cancer diagnosis in the family; endoscopy interval can be increased after two consecutive normal biopsies at the discretion of the endoscopist. Referral to a high-risk breast cancer screening program; in those with a personal or family history of breast cancer of any type, monthly self-exams beginning at age 20 years, annual clinical breast exam and education of clinical features of breast cancer beginning at age 30 years; additional breast screening as recommended by high-risk breast cancer specialists.

Evaluation of relatives at risk: Offer at-risk relatives of a proband with CDH1- or CTNNA1-related DGLBCS predictive testing for the familial pathogenic variant. This will allow identification of individuals who would benefit from intensive surveillance for early cancer detection and/or prophylactic surgeries targeting organs associated with DGLBCS. Offer first-degree relatives of a proband with suspected DGLBCS of unknown genetic cause (HDGC-like) surveillance tailored to the individual's personal and family history.

Pregnancy management: Nutritional consequences of total gastrectomy should be discussed before and during pregnancy. Pregnancy should be delayed at least six to 12 months after total gastrectomy, to allow for weight stabilization and nutritional recovery.

Genetic counselling.

DGLBCS is inherited in an autosomal dominant manner. The majority of individuals diagnosed with CDH1-related DGLBCS inherited the CDH1 pathogenic variant from a parent (because of reduced penetrance, the parent from whom the pathogenic variant was inherited may not have developed cancer). Some individuals diagnosed with CTNNA1-related DGLBCS have an affected first- or second-degree relative with gastric or breast cancer. Some individuals with DGLBCS have the disorder as the result of a de novo pathogenic variant. Each child of an individual with DGLBCS has a 50% chance of inheriting the DGLBCS-related pathogenic variant. If the DGLBCS-related pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

DGLBCS should be suspected in a proband with ANY of the following clinical features or family history [Blair et al 2020]:

Clinical features

• Diffuse gastric cancer (DGC) diagnosed at age <50 years
• DGC in an individual of Māori ethnicity diagnosed at any age
• DGC diagnosed at any age in an individual with a personal history or first-degree relative with cleft lip or cleft palate
• DGC and lobular breast cancer (LBC), both diagnosed in an individual at age <70 years
• Bilateral LBC, diagnosed at age <70 years
• Pathologically confirmed gastric signet ring cell carcinoma in situ or pagetoid spread of signet ring cells identified at age <50 years

Family history

• ≥2 first- or second-degree relatives with gastric cancer diagnosed at any age, and at least one of these family members diagnosed with DGC
• ≥1 first- or second-degree relative with DGC at any age and ≥1 first- or second-degree relative with LBC diagnosed at age <70 years
• ≥2 first- or second-degree relatives with LBC diagnosed at age <50 years

Note: Although it is advisable for all cancer diagnoses to be confirmed with histopathology findings, in criteria with two or more cancer diagnoses, at least one should be accompanied by confirmed histologic evidence.

Establishing the Diagnosis

A diagnosis of DGLBCS can be established in a proband with any of the clinical features and/or family history in Suggestive Findings and a germline heterozygous pathogenic (or likely pathogenic) variant in CDH1 or a germline heterozygous truncating variant in CTNNA1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this GeneReview is understood to include likely pathogenic variants. (2) CDH1 variants should be classified according to the ClinGen CDH1 Variant Curation Expert Panel (VCEP) Specifications to the ACMG/AMP Variant Interpretation Guidelines [Luo et al 2023] (see Version 3.1 here). Most DGLBCS-related CDH1 variants are truncating variants, splice site variants, or missense variants that impact splicing [Lee et al 2018, Garcia Pelaez et al 2023, Luo et al 2023]. However, affected individuals from some families who meet genetic testing for DGLBCS have CDH1 missense variants that do not affect splicing. Therefore, any CDH1 missense variant of concern should be reported to the ClinGen CDH1 VCEP for further investigation. (3) Because ClinGen VCEP interpretation guidelines are not currently available for CTNNA1, the general ACMG/AMP variant interpretation guidelines for germline variants may be used [Richards et al 2015].

