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Hereditary Diffuse Gastric Cancer Syndrome (CDH1)

What is hereditary diffuse gastric cancer (HDGC) syndrome?

Hereditary diffuse gastric (stomach) cancer (HDGC) is a genetic cancer susceptibility syndrome characterized by a high risk for stomach and lobular breast cancer.  HDGC is inherited in an autosomal dominant pattern, therefore several generations of relatives with stomach or lobular breast cancer are often seen clustering on one side of the family.  Gastric cancers that occur in this syndrome are of the “diffuse” type (as opposed to “intestinal”) and often have “signet ring” cells through the stomach wall causing thickening (“linitis plastica”) without forming a discrete mass.  The average age of onset of gastric cancer in HDGC is 38 years old, with individuals as young as 14 having been diagnosed.  The estimated lifetime risk of developing gastric cancer by age 80 is 67% for men and 83% for women.  Women with HDGC also have an elevated risk of breast cancer, predominantly of the lobular type, with a 20 -- 40% lifetime risk.  Most of these women are over 50 at diagnosis.  Mutations in the E-cadherin (CDH1) gene have been identified in SOME families with this syndrome and genetic testing is now available.  However, CDH1 mutations cause only 1-3% of all gastric cancers and in families with a strong history of diffuse gastric cancer, only one-third to one-half are due to CDH1 mutations.  Therefore genetic testing for CDH1 should be undertaken in partnership with a genetics professional who can assess the likelihood that CDH1 testing would be useful for a particular family and is able to interpret test results appropriately.  CDH1 testing should be considered in any of the following situations:

1) Two or more cases of diffuse gastric cancer in a family, with at least one diffuse  gastric cancer diagnosed before the age of 50 years.

2) Three or more cases of diffuse gastric cancer in a family diagnosed at any age.

3) An individual diagnosed with diffuse gastric cancer before 35 years of age.

4) An individual diagnosed with both diffuse gastric cancer and lobular breast  cancer.

5) One family member with diffuse gastric cancer and another with either lobular  breast cancer OR signet ring colon cancer.

Genetic Counseling and Genetic Testing for HDGC

CDH1 is the only gene known to be associated with HDGC at this point in time, and only accounts for one-third to one-half of families with HDGC.  Mutations of CDH1 have now been found over 100 families of diverse ethnic background, European, African American, Pakistani, Japanese, Korean and others.

Sequence analysis of the CDH1 gene has been available for several years on a research basis, and is now performed on a clinical basis through the Stanford Molecular Diagnostics Laboratory .A parent who carries a CDH1 mutation will have a 50% chance of passing on the mutation to each of their children. Most CDH1 families will have several generations of relatives affected, but it is possible to have a carrier parent who has not been diagnosed with gastric cancer or breast cancer.  In addition, an individual with HDGC may have the disorder as a result of a new (de novo) gene mutation.  This means the individual has a new change in one of their CDH1 genes that occurred prior to their conception but was not present in either parent.  

For families that meet criteria 1 or 2, above, approximately 30 - 40% have been found to carry CDH1 mutations.  Individuals meeting criteria 3 (no family history, gastric cancer less than 35 years old) have had a 10 - 20% chance of harboring a CDH1 mutation. 

Genetic testing ideally should begin with a relative who has had gastric or lobular breast cancer to determine whether a CDH1 mutation is associated with their cancer.  If a mutation is found, then unaffected relatives can be confident that the CDH1 test will accurately predict whether they have inherited HDGC or not.  However, given the poor outcomes of individuals diagnosed with gastric cancer, many families do not have a living affected relative, and will need to consider CDH1 testing that may be inconclusive.  Testing at-risk children younger than 18 from HDGC families is generally not recommended.  However, there have been isolated reports of teenagers being diagnosed with diffuse gastric cancer, and so individual situations will need to be carefully discussed with the genetic counselor.

Gastric cancers have also been found in other hereditary cancer syndromes.  For example, up to 10% of hereditary non-polyposis colon cancer (HNPCC) families include gastric cancers, though mostly of the “intestinal” pathologic type.  In addition, Li-Fraumeni syndrome (p53 gene), familial adenomatous polyposis (APC gene) and Peutz-Jehgers syndrome (STK11 gene) all exhibit elevated rates of gastric cancers compared to the general population.   The incidence of HDGC in the general popoulation remains to be well-defined, but HDGC probably accounts for only 1 - 3% of gastric cancers. Estimates suggest that up to 10% of patients diagnosed with gastric cancer will have some family history of gastric cancer.  Many of these will likely be attributable to other gastric cancer genes and/ or environmental factors that families tend to share.

Screening and Management of Gastric Cancer in HDGC Syndrome

Diagnosing gastric cancer in its early stages provides the best chance for survival but is a difficult task. Symptoms due to gastric cancer often do not appear until the disease is more advanced and are generally non-specific.  When the diagnosis of gastric cancer is established, it is most often advanced.  A total gastrectomy (surgery to remove the entire stomach) is indicated in an individual with HDGC and any evidence of stomach cancer, as typically even a small number of cancer cells on a biopsy means there are multiple areas of hidden tumor throughout the entire stomach.

