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HDGC CLINICAL GUIDELINES – COMMENTARY

The content on this page is intended to be a companion resource for the patient audience, providing additional explanation, information and definition of terms found in the HDGC Clinical Guidelines publication. The format is laid out in sections that follow the sections in the HDGC Clinical Guidelines publication. Also included are suggestions for questions to ask your health care provider(s) as well as food for thought when relevant.

The intent is to provide a tool to improve patient and family understanding of the nature of the disease and associated risk, and to improve communication with your health care team, all of which will lead to making informed decisions and advocating for the health care needs for yourself and your family.

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THIS SECTION IS A WORK IN PROGRESS. THANK YOU FOR YOUR PATIENCE!

HEREDITARY DIFFUSE GASTRIC CANCER: UPDATED CLINICAL GUIDELINES WITH AN EMPHASIS ON GERMLINE CDH1 MUTATION CARRIERS

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

van der Post RS, et al. J Med Genet 2015;52:361–374. doi:10.1136/jmedgenet-2015-103094

ABSTRACT

FULL TEXT OF ABSTRACT

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient’s perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

KEY POINTS | SUMMARY

The document abstract is a brief summary of the HDGC Clinical Guidelines to help in understanding the purpose of the document. The full text of the abstract is provided above.

The glossary of terms below contains terms found within this abstract section. A full glossary of terms for the entire HDGC Clinical Guideline document is provided following the summary of all guideline sections.

The following is an easy to read overview of the newly revised CDH1 testing criteria stated in the abstract above.

The updated HDGC Clinical Guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives), as follows:

  • families with two or more cases of gastric cancer at any age, one confirmed to be DGC
  • individuals diagnosed with DGC before the age of 40
  • families with diagnoses of both DGC and LBC, with one diagnosis occurring under age 50

CDH1 testing could also be considered in the following situations:

  • patients with bilateral or familial LBC before age 50
  • patients with DGC and cleft lip/palate
  • patients with precursor lesions for signet ring cell carcinoma

GLOSSARY OF TERMS

abstract – A brief summary of a paper (research article, thesis, review, in-depth analysis of a particular subject, etc.) and is often used to help the reader quickly ascertain the paper’s purpose.

bilateral LBC – Independent cancers in both breasts. The cancer in one breast hasn’t spread from the other.

CDH1 gene – The human genome is made up of 20,000 genes, each encoding a different protein that carries out one or more of the jobs a cell needs to live and grow. CDH1 is one of those genes, and encodes a protein called E-cadherin. The role of E-cadherin is to hold cells together, helping to build tissues and organs.

cleft lip/palate – Openings or splits in the upper lip, the roof of the mouth (palate) or both. Cleft lip and cleft palate result when facial structures that are developing in an unborn baby don’t close completely.

diffuse gastric cancer (DGC) – Also known as signet ring cell adenocarcinoma or linitis plastica, DGC grows rapidly in the lining of the stomach wall. These aggressive cancer cells do not form a mass; rather they are diffused (scattered widely or thinly) in the lining of the stomach wall.

familial cancer – Cancer that occurs in families more often than would be expected by chance. These cancers often occur at an early age, and may indicate the presence of a gene mutation that increases the risk of cancer. They may also be a sign of shared environmental or lifestyle factors.

first-degree relative – The parents, siblings, or children of an individual.

germline mutation – A germline mutation is a genetic variant that is present in a body’s germ cells (reproductive cells: sperm or egg) that becomes incorporated into the DNA of every cell in the body of the offspring. Germline mutations can be passed on from a parent to their offspring at the time of conception. Understanding a somatic mutation may help in understanding differences between hereditary gene mutations and non-hereditary mutations. A somatic mutation can occur in any of the cells of the body (skin, breast, stomach, liver, muscle, etc.) except the germ cells (sperm and egg) and therefore are not passed on to offspring. An alteration in DNA occurs after conception. These alterations can (but do not always) cause cancer or other diseases. Sporadic cancers (i.e. non-hereditary) are caused by somatic mutations in a cell where the cancer starts.