A proband with one of the clinical features described in Suggestive Findings who does not have an identified pathogenic variant in CDH1 or CTNNA1 but meets the following family history criteria has suspected DGLBCS of unknown genetic cause (also referred to as HDGC-like) and should be offered modified surveillance (see Table 7b) [Blair et al 2020]. Criteria are:

• ≥2 family members (first- or second-degree relatives of each other) with gastric cancer regardless of age of diagnosis, with at least one of these individuals with confirmed DGC; OR
• ≥1 family member with DGC at any age and ≥1 different family member with LBC diagnosed at age <70 years (first- or second-degree relatives of each other).

Note: For these criteria, the proband is included in the family member(s).

Molecular genetic testing approaches can include a combination of gene-targeted testing (serial single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Diffuse gastric and lobular breast cancer syndrome (DGLBCS) is characterized by an increased risk of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Cleft lip with or without cleft palate has been reported in some individuals with CDH1-related DGLBCS.

Diffuse gastric cancer (DGC). The average age of onset of DGC in the largest cohorts of individuals with CDH1-related DGLBCS ranges from age 42 to 49 years [Xicola et al 2019, Garcia-Pelaez et al 2023, Ryan et al 2024], and DGC onset may occur as young as age 14 years [Gullo et al 2018, Xicola et al 2019, São José et al 2023].

Signet ring cancer cells are often identified at the initial endoscopy in individuals with a germline CDH1 pathogenic variant [Mi et al 2018, Jacobs et al 2019], and in one study only 42% (5/12) had a first-degree relative with DGC [Jacobs et al 2019]. The age of onset and clinical behavior is variable between and within families [Hansford et al 2015, Gullo et al 2018, Blair et al 2020, Garcia-Pelaez et al 2023, São José et al 2023]. Average age of onset of DGC in CTNNA1-related DGLBCS is 40 years [Lobo et al 2021, Coudert et al 2022].

Symptoms of DGC are nonspecific in the early stages and consequently tend to be dismissed both by affected individuals and physicians. Intramucosal occult signet ring cell carcinomas have been identified in prophylactic gastrectomy specimens from women with a history of LBC despite not having a personal or family history of gastric cancer [Gamble et al 2022]. By the time specific symptoms appear, affected individuals present with advanced disease [Iyer et al 2020]. Symptoms of late-stage DGC may include abdominal pain, nausea, vomiting, dysphagia, postprandial fullness, loss of appetite, and weight loss. A palpable mass may be present late in the course of DGC. Advanced DGC often involves metastatic spread into the gastrointestinal tract, peritoneum, omentum, mesocolon, and female reproductive tract; metastatic spread to other organs is rare [Decourtye-Espiard & Guilford 2023].

Lobular breast cancer (LBC). LBC is the second most common cancer type in individuals with DGLBCS and can present as invasive LBC or lobular carcinoma in situ. The average age of onset for breast cancer in females with a germline CDH1 pathogenic variant ranges from 45 to 54 years [Pharoah et al 2001, Xicola et al 2019, Garcia-Pelaez et al 2023, Ryan et al 2024]. In large studies the presence of a germline pathogenic variant in CDH1 was observed in 0.1%-0.5% of individuals with LBC [Petridis et al 2019, Yadav et al 2021, Adib et al 2022]. Additionally, a cohort analysis of invasive LBC and lobular carcinoma in situ revealed that 8% of individuals with bilateral cancer had a germline CDH1 pathogenic variant [Petridis et al 2014]. These findings collectively indicate that LBC in women with DGLBCS tends to be bilateral [Petridis et al 2014] and often metastasizes to the gastrointestinal and female reproductive tract and peritoneal surface [Pilonis et al 2021].

