Hereditary Diffuse Gastric Cancer

Watchlist

(log in to enable)

Retrieved

2021-01-18

Source

Gene_reviews

Trials

—

Genes

CDH1, CTNNA1, FZR1, APC, MRC1, ST8, TP53, PALB2

Drugs

—

Interested in hearing about new therapies?

Summary

Clinical characteristics.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant susceptibility for diffuse gastric cancer, a poorly differentiated adenocarcinoma that infiltrates into the stomach wall causing thickening of the wall (linitis plastica) without forming a distinct mass. Diffuse gastric cancer is also referred to as signet ring carcinoma or isolated cell-type carcinoma. The average age of onset of HDGC is 38 years (range: 14-69 years). The majority of the cancers in individuals with a CDH1 pathogenic variant occur before age 40 years. The estimated cumulative risk of gastric cancer by age 80 years is 70% for men and 56% for women. Women are also at a 42% risk for lobular breast cancer.

Diagnosis/testing.

A diagnosis of HDGC is established in a proband with:

Diffuse gastric cancer (DGC) and a family history of one or more first- or second-degree relatives with GC; OR
A personal and/or family history of DGC diagnosed before age 40 years; OR
A personal and/or family history of DGC and LBC, one diagnosed before age 50 years.

If clinical features and family history are inconclusive, identification of a heterozygous germline CDH1 pathogenic variant by molecular genetic testing confirms the diagnosis and allows for family studies.

Management.

Treatment of manifestations: Ideally, management of individuals who have a CDH1 cancer-predisposing variant is either intense surveillance for early detection and treatment of gastric cancer or prophylactic total gastrectomy. Care by a multidisciplinary team comprising those with expertise in medical genetics, gastric surgery, gastroenterology, pathology, and nutrition is recommended. For women, referral to a high-risk breast cancer clinic is recommended; prophylactic mastectomy may be considered.

Surveillance: To date, the optimal management of individuals at risk for a cancer-predisposing variant has been controversial because of the unproven value of surveillance regimes and the potential morbidity and mortality from prophylactic gastrectomy.

Pregnancy management: Women who have undergone prophylactic total gastrectomy (PTG) and are pregnant should be followed closely by their physician and a dietician who is aware of the situation.

Genetic counseling.

Hereditary diffuse gastric cancer is inherited in an autosomal dominant manner. The vast majority of individuals with a pathogenic variant predisposing to diffuse gastric cancer have inherited it from one parent. De novo pathogenic variants have been reported. Each child of a proband has a 50% risk of inheriting the cancer-predisposing variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known; however, requests for prenatal testing for conditions that (like HDGC) do not affect intellect and have some treatment available are not common.

Diagnosis

Suggestive Findings

According to the latest International Gastric Cancer Linkage Consortium (IGCLC) consensus guidelines [van der Post et al 2015] (see full text), hereditary diffuse gastric cancer (HDGC) should be suspected in a proband with ANY of the following:

A diagnosis of gastric cancer and a family history of one or more individuals with gastric cancer, in which one affected individual has confirmed diffuse gastric cancer (DGC)
A diagnosis of DGC occurring before age 40 years, regardless of family history
A personal and/or family history of DGC and lobular breast cancer (LBC), with at least one individual diagnosed with one of these cancers before age 50 years

In addition, molecular genetic testing should be considered in a proband with any of the following:

A diagnosis of DGC and pathologically confirmed in situ signet ring cells and/or pagetoid spread of signet ring cells adjacent to DGC
A diagnosis of DGC and a family history of two first- or second-degree relatives with DGC or LBC
A diagnosis of DGC and a personal or family history of cleft lip/palate

Establishing the Diagnosis

A clinical diagnosis of HDGC is established in a proband with diffuse gastric cancer confirmed on endoscopic biopsy AND one of the following:

A family history of one or more first- or second-degree relatives with gastric cancer
A personal and/or family history of one individual with DGC diagnosed before age 40 years
A personal and/or family history of DGC and LBC, one diagnosed before age 50 years

If clinical features and family history are inconclusive, identification of a heterozygous pathogenic variant in CDH1 by molecular genetic testing (see Table 1) confirms the diagnosis and allows for family studies. Therefore, molecular testing is recommended in all individuals with one of the Suggestive Findings and in individuals with a clinical diagnosis of HDGC.