histopathological – The area of pathology that deals with the structure of diseased or abnormal tissue. Pathology is the scientific study of disease and its causes, processes, development and consequences.

lobular breast cancer (LBC) – Cancer that begins in the lobules (milk glands) of the breast.

mortality – Mortality is another term for death. A mortality rate is the number of deaths due to a disease divided by the total population.

multidisciplinary – Combining or involving more than one field of study or area of specialty.

pathogenic – Causing or capable of causing disease.

precursor lesion – A cluster of abnormal cells that have not yet become cancerous. In situ lesions are an example of a precursor lesion. This refers to cells that are abnormal looking but have not moved from their normal cellular location. Stage T1a is the earliest stage of cancer in which abnormal cells have begun to move into the stomach’s underlying layers. Stage 1a cancers are sometimes also called precursor lesions because they are very slow growing and do not readily invade into deeper layers.

prophylactic total gastrectomy (PGT) – Preventive complete surgical removal of the entire stomach.

screening – Individuals having endoscopy who do not know their mutation status, or those who do not have a proven pathogenic CDH1 mutation undergo screening.

second-degree relative – The aunts, uncles, grandparents, grandchildren, nieces, nephews, or half-siblings of an individual.

signet ring cell carcinoma – Also known as Diffuse Gastric Cancer (DGC) an aggressive type of cancer cell usually found in glandular cells that line the stomach or other digestive organs. The cells resemble signet rings (a finger ring with a small seal) when examined under a microscope.

surveillance – Individuals having endoscopy who are mutation-positive undergo surveillance.

VUS (Variant of Uncertain Significance) mutation – A VUS is a germline mutation with unclear effect, meaning that it is unclear whether or not the DNA change actually increases disease risk.

INTRODUCTION

KEY POINTS | SUMMARY

Gastric Cancer Statistics

  • Gastric cancer is the fifth leading cause of cancer and the third most common cause of cancer death worldwide.
  • Estimated number of deaths from gastric cancer globally is 723,000 annually.
  • The majority of gastric cancers are sporadic.
  • 1-3% of gastric cancers arise as a result of inherited cancer predisposition syndromes.

HDGC and CDH1 Gene Mutations

  • Over 15 years ago, the CDH1 gene was implicated as the genetic cause of Hereditary Diffuse Gastric Cancer (HDGC). Mutations in the CDH1 gene stop the normal function of a protein called E-cadherin.
  • Heterozygous germline CDH1 mutations increase lifetime risk of developing DGC, and also for LBC in women.
  • Criteria have been set to select families eligible for screening of germline CDH1 mutations, and they were updated in 2010.
  • Not all families fulfilling these criteria have mutations in CDH1, indicating that other genes may be involved in DGC predisposition.
  • Germline mutations in CTNNA1 were described in three families that presented with DGC, one of them fulfilled the 2010 HDGC criteria.

About the HDGC Guidelines

  • Increasing awareness of HDGC and the rapid advances in genetic diagnostic tools, endoscopic modalities and the increasing use of laparoscopic surgery led a group of clinical geneticists, gastroenterologists, surgeons, oncologists, pathologists, molecular biologists, dieticians and patients’ representatives from nine different countries to convene a workshop in order to update the management guidelines for this condition set in 2010 and to propose directions for future research.
  • The workshop discussions were focused on five major topics: (1) genetic counselling and mutation analysis; (2) endoscopic surveillance and screening of cancer; (3) risk-reduction surgery of the stomach and breasts; (4) pathological specimen processing and diagnosis; and (5)patients’ and dieticians’ perspective.

FOOD FOR THOUGHT

Criteria have been set to select families eligible for screening of germline CDH1 mutations, and they were updated in 2010

The Chelcun family, along with other families, did not meet the 1999 criteria, nor these updated 2010 criteria that were published a few years after our family diagnosis in 2008. We pushed for genetic testing after learning about HDGC online. I trusted my gut. Had we not pushed, had we not advocated for ourselves, it is hard to say how many more losses we would have endured in our small family.