Cleft lip with or without cleft palate has been a recurrent finding in individuals with CDH1-related DGLBCS. Cleft lip with or without cleft palate has been described in at least one individual in 19% of families with CDH1-related DGLBCS [Green et al 2022]. Information regarding the type of cleft and severity are limited. Presence of cleft lip/palate varies among affected individuals from the same family.

Other cancers

• CDH1. Germline CDH1 pathogenic variants have been identified in individuals with other primary cancers including other types of gastric cancer, other types of breast cancer, colorectal cancer (CRC), and other cancer types. In a United States study of 212,944 individuals, 141 individuals (0.06%) had a germline CDH1 pathogenic variant [Adib et al 2022]. Breast cancer (54.6% of individuals) and gastric cancer (39.7% of individuals) were the most common cancer types among individuals with a germline CDH1 pathogenic variant. CRC was reported in 9.9% of individuals (3.8% had signet ring cell CRC), and other types of cancer were reported in 3.5% of individuals. In a second US study, in 12% of families with a germline CDH1 pathogenic variant, there was no history of gastric or breast cancer [Xicola et al 2019]; CRC was the most frequent cancer type after gastric and breast cancer in these families. A study of 176 European families with a germline CDH1 pathogenic variant reported gastric (62%: 38% DGC) and breast (25%: 11% LBC) as the most frequent cancer types; CRC accounted for less than 2%, and other cancer types were even rarer [Garcia-Pelaez et al 2022].
• CTNNA1. A systematic review including 105 individuals from 41 families with a germline CTNNA1 truncating pathogenic variant found that only 24% of families met the criteria for DGLBCS, and affected individuals presented most often with DGC at around age 40 years. Affected individuals from the remaining 76% of families with a germline CTNNA1 truncating pathogenic variant presented with other cancer types, mostly unspecified breast cancer, or remained cancer-free [Lobo et al 2021].

Prognosis

• DGC. A single study assessed the survival of individuals with CDH1-related DGC and reported that individuals with CDH1-related DGC had shorter survival than individuals who met genetic testing criteria but did not have a germline CDH1 pathogenic variant [van der Post et al 2015b]. When sporadic DGC is detected early (i.e., before it has invaded the stomach wall), the five-year survival rate can be greater than 75%-90%, depending on the geographic region [Pereira et al 2022]. Overall and disease-free survival of individuals with CDH1- and CTNNA1-related advanced DGC is believed to be the same as individuals with advanced sporadic DGC. The five-year survival rate is less than 30% when DGC is identified at a late stage [Stiekema et al 2013, Pereira et al 2022].
• LBC. The reported five-year overall survival rate for infiltrating LBC is approximately 93%; however, the impact of a germline CDH1 pathogenic variant on the survival rate of individuals with LBC remains uncertain [Han et al 2022]. While some studies have suggested that a somatic CDH1 variant does not significantly affect the prognosis of individuals with invasive LBC, the presence of both CDH1 and ERBB2 variants in LBC tumor tissue has been associated with a poorer prognosis [Ping et al 2016].