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

Single-gene testing. Sequence analysis of CDH1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
A multigene panel that includes CDH1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Hereditary Diffuse Gastric Cancer

Gene ¹	Test Method	Proportion of Probands with a Pathogenic Variant ² Detectable by This Method
CDH1	Sequence analysis ³	30%-50% ⁴
CDH1	Gene-targeted deletion/duplication analysis ⁵	4% ⁶
Unknown ⁷	NA

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Oliveira et al [2006], Kaurah et al [2007]
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6.: 6.5% of individuals with HDGC who do not have a pathogenic variant identified on sequence analysis [Oliveira et al 2009]
7.: Since 50%-70% of families with HDGC reported to date have no identifiable CDH1 germline pathogenic variant, it is likely that some of these families may have pathogenic variants in other unidentified HDGC-susceptibility genes. Although candidate genes have been analyzed, no pathogenic variants have been identified.

Clinical Characteristics

Clinical Description

Age of onset. The average age of onset of hereditary diffuse gastric cancer (HDGC) is 38 years (range: 14-69 years). The majority of the gastric cancers occur before age 40 years. The age of onset is variable both between and within families [Gayther et al 1998, Guilford et al 1998]. For age-related risks of developing cancer, see Penetrance.

Symptoms are nonspecific in the early stages of the disease and consequently tend to be dismissed both by affected individuals and by physicians. By the time specific symptoms appear, affected individuals are in an advanced stage of the disease [Wanebo et al 1993]. Symptoms in the late stage may include abdominal pain, nausea, vomiting, dysphagia, postprandial fullness, loss of appetite, and weight loss. Late in the course of stomach cancer, a palpable mass may be present.

Tumor spread or metastasis may lead to an enlarged liver, jaundice, ascites, skin nodules, and fractures.

Other cancers reported in family members include:

Lobular breast cancer (LBC). Females with a CDH1 germline pathogenic variant are at an increased lifetime risk (42% [95% confidence interval: 23%-68%]) for LBC [Hansford et al 2015]. The average age of onset for breast cancer is 53 years [Pharoah et al 2001].
In a study of 318 women who had a personal and family history of LBC but no family history of DGC, Schrader et al [2011] found that 1.3% had a CDH1 germline pathogenic variant.
Colorectal cancer [Richards et al 1999, Oliveira et al 2002, Brooks-Wilson et al 2004]. There is no direct evidence that colorectal cancer is part of the spectrum of cancers associated with CDH1 germline pathogenic variants. Therefore, these families need to be counseled accordingly on a case-by-case basis. In families where there is a clustering of colon cancer and a CDH1 pathogenic variant, it is imperative to obtain as much clinical and pathologic information as possible on all individuals who have colon cancer.

Survival. When sporadic (i.e., non-hereditary) diffuse gastric cancer is detected early (i.e., before it has invaded the stomach wall), the five-year survival rate can be greater than 90%. The five-year survival rate drops below 30% when the diagnosis is made at a late stage [Stiekema et al 2013].

If gastric cancer is detected early and resected, the five-year survival rate is 90%. Because early detection of DGC is difficult, survival of individuals with CDH1 pathogenic variants is believed to be the same as in individuals with sporadic DGC. Therefore, in individuals with a CDH1 germline pathogenic variant, clinical management options include prophylactic gastrectomy and an intensive regimen of endoscopic surveillance.

Apart from the two of 17 individuals who had prophylactic gastrectomy and previous Helicobacter pylori infection on serologic testing [Blair et al 2006], there is no evidence of increased rates of H pylori infection associated with the microscopic DGCs in the prophylactic gastrectomy specimens of individuals with a germline CDH1 pathogenic variant.

Pathology. In DGC, loss of the E-cadherin protein causes the individual tumor cells to grow and invade neighboring structures. The individual 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, unlike that of the intestinal type. The malignant cells have a distinctive signet ring appearance, which 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].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been reported to date.

Penetrance

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

Prevalence

The worldwide incidence of gastric cancer has been falling steadily since the 1970s with the phenomenon being most noticeable in developed countries [GLOBOCAN]. Given that the incidence of gastric cancer varies by geographic region, the percentage of individuals with gastric cancer who have a germline CDH1 pathogenic variant identified ranges from 1% to 3% [Corso et al 2012].

Differential Diagnosis

An estimated 5%-10% of all gastric cancer is thought to be familial [Zanghieri et al 1990, La Vecchia et al 1992]. Familial gastric cancer is both clinically and genetically heterogeneous.