To patients and families who feel they may be at risk: this criteria is a guideline for genetic testing. It is not a rule. If you feel that something is going on medically or genetically in your family, whether HDGC or something else, keep pressing on until you get the answers you need to care for yourself and your family.

The 2015 guideline (the one we are looking at here) has also been updated with expanded criteria for screening of families for the CDH1 mutation. You’ll learn more about this in the next section on Genetic Counselling and Mutation Analysis. This is due in part to the patient advocacy voice being heard. Never hesitate to Make Your Voice Heard! Under the 2015 guideline my family would have met the screening criteria back in 2008.

GLOSSARY OF TERMS

diffuse gastric cancer (DGC) – Also known as signet ring cell adenocarcinoma or linitis plastica, DGC grows rapidly in the lining of the stomach wall. These aggressive cancer cells do not form a mass; rather they are diffused (scattered widely or thinly) in the lining of the stomach wall.

heterozygous germline CDH1 mutation –

linkage analysis – A technique used to find genes associated with particular traits or illnesses. If two genes sit near each other in the genome, they will be ‘linked’. That is, if someone inherits one of the genes, it is highly likely they will inherit the other one too. Linkage analysis relies on a genetic map, which is a large collection of markers with known locations in the genome. In the analysis, researchers look for a marker which happens to always occur in people from a family with the trait or disease. If they find one, they know the trait or disease gene (a normal gene, but with a mutation in it that affects its function) is very close to that marker. Since the location of that marker is known, its a small additional step to then find the gene you are after.

lobular breast cancer (LBC) – Cancer that begins in the lobules (milk glands) of the breast.

sporadic – Appearing in scattered or isolated instances.

GENETIC COUNSELLING AND MUTATION ANALYSIS (in progress . . . )

KEY POINTS | SUMMARY

Genetic evaluation of patients with HDGC

Genetic counselling is essential, and the process should include a professional evaluation by a genetic counselor specializing in genetic cancer.

The evaluation should include:

  • a detailed three generation family disease history (pedigree). These generations would generally be:
    • your grandparents on your mother’s side and your father’s side (maternal and paternal)
    • your birth parents (mother and father) and their blood relatives (their siblings | your aunts and uncles)
    • your generation (self, sisters, brothers)
  • histopathological confirmation of DGC diagnoses and/or precursor lesions. This information would come from a tissue biopsy report (pathology report) from someone in the family who has been diagnosed with DGC.
  •  

  • discussion about what your lifetime risk of developing DGC and LBC may be if you have a CDH1 gene mutation.

A full multidisciplinary team (MDT) should be involved in the management of individuals with a CDH1 mutation. The team should be comprised of those with relevant expertise in gastric surgery, gastroenterology, breast oncology, pathology, psychosocial support and nutrition.

Informed consent is required for genetic testing meaning that permission is granted with the knowledge of the possible implications of testing. Typically informed consent is given by a patient to a doctor for treatment. In this instance it is with full knowledge of the potential risks and benefits of genetic testing.

Genetic testing can be offered from the age of consent. This age may vary between states and countries, but is generally age 16-18. Younger people who do not have the disease can be considered for testing on a case-by-case basis. Rare cases have been reported in affected families, however the overall risk of this disease before the age of 20 is low.

Cancer risks in CDH1 mutation carriers

The following statistics were reported in the HDGC Guideline published in May 2015. Statistics will change as data changes. Data collection is ongoing.

In a recent study, penetrance data for CDH1 mutation carriers has been updated based on affected individuals, who presented clinically with DGC or LBC, from 75 families with pathogenic CDH1 mutations. Families with CDH1 missense mutations and families for which no carrier test information was available were excluded from this analysis.

The cumulative risk of DGC for CDH1 mutation carriers by age 80 years is reported to be:
70% for men (95% CI 59% to 80%)
56% for women (95% CI 44% to 69%)

The cumulative risk of LBC for women with a CDH1 mutation by age 80 yearis estimated to be:
42% (95% CI 23% to 68%)

What exactly does this mean? Parry Guilford explains . . .