Pathophysiology

• DGC. The loss of E-cadherin causes individual tumor cells to grow and invade neighboring structures. Malignant cells infiltrate and spread under histologically normal-looking mucosa, causing widespread thickening and rigidity of the gastric wall, a phenomenon known as linitis plastica [McColl 2006]. No tumor mass is formed.
  DGC is characterized by the presence of multiple gastric intramucosal signet ring cell carcinomas (SRCC) with abnormal or absent E-cadherin immunohistochemistry. This distinctive signet ring appearance is caused by an accumulation of intracellular mucin that pushes the nucleus to one side. A clearly defined preneoplastic lesion is not seen in DGC. A progression model for DGC developed from studying prophylactic total gastrectomy (PTG) specimens from individuals with a germline CDH1 pathogenic variant describes isolated neoplastic signet ring cells at the base of the glands and pagetoid spread of signet ring cells below the preserved epithelium of glands/foveolae into the stroma [Carneiro et al 2004, Monster et al 2022]. In individuals with CDH1 pathogenic variants and in individuals with CTNNA1 truncating pathogenic variants, these lesions consist of both T1a stage SRCC that have invaded the lamina propria, as well as in situ SRCC that are confined within the basement membrane (pTis). Both the T1a stage and in situ foci show significant overexpression of cytokeratin 7. Although individuals with CTNNA1-related DGC also exhibit multifocal intramucosal SRCC, in situ foci have not been observed to date [Benusiglio et al 2019, Decourtye-Espiard & Guilford 2023].
• LBC. CDH1-related and sporadic LBC share similar histopathologic and immunohistochemical characteristics, including the presence of small tumor cells that are loosely dispersed in the stroma or arranged in single-file infiltrating patterns and absence of E-cadherin staining [Christgen et al 2016, Decourtye-Espiard & Guilford 2023]. LBC can be differentiated from other neoplasms by observing cytoplasmic staining of p120-catenin, while beta-catenin is negative [Blair et al 2020]. CDH1-related and sporadic LBC are also both associated with noninvasive conditions such as atypical lobular hyperplasia and lobular carcinoma in situ [Decourtye-Espiard & Guilford 2023].

Phenotype Correlations by Gene

CDH1. Germline pathogenic variants in CDH1 are associated with an increased risk of DGC, LBC [Garcia-Pelaez et al 2023], and cleft lip with or without cleft palate.

CTNNA1. DGC frequently occurs in families bearing germline truncating variants in CTNNA1, while LBC is extremely rare [Lobo et al 2021]. Truncating variants in CTNNA1 have not been associated with cleft lip/palate.

Genotype-Phenotype Correlations

CDH1. Pathogenic variants located in the CDH1 linker regions between the extracellular domains have been associated with cleft lip/palate. A specific protein region responsible for calcium ion chelation displayed high intolerance to missense substitutions (between amino acids 253 and 260) [Selvanathan et al 2020].

Penetrance

The penetrance of DGLBCS is reduced.

CDH1. A study that included 75 families with germline CDH1 pathogenic variants found that by age 80 years, the cumulative incidence of gastric cancer including DGC was 70% (95% CI: 59%-80%) for males and 56% (95% CI: 44%-69%) for females, and the risk of breast cancer including LBC for females was 42% (95% CI: 23%-68%) [Hansford et al 2015].

In a second study not exclusively selected based on strict DGLBC criteria, the cumulative incidence of gastric cancer including DGC by age 80 years was 42% (95% CI: 30%-56%) for males and 33% (95% CI: 21%-43%) for females with a CDH1 pathogenic variant. Additionally, the estimated cumulative incidence of female breast cancer in this cohort was 55% (95% CI: 39%-68%) [Roberts et al 2019].

A recent analysis of 70 individuals from 11 families from northern Portugal with a CDH1 founder pathogenic variant (c.1901C>T) showed that fewer than 20% of individuals with the variant developed DGC or LBC, even in a region where gastric cancer is highly prevalent [Barbosa-Matos et al 2021].

In a recent study involving a North American cohort of 7,323 individuals from 213 families with CDH1 pathogenic variants, the prevalence of gastric cancer was 13.9%, while breast cancer prevalence was 26.3%. Additionally, the lifetime risk for advanced gastric cancer varied significantly depending on family history. The risk ranged from 7%-10% regardless of family history to an estimated 38% in families with three first-degree relatives diagnosed with gastric cancer.

CTNNA1. Initial estimates from 46 individuals from 13 families with a germline CTNNA1 truncating variant showed a cumulative risk of DGC of 49% and 57% by age 80 years, depending on the statistical method used [Coudert et al 2022]. This may represent a risk overestimation given the low number of families included and their small size.

Prevalence

Approximately 7% of individuals with DGC have been found to have a germline CDH1 pathogenic variant [Adib et al 2022].

