What is A Review of Hereditary Colorectal Cancers (Familial Colon Cancer)?
Colorectal cancer (CRC) is the fourth leading cause of death globally. Factors like an unhealthy diet (low intake of fruits, vegetables, fiber, fish, vitamin C, dairy products, and vitamin D, and high consumption of red and processed meats), as well as lifestyle habits like drinking a lot of alcohol, obesity, and lack of physical activity can increase the risk of developing this disease. Certain inherited diseases also make people more susceptible to CRC. These inherited conditions can be more aggressive and harder to treat when they relate to other forms of cancer and are resistant to chemotherapy.
It’s hard for doctors to diagnose this disease early because there are often no clear signs. Studies show that half of the patients don’t show symptoms and the disease is usually discovered late when symptoms like rectal bleeding, weight loss, and intestinal obstruction appear. Genetic conditions like Familial adenomatous polyposis (FAP) and Lynch syndrome are commonly seen linked to CRC. Combined, they constitute 6% to 10% of all CRC cases.
Research suggests that tumors found in young adults are often associated with hereditary CRC conditions. This article discusses the most common genetic conditions related to CRC development and explores the treatment approach based on the latest scientific evidence.
What Causes A Review of Hereditary Colorectal Cancers (Familial Colon Cancer)?
Hereditary colorectal cancer (HCRC) is a group of diseases known to have a genetic element causing them. These diseases tend to have different clinical signs and symptoms. Hereditary colorectal cancer falls into two main categories: HNPCC and HPCC.
Hereditary non-polyposis colorectal cancer (HNPCC) is a cancer that comes from one’s parent and is quite common among all colorectal cancers (CRCs), approximately affecting 3 to 8 people out of every million worldwide.
The most common among these is Lynch syndrome, known for increasing the risk of various cancers including colorectal, endometrium, ovary, stomach, and small bowel cancer. This syndrome is connected to mutations in the DNA mismatch repair system (MMR) and it affects approximately 3 to 5 in every million people across the globe.
Other, less common types of HNPCC include sporadic colorectal carcinomas, Muir-Torre syndrome and Turcot syndrome type I, each associated with specific gene mutations and affecting fewer people per million.
Hereditary polyposis colorectal cancer (HPCC) accounts for about 3 to 5% of all CRC cases and affects 5 to 9 people in every million globally. This type of cancer is associated with multiple polyps in the colon. It includes diseases like Familial adenomatous polyposis (FAP) which is linked to mutations in the APC gene and adenomatous polyposis syndromes, attributed to APC and MUTYH gene mutations.
Juvenile polyposis coli, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome, Cowden syndrome, Turcot syndrome type II, and Gardner syndrome are less common types of HPCC, associated with different gene mutations and affecting fewer people per million globally.
Risk Factors and Frequency for A Review of Hereditary Colorectal Cancers (Familial Colon Cancer)
Colorectal cancer, or CRC, is globally the third most common cancer and the fourth leading cause of cancer-related death. The incidence of colorectal cancer for all ages and both sexes around the world is estimated at 19.7 cases per 100,000 people in 2018, with a mortality rate of 8.9 per 100,000 patients, as reported by Globocan. Being obese significantly increases the risk, making the likelihood of incidence rise by six times.
Additionally, some instances of colorectal cancer are hereditary and can be seen in people that have a family history of the disease. This can be especially true for inherited conditions like familial adenomatous polyposis or Lynch syndrome, a common type of hereditary nonpolyposis colorectal cancer. Such hereditary cases account for 6-10% of colorectal cancer diagnoses in people under 50, equating to about 2 cases per 100,000 people worldwide.
Besides, if someone tests positive for a small tubular adenoma during their first colonoscopy, they are four times more likely to develop serious neoplasia. Also, those who have a history of colon cancer have a higher risk of developing colorectal cancer compared to those with a history of rectal cancer.
