GENETIC SYNDROMES

Cowden Disease (also known as “Multiple hamartoma syndrome”) is a rare autosomal dominant inherited disorder characterized by multiple colonic hamartomatous polyps. It is also associated with a number of benign skin tumours (multiple trichilemmomas, papillomatous papules, and acral keratoses) and dysplastic gangliocytoma of the cerebellum.

Patient’s with Cowden disease are at increased risk of colorectal, breast, thyroid (follicular) and endometrial carcinoma.

Genetics

Cowden syndrome is associated with loss-of-function mutations in PTEN, a tumour suppressor gene, leading to hyperactivity of the mTOR pathway.

Management

Intensive surveillance with regular gastroscopy and colonoscopy, and ultrasound of thyroid and breast and endometrium are needed to detect early changes leading to cancer.

Familial adenomatous polyposis (FAP) is an inherited condition in which numerous polyps form mainly in the lining (epithelium) of the large intestine (also called the colon). While these polyps start out benign, malignant transformation into colon cancer occurs when left untreated.

Signs and symptoms

From early teens onward, hundreds to thousands of polyps develop. These may bleed, leading to blood in the stool or anaemia. If malignancy develops, this may present with weight loss, altered bowel habit, or even metastasis to the liver causing yellow skin (jaundice). Those with the genetic defect for FAP may also be predisposed to other malignancies, of the small intestine (duodenum) and stomach. Rarer tumours include connective tissue (Desmoid) tumours of the abdomen (Desmoid). Even rarer tumours include pigmented lesions of the retina (“CHRPE – congenital hypertrophy of the retinal pigment epithelium”), jaw cysts, sebaceous cysts, and osteomata (benign bone tumours). The combination of polyposis, osteomas, fibromas and sebaceous cysts is termed Gardner’s syndrome.

Diagnosis and cancer prevention

Making the diagnosis of FAP before the development of colon cancer or duodenal cancer is important. Colonoscopy and gastroscopy are considered the diagnostic test of choice as they can provide not only a quantification of polyps but also endoscopic removal of polyps allowing for histologic diagnosis.

Once the diagnosis of FAP is made, close colonoscopic surveillance with polypectomy is required. Prophylactic total proctocolectomy with formation of a J-Pouch is indicated if more than a hundred polyps are present, if there are severely dysplastic polyps, or if multiple polyps larger than 1 cm are present. When a partial colectomy is performed, colonoscopic surveillance of the remaining colon is necessary as the individual still carries significant risk of developing colon cancer.

Genetic testing

Genetic testing provides the ultimate diagnosis in 95% of cases; genetic counselling is usually needed in families where FAP has been diagnosed.

Genetic mutation

APC is a tumour suppressor gene, acting as a “gatekeeper” to prevent development of tumours. Mutation of APC also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer.

Although the polyps are at first benign, the first step of the two-hit hypothesis has already taken place: the inherited APC mutation. Often, the remaining “normal” allele is mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in kras, DCC or p53 genes) to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated epithelial cells.

Genetic registries

Because of the genetic nature of FAP, polyposis registries have been developed around the world. The purpose of these registries is to increase knowledge about the transmissibility of FAP, but also to document, track, and notify family members of affected individuals.

Juvenile polyposis syndrome (JPS) is characterized by an increased number of hamartomatous polyps in the gastrointestinal tract (GI). They can occur in the stomach, small intestine, colon, and rectum.

Most individuals with JPS have some polyps by age 20 years. The number varies from persons to person, with some may have only four or five polyps and others having more than a hundred. If the polyps are left untreated, they may cause bleeding and anaemia. Most juvenile polyps are benign however, malignant transformation can occur.

Lifetime risk of cancer

Risk of GI cancer is much lower than in FAP or Lynch syndrome, and is thought to be between 10% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas can also occur.

Diagnosis

JPS is diagnosed clinically if any one of the following is present:

• More than five juvenile polyps of the colorectum.
• Multiple juvenile polyps throughout the GI tract.
• Any number of juvenile polyps and a family history of juvenile polyps.

Juvenile polyps are hamartomas (normal tissue in abnormal location and proportions) and a distinctly different from adenomatous polyps. The genes known to be associated with JPS are BMPR1A and SMAD4. Approximately 20% of individuals with JPS have mutations in BMPR1A; approximately 20% have mutations in SMAD4. Molecular genetic testing of both genes is available on a clinical basis.