Invasive LBC represents 5%-15% of all invasive breast cancers. In two large studies, a germline CDH1 pathogenic variant was identified in 0.1%-0.5% of women with LBC [Petridis et al 2019, Yadav et al 2021, Adib et al 2022].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DGLBCS, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Tables 7a (individuals with CDH1- or CTNNA1-related DGLBCS) and 7b (individuals with DGLBCS of unknown genetic cause) are recommended.

Evaluation of Relatives at Risk

Family members of a proband with a molecular diagnosis of DGLBCS. Once a molecular diagnosis of DGLBCS has been established in the proband, it is appropriate to offer at-risk relatives predictive testing for the familial CDH1 or CTNNA1 pathogenic variant. Predictive genetic testing can reduce morbidity and mortality by identifying individuals with DGLBCS who would benefit from intensive surveillance (see Table 7a) for early cancer detection and/or risk-reduction surgeries targeting organs associated with DGLBC. Of note, predictive testing should be offered in the context of formal genetic counseling.

Family members of a proband with suspected DGLBCS of unknown genetic cause (i.e., a proband with clinical features and a family history consistent with DGLBCS in whom molecular genetic testing has not identified a CDH1 pathogenic variant or a CTNNA1 truncating variant, also referred as HDGC-like). It is appropriate to offer first-degree relatives surveillance tailored to the individual's personal and family history (see Table 7b).

See Genetic Counseling, Predictive testing in minors for discussion of issues related to testing of this population and issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Nutritional consequences of total gastrectomy should be discussed before and during pregnancy. Pregnancy should be delayed at least six to 12 months after total gastrectomy, to allow for weight stabilization and nutritional recovery. Kaurah et al [2010] reported six healthy pregnancies and infants born to four women after total gastrectomy. However, pregnant women who have undergone prophylactic gastrectomy should be followed closely by their physician and a dietician, as pregnancies after bariatric surgery show an increased risk of adverse perinatal outcomes (e.g., preterm births, intrauterine growth deficiency, and intensive care unit admissions).

Therapies Under Investigation

Clinical trials, targeted therapies, and predictive markers of therapy response directed to DGC or LBC are scarce.

Ongoing studies are mainly investigating alternate medication doses and combining therapeutic agents that are approved for sporadic gastric cancer and other solid tumors (e.g., platinum compounds, fluropyrimidines, and topoisomerase I inhibitors). Immunotherapy for anti-HER2, anti-VEGDR2, and anti-PD1 have been approved for treatment of gastric adenocarcinoma; however, treatment data for DGC is weak.

The MONO study (NCT01197885), a Phase II clinical trial, examined the outcome of zolbetuximab (monoclonal antibody against CLDN18.2: IMAB362) monotherapy in a series of individuals with recurrent or refractory, locally advanced or metastatic, CLDN18.2‐positive gastric, gastro‐esophageal junction, or esophageal adenocarcinoma. Of the 54 individuals enrolled in this trial, 22 had advanced DGC with CLDN18.2 expression in ≥50% of tumor cells. Zolbetuximab was well tolerated and exhibited antitumor activity with a clinical benefit rate of 23% [Türeci et al 2019]; whether individuals benefiting from this targeted therapy had DGC was not reported.

There are active clinical trials for individuals with invasive LBC or enriched in individuals with lobular histology. These studies are testing small molecules including tyrosine kinase ROS1 inhibition, CDK4/6 inhibition, endocrine therapy strategies, immunotherapy with checkpoint inhibition, and inhibition of HER2 in individuals with HER2 alterations [Mukhtar & Chien 2021]. Novel imaging tools are also being studied to decrease rates of positive margins and improve surgical outcomes [Jones et al 2020].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Diffuse gastric and lobular breast cancer syndrome (DGLBCS) is inherited in an autosomal dominant manner.