These statistics will continue to change as researchers have more data, which is why you see a change in the last guideline update. Using the statistics for LBC risk stated above and in the 2015 guideline:

LBC risk for women as stated – – – 42% for women (95% CI 23% to 68%)

This means the most likely risk of LBC for a woman with a pathogenic CDH1 mutation is 42% in her lifetime. However, there is some uncertainty about that number. Uncertainty decreases with more data, but for LBC we don’t have that much data yet, so the uncertainty is quite high.

The confidence interval (CI) is a way of quantifying this uncertainty. If the CI is really broad, there is quite a bit of doubt about the exact figure; a narrow CI indicates more confidence.

A 95% CI followed by a range means we are 95% certain the actual risk falls inside the specified range. So we are 95% certain that a woman’s risk is somewhere between 23% and 68%. Inside that range, imagine a bell shape. The edges of the bell are at 23% and 68% and the deepest part of the bell (the middle) is at 42%. The depth of the bell indicates the probability, so the most likely risk is 42%, and it decreases from there (in both directions, but not in a straight line but instead in the shape of a bell).

As we get more data, the confidence interval should get smaller- meaning the body of the bell will get narrower. It might keep the same peak (42%) but the possible range should tighten, although a lip might remain on the bell. This lip represents the outliers – the people who just behave quite differently.

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On other cancer risks the 2015 Guideline states the following: “There is currently no evidence that the risk of other cancer types in individuals with a CDH1 mutation is significantly increased”

This is a change from the 2010 guideline, which stated the following: “There is also emerging evidence for an increased risk of colon cancer in HDGC families and these colon cancers can display signet ring cell features. In CDH1 families in which colon cancer is reported, information should be collected concerning the age at diagnosis, whether the affected member(s) are first or second degree relatives, and whether the pathology was mucinour or showed signet ring cells. Depending on these factors enhanced screening should be considered with colonoscopy beginning at age 40 or 10 years younger than the youngest diagnosis o colon cancer, whichever is younger, and repeated at intervals of 3-5 years. It is imperative that data on colonoscopies screening in these individuals are collated so that these guidelines can be evidence based in the future.”

Implications of counselling

Clinical geneticists or another member of the multidisciplinary team should inform the patient about gastric surgery and options of surveillance. The recommended course of treatment for patients having a pathogenic CDH1 mutation should be to undergo preventive total gastrectomy. More information on this can be found in the Gastrectomy and Mastectomy section of the guideline.

It is acknowledged that patients may choose to delay surgery for personal and/or work related reasons. For these patients endoscopic surveillance should be considered in the interim. Protocols for surveillance are detailed in the Screening and Surveillance section of the guideline. In addition, a supplemental endoscopy protocol can be found here.

The management of patients and families who meet the criteria for genetic testing but do not have a germline CDH1 mutation is not straightforward. Intensive endoscopic surveillance in an expert centre for first-degree relatives of patients meeting the criteria outlined in Figure 1 below, and for those carrying a CDH1 variant with unproven deleterious effect is advised. Endoscopic surveillance is performed by a gastroenterologist, following the endoscopy protocol in the Screening and Surveillance section of the guideline that includes examining the inside of the stomach using a camera and taking many biopsy samples in specific areas of the stomach for biopsy.

Recommendations on breast cancer surveillance and therapy in CDH1 mutation carriers is found in the Screening and Surveillance section of the guideline.

Criteria for germline CDH1 mutation testing

The first paragraph of this guideline section discusses statistics related to the broadened clinical criteria for genetic testing for CDH1 from 1999 to 2010. Those interested in these statistics would be best served to read them directly from the original guideline document.

An important change occurred in the HDGC genetic testing criteria from the 2010 guideline to the 2015 guideline as follows:

The first two testing criteria from 2010 guideline…

  • Two or more GC (gastric cancer) cases in a family, one confirmed DGC (diffuse gastric cancer) under age 50
  • Three or more DGC cases in 1st or 2nd degree relatives regardless of age

…have been merged together and updated in the 2015 criterion:

  • Two or more GC cases regardless of age, at least one confirmed DGC, in 1st and 2nd relatives

The revised criteria are depicted in Figure 1 of the guideline document (above). The revised criterion now covers families for whom detailed pathology (confirmed DGC) is incomplete.