Management

Routine gastroscopy and colonoscopy with endoscopic polypectomy to reduce the risk of bleeding, intestinal obstruction, and colon cancer. Total colectomy is sometimes needed when the number of polyps is large, or risk of cancer high. Gastroscopy and colonoscopy should start in the mid-teens (age 15 years) or earlier when symptoms occur.

Lynch syndrome, often called hereditary non-polyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many types of cancer, particularly cancers of the colon (large intestine) and rectum, which are collectively referred to as colorectal cancer.

People with Lynch syndrome also have an increased risk of cancers of the stomach, small intestine, urinary tract. Additionally, women with this disorder have a high risk of cancer of the ovaries and lining of the uterus (the endometrium).

Prevalence

Approximately 3 to 5 percent of these cancers are caused by Lynch syndrome.

Genetics

Variations in the MLH1, MSH2, MSH6, PMS2, or EPCAM gene increase the risk of developing Lynch syndrome. The MLH1, MSH2, MSH6, and PMS2 genes are involved in the repair of mistakes that occur when DNA is copied in preparation for cell division (a process called DNA replication). Mutations in any of these genes prevent the proper repair of DNA replication mistakes. As the abnormal cells continue to divide, the accumulated mistakes can lead to uncontrolled cell growth and possibly cancer.

How is Lynch syndrome inherited?

Lynch syndrome cancer risk is inherited in an autosomal dominant pattern, which means one inherited copy of the altered gene in each cell is sufficient to increase cancer risk. It is important to note that people inherit an increased risk of cancer, not the disease itself. Not all people who inherit mutations in these genes will develop cancer.

How is Lynch syndrome diagnosed?

A strong family history of colorectal cancer, or any of the other cancers (stomach, ovary, urinary, ovarian or endometrial) in young relatives (less than fifty years of age), across a number of generations raises the suspicion of Lynch Syndrome. Loss of normal staining pattern in the cells of abnormal polyps or cancers can also suggest Lynch syndrome and direct further definitive testing for the known genetic mutations seen in Lynch syndrome.

How is cancer prevented in Lynch syndrome?

Regular gastroscopy and colonoscopy are needed to remove polyps or detect cancer early from the gastrointestinal tract. Sometimes preventative (prophylactic) total colectomy surgery is needed. Close surveillance for other non-gastrointestinal cancer is also required.

MYH-associated polyposis (MAP) is an autosomal recessive condition that results in an excessive number of polyps in the colon (polyposis), with an increased lifetime risk of colorectal cancer.

Peutz Jeghers Syndrome (PJS) is a rare disease of autosomal dominant inheritance that is characterised by hamartomatous polyps throughout the gastrointestinal tract and pigmentation (freckles) of the lips and skin. It has a prevalence of around 1 in 200 000 births.

Diagnosis requires one of the following:

• 2 or more hamartomatous polyps in the gastrointestinal tract; or
• 1 hamartomatous polyp together with a family history of PJS’ or
• classical pigmentation of the lips or skin.

The polyps are hamartomas and are typically very large and pedunculated with a lobulated appearance. They most commonly occur in the small bowel (jejunum most common followed by ileum) but can also occur in the stomach, colon. Occasionally they occur in the bladder and lungs.

Cancer risk

PJS carries an increased risk of both gastrointestinal and non-gastrointestinal tumours. The rarity of this condition makes it difficult to estimate the exact cancer risk. Those with the STK11/LKB1 mutation have four times the population risk of developing a cancer at any site (described above) [1].

The commonest site for cancer is the gastrointestinal tract (gastroesophageal, small bowel, colorectal, pancreatic) with colorectal cancers the most common. The risk of a colorectal cancer by age 70 is 40%, breast cancer 55%, pancreatic cancer 35%, stomach cancer 30%, and ovarian cancer 20% [2].

References

1. Hearle N, Schumacher V, Menko F et al. Frequency and spectrum of cancers in the Puetz Jeghers syndrome. Clin.
2. Giardiello F, Brensinger J, Tersmette A et al. Very high risk of cancer in familial Puetz Jeghers syndrome. Gastroenterology 2000; 119: 1447-453Cancer Res 2006; 12: 3209-215.