Risk to Family Members – Proband with a DGLBCS-Related CDH1 Pathogenic Variant or CTNNA1 Truncating Variant

Parents of a proband

• The majority of individuals diagnosed with CDH1-related DGLBCS inherited the CDH1 pathogenic variant from a parent. Because of reduced penetrance, the parent from whom the pathogenic variant was inherited may not have developed cancer. Some individuals diagnosed with CTNNA1-related DGLBC have an affected first- or second-degree relative with gastric or breast cancer [Lobo et al 2021].
• Some individuals with DGLBCS have the disorder as the result of a de novo pathogenic variant. De novo CDH1 pathogenic variants have been reported [Shah et al 2012, Sugimoto et al 2014].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing of the parents for the DGLBCS-related CDH1 or CTNNA1 pathogenic variant identified in the proband is recommended in order to determine if a parent is at increased risk for diffuse gastric cancer and lobular breast cancer (and should be referred for evaluation/surveillance) and to allow reliable risk assessment for sibs of the proband and other family members.
• If the DGLBCS-related pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of an individual with DGLBCS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has confirmed that neither parent is heterozygous for the DGLBCS-related pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected and/or known to have a DGLBCS-related pathogenic variant, the risk to the sibs of inheriting the pathogenic variant and having DGLBCS is 50%.
• Because DGLBCS is associated with reduced penetrance and intrafamilial clinical variability, age of onset and manifestations may differ among sibs with the same DGLBCS-related pathogenic variant.
• If the DGLBCS-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [Pan et al 2021].
• The absence of DGLBCS-related manifestations in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with DGLBCS has a 50% chance of inheriting the DGLBCS-related pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has a DGLBCS-related pathogenic variant, the parent's family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling (PDQ^® – Health Professional Version (part of National Cancer Institute).

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible if a DGLBCS-related pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing is not possible for family members of a proband with suspected DGLBCS of unknown genetic cause (i.e., a proband with clinical features and a family history consistent with DGLBCS in whom molecular genetic testing has not identified a pathogenic variant in CDH1 or a truncating variant in CTNNA1 [see Establishing the Diagnosis]). In these families, it is appropriate to offer first-degree relatives of the proband DGLBCS-related cancer surveillance tailored to the individual's personal and family history (see Table 7b). It is also appropriate to continue the search for a potential genetic cause of DGLBCS in the affected proband.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years). Genetic testing in individuals younger than age 18 years is controversial. Because there have been reports of individuals younger than age 18 years diagnosed with DGLBCS-related cancer [Guilford et al 1998, Gullo et al 2018], it has been suggested that genetic testing in individuals younger than age 18 years may be beneficial, particularly if there is very early onset of diffuse gastric cancer in the family [Caldas et al 1999, Fitzgerald et al 2010]. Overall, a request from parents for testing of asymptomatic at-risk individuals younger than age 18 years should be met with sensitivity and understanding, and comprehensive genetic counseling should be provided to both the parents and the child. The International Gastric Cancer Linkage Consortium (IGCLC) has agreed that genetic testing of at-risk individuals at age 16 years can be considered if the age of onset in the family is early [Fitzgerald et al 2010].

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Counseling about nutritional consequences of prophylactic gastrectomy should be discussed before and during pregnancy (see Pregnancy Management).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

If the DGLBCS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and in families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

E-cadherin (epithelial cadherin; also known as cadherin-1) is a transmembrane glycoprotein that is predominantly expressed at the basolateral membrane of epithelial cells, where it exerts calcium-dependent cell-cell adhesion and invasion-suppression functions [Takeichi 1991, Berx et al 1995, Nagar et al 1996]. E-cadherin is critical for establishing and maintaining polarized and differentiated epithelia during development [Keller 2002]. It also plays important roles in signal transduction, differentiation, gene expression, cell motility, and inflammation.

