Polyposis syndromes

In an earlier post we wrote about hereditary colorectal cancer syndromes, which can be divided into Lynch syndrome and polyposis syndromes. In this post we will tell you more about the different polyposis syndromes, their causes, associated cancer types, and preventative or risk-reducing measures. Polyposis syndromes are all characterized by a large number of polyps in the gastrointestinal tract (up to 1000), The various polyposis syndromes are as follows:

Familial adenomatous polyposis (FAP)¹

90% of FAP cases are caused by pathogenic variants in the APC-gene. In about 80% of these cases the variant is inherited from a parent. For the remaining 20% the variant first occurred in an egg or sperm cell and after fertilization it was passed on to all cells in the body (de novo variant). The frequency of FAP is about 35 per 100 000 individuals.

FAP is characterized by the presence of between one hundred to one thousand polyps in the gastrointestinal tract, which can become cancerous if not removed. Therefore, individuals with FAP have a very high lifetime risk of developing colorectal cancer. By 40 years of age (median age) most of the individuals with untreated FAP will have developed cancer in the colon or rectum^1,2. There also exists a milder form of FAP with a slower tumor progression. Which form you have is dependent on where in the APC-gene the pathogenic variant is located.

To reduce risk of cancer, it is recommended that individuals with FAP undergo colonoscopy from about 12–15 years of age and until the number of polyps become too large. The latter usually occurs around 20 years of age, after which prophylactic removal of the colon by surgery is recommended. Endoscopy of the stomach and duodenum is recommended from 20-25 years of age.

MUTYH-associated polyposis (MAP)^1,3

MAP is caused by pathogenic variants in the MUTYH-gene. Unlike the other hereditary colorectal cancer syndromes, a pathogenic variant in MUTYH must be inherited from both parents to cause MAP. This is called autosomal recessive inheritance. Individuals with a pathogenic variant in one of their MUTYH-genes does not develop MAP. About 1% of the population are healthy carriers of a pathogenic variant in one of their MUTYH-genes. While these individuals will not develop MAP, they will have a somewhat increased risk of colorectal cancer as well as some other cancers.

MAP is characterized by the presence of a large number of polyps in the gastrointestinal tract (but fewer than in individuals with FAP) which can become cancerous if not removed. Therefore, individuals with MAP have a very high lifetime risk of developing colorectal cancer. MAP also increases risk of cancer in the duodenum, ovaries, bladder and breasts³.

It is recommended that individuals with MAP be offered the same risk-reducing measures as individuals with FAP.

Peutz-Jegher syndrome (PJS)⁴

80-94% of PJS cases are caused by pathogenic variants in the STK11-gene. In about 75% of these cases the variant was inherited from a parent. In the remaining 25% the variant first occurred in an egg or sperm cell and after fertilization it was passed on to all cells in the body (de novo variant). The frequency of PJS is about 1 in 8 300–29 000 individuals.

PJS is characterized by the presence of a large number of hamartomatous polyps in the gastrointestinal tract, which can become cancerous if not removed. Individuals with PJS have an increased lifetime risk of developing cororectal cancer. Women with PJS also have an increased risk of gynecological and breast cancer.

To reduce their risk of cancer, it is recommended that women with PJS undergo breast exams from 25 years of age as well as gynecological exams. It is recommended that men undergo screening to prevent testicular cancer. All individuals with PJS should undergo screening for colorectal, gastric, duodenum, and pancreatic cancer.

Juvenile polyposis syndrome (JPS)⁵

JPS is typically caused by pathogenic variants in either the BMPR1A gene (40%) or the SMAD4 gene (40 %). Some individuals with JPS have a deletion that encompass the entire PTEN and BMPR1A genes. It is a rare syndrome with a frequency of about 1 in 100 0000 to 1 in 160 000 individuals.

JPS is characterized by the presence of a large number of polyps in the gastrointestinal tract, which can become cancerous if not removed. Therefore, individuals with JPS have an increased lifetime risk of developing cancerin the stomach, small intestine, colon, rectum, and pancreas. The exact risk varies between individuals, likely depending on the gene in which the pathogenic variant is located.

To reduce risk of cancer, it is recommended that individuals with JPS undergo colonoscopy every 1-2 years from about 15–18 years of age (or earlier in the case of symptoms) and until 35 years of age. After that colonoscopy is done less frequently up until 70 years of age. Endoscopy of the stomach and duodenum every sixth months is recommended from about 25 years of age. Prophylactic removal of the colon by surgery may be considered in individuals with JPS.

Cowden syndrome^6,7

Pathogenic variants in the PTEN-gene can cause Cowden syndrome and individuals with this syndrome often have polyps in the gastrointestinal tract. It is not clear if these polyps can become cancerous if not removed, but it is likely. The risk of developing colorectal cancer is moderate in individuals with Cowden syndrome. Individuals with pathogenic variants in PTEN have an increased risk of thyroid cancer and women have an increased risk of breast and uterine cancer.

To reduce risk of cancer, individuals with a pathogenic variant in PTEN are recommended to be screened for thyroid, colorectal, and kidney cancer. It is recommended that women undergo yearly breast exams beginning at 30 to 35 years of age, as well as gynecological screening.

When to suspect a hereditary colorectal cancer syndrome, including polyposis syndromes¹

If anyone in the family has been diagnosed with colorectal or uterine cancer before 50 years of age.
If two or more in the same branch of the family have been diagnosed with colorectal cancer, one of which before 60 years of age.
If two or more in the same branch of the family have been diagnosed with colorectal, uterine, ovarian, small intestine, or urinary tract cancer, one of which before 60 years of age.

Risk-reducing measures in the absence of a genetic variant

As described in an earlier post, only a subset of the hereditary colorectal cancer risk is due to an identifiable pathogenic variant. Even in the absence of an underlying pathogenic variant, individuals may still have an increased risk as indicated by the family history. In these cases, a one-time colonoscopy is offered at 55 years of age to first-degree relatives of a family member diagnosed with colorectal cancer before 50 years of age or two family members^# diagnosed at 50 years or older. In the case of three family members^# with colorectal cancer, first-degree relatives should be offered colonoscopy every 5 years, starting 5 years before the earliest age of diagnosis in the family.

The GeneMate^® test includes a genetic test and an assessment of your family’s cancer history, either of which can indicate an increased risk of colorectal cancer. Therefore, it is important that you fill in your family history when ordering the test. We will help you get in contact with the appropriate care provider if cancer screening is motivated.

* GeneMate^®tests for pathogenic variants in the following genes: APC, MUTYH, STK11, BMPR1A, SMAD4 och PTEN. The complete panel is available at genemate.se.

^#The individuals diagnosed with colorectal cancer should all be first-degree relatives to each other

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

Polyposis syndromes

Familial adenomatous polyposis (FAP)1

MUTYH-associated polyposis (MAP)1,3

Peutz-Jegher syndrome (PJS)4

Juvenile polyposis syndrome (JPS)5

Cowden syndrome6,7

When to suspect a hereditary colorectal cancer syndrome, including polyposis syndromes1