Intestinal-type gastric cancer (IGC) arises from a precursor lesion, intestinal metaplasia, which forms a large protruded, ulcerated, or infiltrative lesion in the stomach. Histologically IGC is composed of tubular or glandular formations of variable differentiation that resemble adenocarcinomas of the intestinal tract. In contrast to diffuse gastric cancer (DGC), E-cadherin is present. IGC is more common than DGC, although the incidence of IGC appears to be declining [Ajani et al 2010]. Risk factors for IGC include chronic gastric mucosal infection with H pylori [Uemura et al 2001, Suerbaum & Michetti 2002]; smoking; a diet high in nitrites, salt, and smoked or pickled foods and low in fruit and vegetables; age; and male gender. Variants in TNF and IFNGR1 can significantly increase the risk for gastric cancer, particularly in those infected with virulent strains of H pylori [Canedo et al 2008].

Other Cancer Predisposition Syndromes

Gastric cancer is seen in several other autosomal dominant cancer predisposition syndromes, including Lynch syndrome (hereditary non-polyposis colorectal cancer), Li-Fraumeni syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome, and Cowden syndrome (one of the PTEN hamartoma tumor syndrome phenotypes).

Lynch syndrome, which is associated with germline pathogenic variants in mismatch repair genes or EPCAM, predisposes heterozygotes to colorectal and other cancers. Gastric cancer is the third most common cancer in these individuals. IGC is the predominant subtype in Lynch syndrome [Lynch et al 2005, Capelle et al 2010]. Microsatellite instability (MSI) was observed in approximately 15% of gastric cancers from individuals in Florence, Italy, an area with high gastric cancer risk [D'Errico et al 2009]. Gastric cancers with high MSI tend to occur in the antrum of the stomach, be of the intestinal type, and have better survival rates [Falchetti et al 2008].

Familial adenomatous polyposis (FAP) is caused by germline pathogenic variants in APC. Gastric cancer has been seen in 0.6% of persons with FAP in Western populations [Jagelman et al 1988]. The incidence of gastric cancer is significantly higher in individuals with FAP in the East Asian population [Yamaguchi et al 2016].

Li-Fraumeni syndrome (LFS). Cancers in LFS are caused by pathogenic variants in TP53. CHEK2 and CDKN2A, which are genes in the TP53 pathway, may be LFS candidate genes; however, further confirmation of this is needed [Olivier et al 2003, Malkin 2011]. Both DGC and IGC are observed [Keller et al 2004, Oliveira et al 2004].

BRCA1 and BRCA2 hereditary breast and ovarian cancer. Increased risk for gastric cancer has been associated with pathogenic variants in BRCA1 [Brose et al 2002, Friedenson 2005] and BRCA2 [Breast Cancer Linkage Consortium 1999, Risch et al 2001]. Gastric cancer occurs in 5.7% of families with the BRCA2 6174delT pathogenic variant [Figer et al 2001]. Jakubowska et al [2002] found that in 7% of individuals with gastric cancer a BRCA2 pathogenic variant may be the underlying genetic cause, although the histopathology of the gastric cancer was not reported. Testing by multigene panels has identified BRCA1 and BRCA2 pathogenic variants in a number of individuals with diffuse gastric cancer and a family history of breast cancer [Hansford et al 2015, Sahasrabudhe et al 2017, Slavin et al 2017].

Carney complex. A rare gastric lesion, gastric gastrointestinal stromal tumor, previously known as gastric epitheliod leiomyosarcoma, is found in individuals with Carney complex [Carney et al 1977]. Pathogenic variants in PRKAR1A are causative.

Carney-Stratakis syndrome (OMIM 606864). Gastric stromal sarcomas were observed in 12 individuals with this disorder who had paraganglioma, gastric stromal sarcoma, or both [Carney & Stratakis 2002]. Germline pathogenic variants in SDHB, SDHC, and SDHD are causative [Pasini et al 2008]. Inheritance is autosomal dominant.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a recently identified autosomal dominant fundic gastric polyposis syndrome with areas of dysplasia or intestinal-type gastric adenocarcinoma that are restricted to the proximal stomach. Affected individuals are at increased risk for gastric cancer, but there is no evidence of colorectal or duodenal polyposis [Worthley et al 2012]. Heterozygous germline pathogenic variants in the promoter 1B of APC are causative [Li et al 2016, Repak et al 2016, Beer et al 2017].

