Hereditary Diffuse Gastric Cancer

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 04/12/2016
• Curation Status: Released (1.0.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
No assertions found.

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
No scores were found.

Severity of Outcome

Prevalence of the Genetic Condition

Incidence rates for gastric cancers vary internationally, with higher rates in Japan (80 per 100,000) and lower rates in western Europe and the US (10-40 per 100,000). It is estimated that 1-3% of gastric cancers arise as a result of inherited gastric cancer predisposition syndromes, including hereditary diffuse gastric cancer (HDGC). The population prevalence of HDGC is rare, estimated at <0.1 per 100,000 in the general population.

Clinical Features (Signs / symptoms)

HDGC associated with CDH1 mutations is characterized by the development of diffuse (singlet ring cell) gastric cancer. Early stage HDGC is characterized by the presence of multiple foci of diffuse gastric cancer, which initially spreads within the mucosa only and at a later stage invades the gastric wall. Symptoms associated with this early stage are nonspecific and by the time specific symptoms appear, affected individuals are typically in an advanced stage of the disease. 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 gastric cancer, a palpable mass may be present. Tumor spread or metastasis may lead to an enlarged liver, jaundice, ascites, skin nodules, and fractures. Female carriers of CDH1 mutations have an additional risk of developing lobular breast cancer.

Natural History (Important subgroups & survival / recovery)

It is estimated that early stage cancer in HDGC typically develops in most carriers before 20-30 years of age, while advanced disease is generally prolonged with an increasing risk with age: 1% at age 20, 4% for men and women at age 30 and 21% in men and 46% in women at age 50. The average age of diagnosis of gastric cancer for HDGC is around 32-40 years, with a reported range of 14 to 85 years. The average age of onset for breast cancer is 53 years.

When sporadic (i.e., non-hereditary) diffuse gastric cancer (DGC) is detected early prior to invasion into the stomach wall, the 5-year survival rate can be greater than 90%. However, the 5-year survival rate drops to lower than 20% when the diagnosis is made at a late stage. Survival of individuals with CDH1 pathogenic variants is believed to be the same as in individuals with sporadic DGC.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

The population prevalence of CDH1 germline mutations was not available.

CDH1 mutations are found in approximately 25-50% of all families fulfilling the HDGC clinical criteria.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Penetrance estimates have indicated a high penetrance for CHD1 mutations, with risk of gastric cancer by age 80 of 67-80% for men and 56-83% for women and risk of breast cancer by age 80 of 39-60% for women. The combined risk for gastric and breast cancer in women was estimated as 90% by age 80.

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Information on relative risk was not available.

Expressivity

The age of onset is variable between and within families.

Tier 3

Intervention Effectiveness

Patient Management

It is of great importance to centralize the intensive care for HDGC families in specialized centers with multidisciplinary medical teams.

Tier 2

Carriers of pathogenic CDH1 mutations are currently advised to undergo prophylactic total gastrectomy due to their high lifetime risk of developing gastric cancer and the limited value of surveillance modalities. Most guidelines recommend gastrectomy by age 18 to 20, though the timing may be guided by patient preferences and age at onset within the family.

Tier 2

The results of a recent systematic review indicated that of 220 previously reported patients who were positive for CHD1 mutations, 77% underwent a prophylactic gastrectomy while 23% declined. However, there was a high rate of gastric cancer detection at the time of prophylactic gastrectomy. Of the 169 patients who underwent prophylactic gastrectomy, 63% were asymptomatic and had negative preoperative endoscopic and radiologic imaging findings, while 12% tested positive for cancer in their preoperative screening. The final pathology results displayed positive histology in 87% of all cases.

Tier 1

Risk-reducing mastectomy could be considered, but not uniformly recommended, as it may be a reasonable option for some women who carry CDH1 mutations. Literature about prophylactic mastectomy in HDGC is scarce, and it is reasonable to consider prophylactic mastectomy on a case-by-case basis, taking into account the family pedigree.

Tier 2

Surveillance

Gastric cancer surveillance may be used before prophylactic gastrectomy and for patients who decline gastrectomy. It is recommended that at risk individuals undergo screening every 6-12 months beginning at age 20 or 5-10 years before the earliest cancer diagnosis in the family. The surveillance protocol should include gastroscopy with high definition endoscope, random biopsy plus biopsy of any mucosal abnormalities, and H. pylori testing and eradication. However, the efficacy and safety is uncertain and should be used with caution. All patients should be informed that given the very focal and often endoscopically invisible nature of these lesions, it is quite possible that lesions will not be detected by random biopsies.