Somatic inactivation or down-regulation CDH1 expression is caused primarily by hypermethylation and somatic mutation (e.g., deletion) of CDH1 [Oliveira et al 2009, Decourtye-Espiard & Guilford 2023]. CDH1 promoter methylation is more frequent in primary tumors, while somatic deletion of CDH1 is more frequent in lymph node metastases [Oliveira et al 2009]. This second hit leads to loss of E-cadherin, which is seen in most diffuse gastric cancers and in lobular breast cancers. Cells deficient in E-cadherin lose their ability to adhere to each other and consequently become invasive and metastasize [Birchmeier 1995, Perl et al 1998]. Additionally, the development of diffuse gastric cancer has been linked to the loss of E-cadherin, which serves as a spatial landmark responsible for orienting the mitotic spindle. This orientation ensures that mitotic division takes place within the epithelial plane, resulting in daughter cells that maintain their integrin-mediated contacts with the basement membrane even after cell division. Consequently, this mechanism reduces the chances of dividing cells being displaced into the gastric lumen or the lamina propria [Humar et al 2007].

The activity of E-cadherin in cell adhesion is dependent on its association with the actin cytoskeleton via undercoat proteins called catenins (α-, β-, and γ-) [Jou et al 1995, Kallakury et al 2001]. Alpha-catenin functions as the primary protein link between cadherins, which constitute adherens junctions, and the actin cytoskeleton. It interacts with several proteins in at least four signaling cancer-associated pathways (Wnt/β-catenin, NF-kB, Hippo-YAP, and hedgehog). The exact mechanisms of disease development in the context of DGLBCS is unknown [Corso et al 2023].

Catenin alpha-1 (also known as alpha E-catenin), encoded by CTNNA1, is reported to be essential in inhibiting cell proliferation, promoting apoptosis, repressing invasion, and metastasis in malignancies [Huang et al 2023].

Mechanism of disease causation. Loss of function

Author History

Rita Barbosa-Matos, BSc, PhD (2024-present)
Lilian Córdova, MD (2024-present)
David G Huntsman, MD; University of British Columbia (2002-2024)
Pardeep Kaurah, MSc, PhD; University of British Columbia (2002-2024)
Carla Oliveira, PhD (2024-present)
Kasmintan Schrader, MBBS, PhD (2024-present)

Revision History

• 10 October 2024 (sw) Comprehensive update posted live
• 22 March 2018 (sw) Comprehensive update posted live
• 31 July 2014 (me) Comprehensive update posted live
• 21 June 2011 (me) Comprehensive update posted live
• 13 December 2004 (me) Comprehensive update posted live
• 4 November 2002 (me) Review posted live
• 5 April 2002 (pk) Original submission

Published Guidelines / Consensus Statements

• Blair VR, McLeod M, Carneiro F, Coit DG, D'Addario JL, van Dieren JM, Harris KL, Hoogerbrugge N, Oliveira C, van der Post RS, Arnold J, Benusiglio PR, Bisseling TM, Boussioutas A, Cats A, Charlton A, Schreiber KEC, Davis JL, Pietro MD, Fitzgerald RC, Ford JM, Gamet K, Gullo I, Hardwick RH, Huntsman DG, Kaurah P, Kupfer SS, Latchford A, Mansfield PF, Nakajima T, Parry S, Rossaak J, Sugimura H, Svrcek M, Tischkowitz M, Ushijima T, Yamada H, Yang HK, Claydon A, Figueiredo J, Paringatai K, Seruca R, Bougen-Zhukov N, Brew T, Busija S, Carneiro P, DeGregorio L, Fisher H, Gardner E, Godwin TD, Holm KN, Humar B, Lintott CJ, Monroe EC, Muller MD, Norero E, Nouri Y, Paredes J, Sanches JM, Schulpen E, Ribeiro AS, Sporle A, Whitworth J, Zhang L, Reeve AE, Guilford P. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol. 2020;21:e386-e397. [PubMed]

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