For those individuals carrying known CDH1 mutations, but without evidence for gastric cancer, recommendations include intensive and regular screening with endoscopy (a flexible scope passed down the throat to examine the surface of the stomach and take small samples or biopsies) every 6 - 12 months with multiple biopsies of any suspicious site as well as random biopsies throughout the stomach. Endoscopy is generally considered to be the best method to screen for gastric cancer, but diagnosing diffuse gastric carcinoma is most difficult, as these cancer cells do not form a visible mass, but rather spread under the surface of the stomach as single cells or clustered islands of cells.  New techniques for diagnosing diffuse gastric cancer cells are under investigation but none have been proven effective in early detection at this time. 

Therefore, individuals from HDGC families should also discuss the option of prophylactic (preventative) total gastrectomy.  The lifetime risk of stomach cancer is very high in CDH1 carriers and without a proven effective screening test, surgery is a realistic and reasonable option.  Gastrectomy in CDH1 gene carriers has to date been performed in only a very few patients.  However, our experience at Stanford suggests that this may be the best approach to prevention at the current time.  We have studied individuals from several families with HDGC (including one large family with 10 CDH1 mutation carriers) to evaluate the usefulness of several screening tests including upper GI endoscopy with random gastric biopsies, high-magnification endoscopy with methylene blue chromoscopy, endoscopic ultrasonography, CT and PET scans, and circulating tumor markers. 

All these patients elected to proceed with a prophylactic gastrectomy following these studies.  In every patient to date, all screening tests have been normal, and yet on microscopic analysis after surgery, every patient had multiple clusters of invasive signet ring gastric cancer throughout the stomach.  As all these clusters were very early, Stage 1, the likelihood that surgery provided a complete cure is very high.  Nevertheless, this experience makes it difficult to have confidence in our current ability to adequately screen for gastric cancer in HDGC families.  We and other groups are exploring new technologies and approaches for screening, but consideration of a prophylactic gastrectomy should be seriously discussed as part of genetic counseling for HDGC.  The decision to carry out a prophylactic gastrectomy must consider the 1-2% risk of death associated with the procedure and nearly 100% risk of long term complications such as chronic diarrhea, dumping syndrome and weight loss, 10% rate of post-surgical complications including infection, and leakage at the surgery site as well as the fact that not every CDH1 carrier will develop gastric cancer. 

HDGC patients seriously considering prophylactic gastrectomy should make sure their surgeon is well experienced in this procedure and is knowledgeable about HDGC cancer risks to ensure that the best technique is chosen while minimizing the risk of surgical complications.

There remain many open questions that will require long-term follow up of HDGC families, including whether the presence of hidden cancer cells found after surgery absolutely predicts for eventual progression to invasive gastric cancer and at what age is surgical prevention most appropriate. 

Clearly, any such procedures should be discussed with genetic and surgical professionals at an established high-risk cancer program. Future studies will need to evaluate the effect on quality of life after preventative gastrectomy,  long-term survival, and the risk for development of other cancers.

Screening and Prevention of Lobular Breast Cancer in HDGC

Women in families with HDGC and carrying mutations in the CDH1 gene have a significant risk to develop lobular breast cancer, with lifetime estimates from 20 - 40%.  The correct approach to screening for lobular breast cancer in women with HDGC is not known, but it is reasonable to adapt the screening recommendations for women at high genetic risk of breast cancer for other reasons such as carrying a BRCA1 or BRCA2 mutation. 

Calcifications are not ordinarily formed by infiltrating lobular carcinomas, so more intensive screening with mammography, which is especially adept at detecting calcifications, may not be effective.  For BRCA1/2 mutation carriers, prophylactic mastectomy has been shown to effectively prevent the development of breast cancer and to result in improved long-term survival. Such an approach remains completely investigational for women in HDGC families, and at this point no data as to its success or even application have been reported.  Current approaches for screening in high-risk women carrying CDH1 mutations at Stanford include annual bilateral breast MRI, which has been shown to be very sensitive in detecting early breast cancers in women with BRCA1/2 mutations. 

Furthermore, there is evidence that breast MRI is more sensitive than mammography or ultrasound for detecting lobular cancers, and thus may be even more appropriate in women with HDGC.  Also unknown is whether chemoprevention with tamoxifen, raloxifene, or other newly developed drugs may benefit women with HDGC.  However, results from the Breast Cancer Prevention Trial demonstrated a 50% reduction in breast cancer in women at elevated risk due to age, family history or history of lobular carcinoma in situ (LCIS) who were taking tamoxifen.  In particular, the reduced risk of invasive breast cancer seen in women with a history of LCIS suggests that tamoxifen chemoprevention may also benefit women with HDGC. 

A similar benefit was shown for post-menopausal women with LCIS who took raloxifene in the recent Study of Tamoxifen and Raloxifene (STAR).  Given a generally more tolerable side effect profile, raloxifene might be considered as an alternative to tamoxifen in post-menopausal women with HDGC who desire breast cancer chemoprevention, with the understanding that neither drug has been tested specifically in carriers of CDH1 mutations.  The incidence of estrogen or progesterone receptor expression in HDGC associated lobular breast cancer is not known, however, the rate of estrogen positive sporadic lobular carcinomas is close to 50%.

Published Review of Clinical Management and Molecular Genetics of HDGC 
CDH1 Testing at Stanford (Forms)

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