Hereditary stomach cancer

Editorial

How common is stomach cancer?1

Gastric cancer (also called stomach cancer) has historically been the most common form of cancer in the world. During the past decades the frequency has decreased, and today gastric cancer is the fifth most common cancer in the world. This is likely due to a change in diet and better treatment of ulcers caused by Helicobacter pylori (see more under “what causes gastric cancer”). Today gastric cancer is most common in east Asia, predominantly in Japan and South Korea. Gastric cancer is uncommon before 50 years of age and most individuals are over 65 when diagnosed.

What causes stomach cancer?1

About 80-90% of all gastric cancer is caused by DNA damage, which can occur during DNA replication or be due to environmental factors. DNA damage occurs all the time and most of the time it is repaired. But with age comes an accumulation of DNA damage, and in turn a higher likelihood that a normal cell transforms into a cancer cell. Age is therefore the leading risk factor for cancer. One important risk factor for gastric cancer is being infected with the bacteria Helicobacter pylori (which can cause ulcers), doubling the risk for gastric cancer.

The remaining 10 to 20% of all gastric cancer is due to hereditary factors. The impact of hereditary factors on the risk of developing gastric cancer can range from small to very large. What they have in common is that individuals with a hereditary risk of cancer are born with one high-risk genetic variant or several low-risk DNA variants present in all cells. These variants often affect proteins involved in DNA repair or in other ways protect cells from becoming cancer cells. Therefore, the ability to protect cells from becoming cancer cells may be impaired which results in further DNA damage. Normal cells in individuals with a hereditary risk of cancer thus have a higher probability of becoming cancer cells.

Underlying genetic factors1,2

There are two main types of hereditary gastric cancer, diffuse and intestinal gastric cancer. Gastric cancer can also occur in individuals with Lynch syndrome,FAP, juvenile polyposis, and Peutz-Jeghers syndrome. A gastric cancer diagnosis before 50 years of age or two or more close relatives with gastric cancer may indicate an underlying genetic contribution to disease development. Increased risk of lobular breast cancer is also associated with hereditary gastric cancer and may therefore also by an indicator of hereditary gastric cancer. All indicators of hereditary gastric cancer can be found here

A causative pathogenic variant (mutation) can be identified in about 1 – 3% of individuals with hereditary gastric cancer. Clinical genetic testing only tests genes associated with diffuse gastric cancer (or genes associated with other hereditary cancer syndromes if suspected based on the family history). There is no known genetic cause of intestinal gastric cancer as of today.

Families that fulfill the criteria for hereditary diffuse gastric cancer are primarily tested for pathogenic variants in the CDH1 gene, which are the cause of cancer in about 40% of these families3. Pathogenic variants in the CDH1 gene are associated with an increased risk of gastric cancer and lobular breast cancer. The CDH1 gene is included in the GeneMate® test*. Sometimes a gene called CTNNA1 is analyzed as well. Pathogenic variants in this gene have been found in a few families with hereditary gastric cancer.

Risk-reducing measures for healthy carriers of a CDH1 or CTNNA1 variant 1,2

Below screening programs are recommended for individuals with a pathogenic variant in CDH1 or CTNNA1 (full list of recommendations can be found here):

  • For carriers of a CDH1 variant with a family history of diffuse stomach cancer the recommendation is to remove the stomach by prophylactic surgery at about 20 to 30 years of age.

  • For carriers of a CTNNA1 variant with a family history of diffuse stomach cancer the recommendation is yearly gastroscopy and eradication of Helicobacter pylori.

  • For carriers of a CDH1 or CTNNA1 variant without a family history of diffuse stomach cancer the recommendation is yearly gastroscopy and eradication of Helicobacter pylori.

  • Female CDH1 carriers are recommended yearly breast exams from 30 years of age.

Risk-reducing measures for individuals without a variant1,2

As previously mentioned only a subset of the hereditary risk of gastric cancer can be assigned to a pathogenic variant. In most families the cause of the familial cancer is still unknown. What these families have in common is an increased risk of gastric cancer that motivates screening for healthy individuals. Family members in families with a hereditary risk of diffuse gastric cancer are recommended yearly gastroscopy with biopsy from 40 years of age. In families with hereditary intestinal gastric cancer, only first-degree relatives (siblings, children, and parents) of an individual with cancer are recommended yearly gastroscopy.

The GeneMate® test combines a genetic test with an assessment of your family’s cancer history, either of which can indicate an increased risk hereditary gastric cancer. Therefore, it is important that you provide comprehensive information about your family’s cancer history (if available). We will help you get in contact with the appropriate care provider if cancer screening is motivated.

* GeneMate® test for pathogenic variants in the CDH1, APC, SMAD4, BMPR1A, STK11, and TP53 genes, which all are associated with hereditary gastric cancer. The full panel can be found at genemate.se.

 

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Anna Hellquist, Genetic Counselor at iCellate Medical AB, PhD Cell and Microbiology

 

References

  1. Nationellt vårdprogram matstrups- och magsäckscancer - RCC Kunskapsbanken. https://kunskapsbanken.cancercentrum.se/diagnoser/matstrups-och-magsackscancer/vardprogram/bakgrund-och-orsaker/

  2. PM – Ärftlig ventrikelcancer - Version 2020-12-25. https://sfmg.se/download/riktlinjer/Cancergenetik/Arftlig-ventrikelcancer_201225.pdf. Accessed January 27, 2021.

  3. Hansford S, Kaurah P, Li-Chang H, et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. 2015;1(1):23–32. doi:10.1001/jamaoncol.2014.168