Tier 2

There is currently insufficient data on the role and outcome of breast cancer screening in CDH1 mutation carriers, but the high lifetime risk of breast cancer, particularly the lobular subtype, and the precedents established in other hereditary breast cancer syndromes (e.g. due to BRCA1 or BRCA2 mutation) establish a rationale and protocol. Referral to a high risk breast clinic is recommended. Patients who choose to undergo screening, monthly breast self-examinations, biannual clinical breast exams, and annual breast MRI (which can be combined with mammography) starting at age 30-35 are recommended.

Tier 2

Circumstances to Avoid

Surveillance should be accompanied by advice to minimize known gastric cancer risk factors such as smoking and the intake of salted, cured, and preserved foods, and to increase fresh fruit and vegetable intake

Tier 2

Nature of Intervention

Nature of Intervention

The major intervention is prophylactic gastrectomy, which has a low but existent perioperative mortality in a high volume cancer center (<1% for fit patients), and which has post-surgical, lifelong morbidity. Total gastrectomy can have a psychological, physiological, and metabolic impact on the patient. Eating habits must be altered, requiring support from a dietician; dumping syndrome can result in pain, nausea, fatigue, and diarrhea. Other complications may include lactose intolerance, fat malabsorption and steatorrhea, bacterial overgrowth, and post-prandial fullness. Lifelong vitamin B12 supplementation and close monitoring for anemia, hypocalcemia, osteoporosis, and trace element deficiencies are required. \n\nEndoscopic surveillance comes with a bleeding risk given the number of biopsies taken. \n\nSome female CDH1 mutation carriers who are at high risk of lobular breast cancer may elect risk-reducing mastectomy to remove target organs.

Context: Adult

Chance to Escape Clinical Detection

Because early symptoms of HDGC are nonspecific, most cases are not diagnosed until late-stage disease when survival rates are much lower. In addition, the characteristic microscopic disease foci are often not readily detectable by routine upper endoscopy screening and random biopsies.

Context: Adult

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers

References List

Blair V, Martin I, Shaw D, Winship I, Kerr D, Arnold J, Harawira P, McLeod M, Parry S, Charlton A, Findlay M, Cox B, Humar B, More H, Guilford P. (2006) Hereditary diffuse gastric cancer: diagnosis and management. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 4(3):262-75.

Clinical practice guidelines in oncology v1.2016 gastric cancer. (2000) URL: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp

Clinical practice guidelines in oncology v1.2016 genetic/familial high-risk assessment: breast and ovarian. (2000) URL: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp

Fitzgerald RC, Hardwick R, Huntsman D, Carneiro F, Guilford P, Blair V, Chung DC, Norton J, Ragunath K, Van Krieken JH, Dwerryhouse S, Caldas C. (2010) Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. Journal of medical genetics. 47(7):436-44.

Kluijt I, Sijmons RH, Hoogerbrugge N, Plukker JT, de Jong D, van Krieken JH, van Hillegersberg R, Ligtenberg M, Bleiker E, Cats A. (2012) Familial gastric cancer: guidelines for diagnosis, treatment and periodic surveillance. Familial cancer. 11(3):363-9.

Oliveira C, Seruca R, Hoogerbrugge N, Ligtenberg M, Carneiro F. (2013) Clinical utility gene card for: Hereditary diffuse gastric cancer (HDGC). European journal of human genetics : EJHG. 21(8).

P Kaurah, DG Huntsman. Hereditary Diffuse Gastric Cancer. (2002) [Updated Jul 31 2014]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1139/

Seevaratnam R, Coburn N, Cardoso R, Dixon M, Bocicariu A, Helyer L. (2012) A systematic review of the indications for genetic testing and prophylactic gastrectomy among patients with hereditary diffuse gastric cancer. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 15 Suppl 1(1436-3305):S153-63.

Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. (2015) ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. The American journal of gastroenterology. 110(2):223-62; quiz 263.

van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N, Caldas C, Schreiber KE, Hardwick RH, Ausems MG, Bardram L, Benusiglio PR, Bisseling TM, Blair V, Bleiker E, Boussioutas A, Cats A, Coit D, DeGregorio L, Figueiredo J, Ford JM, Heijkoop E, Hermens R, Humar B, Kaurah P, Keller G, Lai J, Ligtenberg MJ, O'Donovan M, Oliveira C, Pinheiro H, Ragunath K, Rasenberg E, Richardson S, Roviello F, Schackert H, Seruca R, Taylor A, Ter Huurne A, Tischkowitz M, Joe ST, van Dijck B, van Grieken NC, van Hillegersberg R, van Sandick JW, Vehof R, van Krieken JH, Fitzgerald RC. (2015) Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. Journal of medical genetics. 52(6):361-74.