Karen’s Note: This may often be the case in families who have had instances of DGC in their family history when there was little knowledge or reference to the disease in pathology reports and on death certificates where it may simply say “gastric adenocarcinoma”. With a second diagnosis of GC in a family today, regardless of age, an experienced pathologist can determine whether or not the cancer is the diffuse type or the intestinal type.

Confirmed intestinal-type GC cases are NOT part of HDGC and in these families no CDH1 mutation analysis should be performed. To properly assess whether a family meets the HDGC criteria pathology reports and preferably review of gastric specimens by a pathologist dedicated to GC are essential.

Karen’s Note: This is why it is imperative to know the type of GC in your family.

Other criteria in which families may be considered for genetic testing are:

  • Bilateral LBC under the age of 50
  • Multiple close relative with LBC (at least two under the age of 50)
  • Personal or family history of cleft lip \ cleft palate in a patient with DGC
  • Cases where expert pathologists detect in situ signet ring cells and/or pagetoid spread of signet ring cells in the stomach

Whenever possible genetic testing would begin first with a person with cancer (the affected proband). If this person is deceased tissue biopsy samples or surgical tissue samples from that person could be tested for a CDH1 mutation.

If no tissue is available from the person with cancer, testing of unaffected relatives is acceptable. This should be performed preferably in at least three first-degree relatives simultaneously, which increases likelihood of detecting a CDH1 mutation. However, unaffected individuals have only a 50% chance of having inherited a mutated CDH1 gene.

If no mutation is found in these cases, endoscopic screening should be discussed with an expert gastroenterologist on a case-by-case basis.

In addition small families with DGC or where family history is unavailable, CDH1 mutation screening can be considered on a case-by-case basis.

Genetic testing: lab perspective

Panel sequencing

CDH1 mutation database

Psychosocial effects of counselling

Pregnancy and assisted reproduction

Future research: other genes involved in HDGC predisposition

FOOD FOR THOUGHT

Work in progress

QUESTIONS TO ASK

Work in progress

GLOSSARY OF TERMS

Work in progress

SCREENING AND SURVEILLANCE (work in progress)

KEY POINTS | SUMMARY

Work in progress

FOOD FOR THOUGHT

Work in progress

QUESTIONS TO ASK

Work in progress

GLOSSARY OF TERMS

Work in progress

GASTRECTOMY AND MASTECTOMY (work in progress)

KEY POINTS | SUMMARY

Work in progress

FOOD FOR THOUGHT

Work in progress

QUESTIONS TO ASK

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GLOSSARY OF TERMS

Work in progress

HISTOPATHOLOGY (work in progress)

KEY POINTS | SUMMARY

Work in progress

FOOD FOR THOUGHT

Work in progress

QUESTIONS TO ASK

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GLOSSARY OF TERMS

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POSTSURGICAL CARE AND NUTRITION (work in progress)

KEY POINTS | SUMMARY

Work in progress

FOOD FOR THOUGHT

Work in progress

QUESTIONS TO ASK

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GLOSSARY OF TERMS

Work in progress

PATIENT ADVOCACY AND NEXT STEPS IN PATIENT CARE AND HDGC RESEARCH (work in progress)

KEY POINTS | SUMMARY

Work in progress

FOOD FOR THOUGHT

Work in progress

QUESTIONS TO ASK

Work in progress

GLOSSARY OF TERMS

Work in progress

GLOSSARY OF TERMS

abstract – A brief summary of a paper (research article, thesis, review, in-depth analysis of a particular subject, etc.) and is often used to help the reader quickly ascertain the paper’s purpose.

bilateral LBC – Independent cancers in both breasts. The cancer in one breast hasn’t spread from the other.

