The Role of Genetic Testing In Evaluating For Inherited Causes Of Stomach Cancer

Most patients diagnosed with cancer will at some point ask the question, “Why did this happen to me?” For the vast majority of patients, however, medical science is unable to provide a satisfying answer to this question. One key exception is when an individual develops cancer due to specific hereditary factors that can sometimes be identified by genetic testing.

It has long been recognized that some families are particularly prone to developing cancer. For some of these families, genetic testing can identify specific changes in the DNA (called mutations) than can be inherited from one generation to the next that can cause an increased risk of cancer. It is worth pointing out that there are different types of genetic testing. Genetic testing can be done to evaluate the DNA that a person inherited from their parents (also known as germline DNA) which does not change throughout someone’s lifetime and can be passed on to an individual’s children. On the other hand, genetic testing can also be performed on a tumor specimen (often called tumor profiling or somatic genetic testing) to help understand the DNA mutations that developed in a person’s tumor. DNA mutations found in a tumor specimen are typically not inherited and cannot be passed on to other family members.

Genetic testing of someone’s germline DNA to look at specific cancer risk genes can be an important tool in identifying people who are born with an increased risk of cancer. Genetic testing, however, is not a perfect science. It can deliver “positive” results (where a proven mutation is found in a cancer risk gene that indicates the person has inherited an increased risk of developing cancer), “negative” results (where no mutation is found, although the person may still be at increased risk for cancer based on their family history and/or other factors), and indeterminate results, also called “variants of uncertain significance,” or VUS (where a germline DNA change is identified, but it is unclear whether or not this change leads to an increased risk of cancer).

Genetic testing can sometimes identify specific inherited syndromes that cause an increased risk of stomach cancer, including Hereditary Diffuse Gastric Cancer Syndrome (caused by germline DNA mutations in the CDH1 gene and, rarely, the CTNNA1 gene), Lynch Syndrome or Hereditary Nonpolyposis Colorectal Cancer (caused by germline DNA mutations in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes), Juvenile Polyposis Syndrome (caused by germline DNA mutations in the BMPR1A or SMAD4 genes), Peutz-Jeghers Syndrome (caused by germline DNA mutations in the STK11 gene), Cowden Syndrome (caused by germline DNA mutations in the PTEN gene), and Li-Fraumeni Syndrome (caused by germline DNA mutations in the TP53 gene). Each of these syndromes is also linked to risks of cancer other than stomach cancer, and anyone who is considering testing for one of these syndromes is strongly recommended to consult with a licensed genetic counselor before and after undergoing testing to assist in accurately interpreting the results. With further research in cancer genetics, it is likely that other genes will eventually be linked to inherited risks of stomach cancer as well.

There are certain features that patients and doctors should know about that can sometimes indicate that someone should undergo genetic testing for one or more of these syndromes. These features include (but are not limited to): an individual who is diagnosed with stomach cancer at a young age (under the age of 50); an individual who is diagnosed with stomach cancer and another cancer (especially breast cancer or colorectal cancer); having numerous family members with stomach cancer; having numerous family members with stomach cancer and other cancers (including colorectal cancer, uterine cancer, ovarian cancer, breast cancer, and pancreatic cancer); having a history of both stomach cancer and many polyps in the intestinal tract. Please note that these are meant to serve only as examples. Many people with these histories will not have a germline DNA mutation identified on genetic testing. On the other hand, some people with a germline DNA mutation in a stomach cancer risk gene may have histories that do not fit with any of these examples.

Genetic testing for inherited risks of cancer is a very personal decision and interpretation of genetic testing results (even negative) can be complex. It is very important that anyone considering such testing talk with their doctors and meet with a licensed genetic counselor and/or cancer genetics specialist to discuss this process before undergoing testing. To find a genetic counselor, visit the Resources on the Debbie’s Dream website at

Matt Yurgelun, MD
Dana-Farber Cancer Institute
Gastrointestinal Cancer Center
Cancer Genetics & Prevention Program
November 20, 2015