Management

The IGCLC has updated consensus guidelines for clinical management of individuals with a CDH1 pathogenic variant [van der Post et al 2015] (see full text and Figure 1 therein).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary diffuse gastric cancer, the following evaluations are recommended:

Baseline endoscopy to look for macroscopic tumor [van der Post et al 2015]
Evaluation of CDH1 heterozygotes for H pylori infection given its ability to induce promoter hypermethylation of CDH1 and its role in gastric cancer carcinogenesis
Clinical breast examination and mammography in females
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Care by a multidisciplinary team comprising those with expertise in clinical genetics, gastric surgery, gastroenterology, pathology, and nutrition is recommended. See Fitzgerald et al [2010] (full text) and van der Post et al [2015] (full text).

Diffuse gastric cancer

Total gastrectomy is recommended [Fitzgerald et al 2010, van der Post et al 2015]. Studies have shown that surgery alone is less than satisfactory, with cure rates approaching only 40%.
Adjuvant therapy. Three large, randomized controlled trials showed the survival benefit of adjuvant therapy over surgery alone [Macdonald et al 2000, Cunningham et al 2006, Sakuramoto et al 2007]. Numerous randomized clinical trials have failed to show consistent survival benefits from adjuvant radiation therapy or chemotherapy alone in the treatment of gastric cancer.
H pylori infection (if present) is treated in the standard manner.

Lobular breast cancer. The treatment of breast cancer in individuals with CDH1-related breast cancer is similar to that in sporadic forms of lobular breast cancer [National Comprehensive Cancer Network Guidelines].

Prevention of Primary Manifestations

Heterozygotes for a Germline CDH1 Pathogenic Variant

Diffuse gastric cancer. Prophylactic total gastrectomy (PTG) is recommended rather than endoscopic surveillance due to the observation of early gastric cancers in PTG samples from individuals with a germline CDH1 pathogenic variant [Norton et al 2007]. PTG involves D-2 dissection and Roux-en-Y esophagojejunostomy and obtaining proximal margins to ensure removal of the gastric mucosa [Norton et al 2007]. A multidisciplinary team including a surgeon, gastroenterologist, and dietician should provide preoperative and postoperative care for an individual undergoing PTG. The multidisciplinary team members can counsel candidates for PTG on the risks and benefits of the surgery. In making the decision to undergo PTG, the affected individual and his/her physicians should consider the following:

In a young, healthy individual, the risk of mortality with PTG in an experienced surgeon's hands is less than 1% [Lynch et al 2005].
The morbidity from PTG is 100% [Worster et al 2014, Muir et al 2016]. All individuals have immediate as well as long-term complications including rapid intestinal transit, dumping syndrome, diarrhea, eating habit alterations, and weight loss [Caldas et al 1999, Lewis et al 2001]. The risk for malabsorption increases, including an increased incidence of osteoporosis, osteomalacia, and malnutrition.
Gastric cancer is associated with age-specific risks: due to nutritional implications, PTG is not generally recommended until the individual's growth period is complete. In families with early-onset gastric cancer, PTG should be considered on a case-by-case basis [Blair et al 2006]. In these individuals, regular endoscopic screening may be begun prior to the consideration of PTG.
Individuals with a CDH1 pathogenic variant are at risk for extragastric cancers (e.g., lobular breast cancer, colorectal cancer) and should follow screening recommendations for these cancers.

Breast cancer. Referral to a high-risk breast clinic is recommended. Prophylactic mastectomy may be considered in women heterozygous for a CDH1 germline pathogenic variant. The authors are aware of a very limited number of women who have undergone prophylactic mastectomy for this reason [Brandberg et al 2008].

Prevention of Secondary Complications

A multidisciplinary team including a surgeon, gastroenterologist, and dietician should provide postoperative care for an individual undergoing PTG (see Prevention of Primary Manifestations).

Surveillance

See Fitzgerald et al [2010] (full text) and van der Post et al [2015] (full text).

Gastric Cancer

The optimal surveillance of individuals with a CDH1 germline pathogenic variant is controversial because of the unproven benefit of screening.

Endoscopy permits direct inspection and biopsy of suspicious areas; however, diffuse gastric cancer is difficult to detect at an early, treatable stage because the lesions tend to spread in the submucosa rather than as exophytic masses. The submucosal lesions are difficult to identify; an additional challenge is sampling bias in a macroscopically normal-appearing gastric mucosa. Therefore, diffuse gastric cancer is often not detected until it reaches an advanced, incurable stage.