CDH1 gene – The human genome is made up of 20,000 genes, each encoding a different protein that carries out one or more of the jobs a cell needs to live and grow. CDH1 is one of those genes, and encodes a protein called E-cadherin. The role of E-cadherin is to hold cells together, helping to build tissues and organs.

cleft lip/palate – Openings or splits in the upper lip, the roof of the mouth (palate) or both. Cleft lip and cleft palate result when facial structures that are developing in an unborn baby don’t close completely.

diffuse gastric cancer (DGC) – Also known as signet ring cell adenocarcinoma or linitis plastica, DGC grows rapidly in the lining of the stomach wall. These aggressive cancer cells do not form a mass; rather they are diffused (scattered widely or thinly) in the lining of the stomach wall.

familial cancer – Cancer that occurs in families more often than would be expected by chance. These cancers often occur at an early age, and may indicate the presence of a gene mutation that increases the risk of cancer. They may also be a sign of shared environmental or lifestyle factors.

first-degree relative – The parents, siblings, or children of an individual.

germline mutation – A germline mutation is a genetic variant that is present in a body’s germ cells (reproductive cells: sperm or egg) that becomes incorporated into the DNA of every cell in the body of the offspring. Germline mutations can be passed on from a parent to their offspring at the time of conception. Understanding a somatic mutation may help in understanding differences between hereditary gene mutations and non-hereditary mutations. A somatic mutation can occur in any of the cells of the body (skin, breast, stomach, liver, muscle, etc.) except the germ cells (sperm and egg) and therefore are not passed on to offspring. An alteration in DNA occurs after conception. These alterations can (but do not always) cause cancer or other diseases. Sporadic cancers (i.e. non-hereditary) are caused by somatic mutations in a cell where the cancer starts.

histopathological – The area of pathology that deals with the structure of diseased or abnormal tissue. Pathology is the scientific study of disease and its causes, processes, development and consequences.

linkage analysis – A technique used to find genes associated with particular traits or illnesses. If two genes sit near each other in the genome, they will be ‘linked’. That is, if someone inherits one of the genes, it is highly likely they will inherit the other one too. Linkage analysis relies on a genetic map, which is a large collection of markers with known locations in the genome. In the analysis, researchers look for a marker which happens to always occur in people from a family with the trait or disease. If they find one, they know the trait or disease gene (a normal gene, but with a mutation in it that affects its function) is very close to that marker. Since the location of that marker is known, its a small additional step to then find the gene you are after.

lobular breast cancer (LBC) – Cancer that begins in the lobules (milk glands) of the breast.

mortality – Mortality is another term for death. A mortality rate is the number of deaths due to a disease divided by the total population.

multidisciplinary – Combining or involving more than one field of study or area of specialty.

pathogenic – Causing or capable of causing disease.

precursor lesion – A cluster of abnormal cells that have not yet become cancerous. In situ lesions are an example of a precursor lesion. This refers to cells that are abnormal looking but have not moved from their normal cellular location. Stage T1a is the earliest stage of cancer in which abnormal cells have begun to move into the stomach’s underlying layers. Stage 1a cancers are sometimes also called precursor lesions because they are very slow growing and do not readily invade into deeper layers.

prophylactic total gastrectomy (PGT) – Preventive complete surgical removal of the entire stomach.

sporadic – Appearing in scattered or isolated instances.

screening – Individuals having endoscopy who do not know their mutation status, or those who do not have a proven pathogenic CDH1 mutation undergo screening.

second-degree relative – The aunts, uncles, grandparents, grandchildren, nieces, nephews, or half-siblings of an individual.

signet ring cell carcinoma – Also known as Diffuse Gastric Cancer (DGC) an aggressive type of cancer cell usually found in glandular cells that line the stomach or other digestive organs. The cells resemble signet rings (a finger ring with a small seal) when examined under a microscope.

surveillance – Individuals having endoscopy who are mutation-positive undergo surveillance.

VUS (Variant of Uncertain Significance) mutation – A VUS is a germline mutation with unclear effect, meaning that it is unclear whether or not the DNA change actually increases disease risk.

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