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HDGC CLINICAL GUIDELINES – COMMENTARY

Additional explanation, information, comments, and glossary of terms related to the published HDGC Clinical Practice Guidelines can be found here.

This page is always evolving. Feel free to suggest additional information for inclusion on this page that is relevant to the HDGC clinical guidelines and management of HDGC patient and family care.

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HEREDITARY DIFFUSE GASTRIC CANCER: UPDATED CLINICAL PRACTICE GUIDELINES

Hereditary Diffuse Gastric Cancer: Updated Clinical Practice Guidelines

Blair, et al. 2020, Hereditary Diffuse Gastric Cancer: Updated Clinical Practice Guidelines. The Lancet Oncology. (Published online August 2020)

HDGC CLINICAL MANAGEMENT GUIDELINES - COMMENTARY

Commentary Topics


About cancer risk statistics
Colon cancer risk
Questions to ask your medical team

About cancer risk statistics

Statistics will change as data changes. Data collection is ongoing.

For purpose of example, these are statistics from the HDGC 2015 Guidelines
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, and what is CI ? 

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.

Colon cancer risk

2020 Guideline states: “…no strong evidence that the risk of other cancer types is significantly increased in individuals with a CDH1 pathogenic variant.”
Note from Karen: Talk to your medical care provider about 2010 guideline and current guidance for colon cancer screening if you have family history of colon cancer.

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

2010 Guideline states: “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 mucinous 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 of colon cancer, whichever is younger, and repeated at intervals of 3-5 years. It is imperative that data on colonoscopic screening in these individuals are collated so that these guidelines can be evidence based in the future.”

Questions to ask your medical team

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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