At-risk individuals who are not ready to undergo PTG should be screened using the Cambridge protocol [Barber et al 2008]:

Detailed 30-minute upper endoscopy every six to 12 months with multiple random biopsies and biopsies of subtle lesions
Screening beginning five to ten years prior to the earliest cancer diagnosis in the family

Mi et al [2018] evaluated the utility of endoscopic surveillance in individuals with an identified CDH1 pathogenic variant who were delaying PTG and a group with clinically diagnosed HDGC but no identified CDH1 pathogenic variant. The authors used autofluorescence imaging and narrow-band imaging with random biopsies; surveillance was performed by the same group of specialists on all individuals. Individuals with a CDH1 pathogenic variant were found to have a high yield of signet ring cell carcinoma foci on their first endoscopy (63.6%) compared to the latter group (9.7%), underscoring the importance of baseline endoscopy in perhaps staging invasive disease before gastrectomy in individuals with a CDH1 pathogenic variant.

Several other screening modalities for diffuse gastric cancer are being tested.

Chromoendoscopy, using indigo-carmine staining, has been shown to improve the detection rate of early gastric cancer [Stepp et al 1998, Fennerty 1999]. Charlton et al [2004] studied six stomachs removed prophylactically after macroscopically normal gastric endoscopies. A pH-sensitive Congo red dye followed by pentagastric stimulation revealed signet ring foci that were five times more prevalent in the transitional zone of the distal stomach, a finding in contrast with other studies [Carneiro et al 2004]. The transitional zone occupies less than 10% of the stomach and lacks gastric-secreting G cells. The authors suggest that chromoendoscopy using Congo red dye and pentagastric stimulation may highlight this area during endoscopy and thus increase the chances of detecting cancer foci. Further research is needed to evaluate this possibility.

The same group of investigators reported a year later on a follow up of 99 surveillance endoscopies over five years [Shaw et al 2005]:

69 of 99 (70%) endoscopies were normal.
23 lesions with signet ring cell cancer were identified in ten individuals.
The Congo red/methylene blue dye detected foci between 4 and 10 mm, not less than 4 mm.

Note: Congo red is no longer available for this use due to concerns over toxicity of the dye.

Hüneburg et al [2016] performed endoscopic detection on seven individuals with CDH1 pathogenic variants by using high-resolution white light endoscopy and pan gastric chromoendoscopy with indigo carmine combined with targeted and random biopsies. All individuals were scheduled for this presurgical procedure. Using the Cambridge protocol, only a single focus of signet ring cell cancer (14%) was detected during the random biopsies. Given the small numbers in these series and the conflicting results, these findings need to be evaluated in more individuals with a CDH1 pathogenic variant.

Endoscopic ultrasound examination is important in the detection and staging of gastrointestinal cancers [Pfau & Chak 2002], but is not believed to be useful in detecting precursor lesions [Fitzgerald & Caldas 2004].

Other tools in use include PET scan [van Kouwen et al 2004], endoscopic ultrasound, stool for guaiac, abdominal CT, and multiple random stomach biopsies [Barber et al 2008]. However, none of these reliably detects DGC, as demonstrated by the finding – one week after a number of these screening investigations were performed – of multiple small cancer foci in six of six gastrectomy specimens from individuals who were heterozygous for a CDH1 pathogenic variant [Norton et al 2007].

Lobular Breast Cancer (LBC)

Currently the data on women with germline CDH1 pathogenic variants and lobular breast cancer are insufficient to determine the best screening strategies. Recommendations for LBC risk management in CDH1 heterozygotes or at-risk women are based on recommendations for women with a BRCA1 or BRCA2 germline pathogenic variant (see BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer) including:

Monthly breast self-examinations starting at age 20
Clinical breast examinations every six months starting at age 30
Referral to a high-risk breast-screening program if possible. Given the low sensitivity of detecting lobular breast cancer by mammography, bilateral breast MRI examination should be performed in females with a CDH1 pathogenic variant. Annual breast MRI examination starting at age 30 in women with a CDH1 pathogenic variant is recommended.

Colon Cancer

Although evidence is insufficient to conclude that colon cancer is a manifestation of HDGC, it is prudent to recommend colonoscopy every three to five years beginning at age 40 years or ten years prior to the youngest age at diagnosis of colon cancer in families in which both DGC and colon cancer have occurred [Fitzgerald et al 2010, van der Post et al 2015].

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing to at-risk relatives if the CDH1 pathogenic variant is identified in an affected family member so that morbidity and mortality can be reduced by early diagnosis and treatment.

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

Evidence shows that pregnancy after PTG can have healthy and normal outcomes. Kaurah et al [2010] discussed six healthy pregnancies and infants born to four women after total gastrectomy. However, it is important that pregnant women who have undergone PTG be followed closely by their physician and a dietician who is aware of their situation.

Therapies Under Investigation

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