Signs and Symptoms of A Review of Hereditary Colorectal Cancers (Familial Colon Cancer)
The two most common types of inherited colorectal cancer fall under the polyposis classification. These are:
- Lynch syndrome (LS), or HNPCC: This typically features flat polyps in the right side of the colon, which can lead to colorectal cancer and various other diseases, including endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, brain, bile duct, small intestine, and sebaceous skin cancers. It often affects younger women and is difficult to diagnose as there are no unique clinical signs. Genetic testing is typically required for a definitive diagnosis, following preliminary selection criteria specified by Bethesda and Amsterdam.
- Familial adenomatous polyposis (FAP), or HPCC: This is characterized by hundreds to thousands of precancerous adenomatous polyps that can lead to a variety of cancers. There are also non-cancerous symptoms, including desmoid tumors, osteomas, skin cysts, and papillary thyroid, pancreatic, stomach, duodenal, liver, bile duct, and brain cancer. FAP is caused by mutations in the gene APC which controls cell growth and a long non-coding RNA regulation. It has two clinical variants:
- Classic FAP: This involves the whole colon and appearance of 100 to 1000 adenomatous polyps usually between the ages of 10 and 20. The diagnosis of colorectal cancer generally occurs between 30 and 40 years of age. It’s associated with most of the cancers listed above, leading to increased comorbidity.
- Attenuated FAP: This usually affects the right colon with around 10 to 100 adenomatous polyps. Polyps usually appear between ages 20 and 30, with the diagnosis of colorectal cancer typically between ages 40 and 50. It’s often associated with stomach, duodenal, and thyroid cancer.
Testing for A Review of Hereditary Colorectal Cancers (Familial Colon Cancer)
The process of diagnosing hereditary colorectal cancer (CRC) involves various steps. These include assessing clinical symptoms, checking family medical history, performing genetic tests, and taking medical images.
In a physical examination, the doctor might check for certain signs such as enlarged lymph nodes, abnormalities in the rectum, any feeling of lumps in the stomach area, signs of fluid build-up in the abdomen, or an enlarged liver that could suggest a spread to the liver.
A procedure called a colonoscopy can also be very useful. It allows doctors to look directly inside the colon and remove or take samples of any suspicious-looking areas. Another method can be the use of a capsule that takes images of the colon, but it might miss small growths since it can’t take samples.
The family history of the patient is highly important, especially if there are clear patterns that suggest Lynch syndrome (LS). The Bethesda and Amsterdam criteria are two sets of standards that help doctors decide if a person’s history suggests LS. They consider factors like the type and number of cancers in the family and the age at which they were diagnosed.
Genetic testing has a key role too. If the tumor testing shows some specific genetic characteristics, it strongly suggests LS. Similarly, if a person has multiple colon polyps and no family history of them, they might be tested for certain gene mutations.
Using computed tomography (CT) or magnetic resonance imaging (MRI) can help to understand the extent and the location of the disease. The choice between CT and MRI might depend on various factors, for example, how detailed the images need to be.
The specific history of colorectal cancer in the family influences the screening plan. Depending on this and other factors such as the size or types of polyps, a schedule is planned for the screenings. Screening might start at age 40 or even earlier and be conducted frequently, if necessary.
People with certain types of genetic mutations or a high risk of MMR mutation may need a specialized screening plan. These people often also need to consider their personal and family history of cancer. For some, screenings might need to start later or be more frequent because of their specific gene mutations.
Treatment Options for A Review of Hereditary Colorectal Cancers (Familial Colon Cancer)
The treatment of patients with hereditary colorectal cancer (HCCR) requires a team approach and is often tailored according to specific patient findings.
Chemotherapy is a standard approach, but its effectiveness can vary depending on the patient’s genetic mutations. In some cases, the immune system doesn’t recognize some proteins in the cancer cells, a condition called “microsatellite instability”. These cancers may be more susceptible to immunotherapy. High-risk rectal cancers often require a combination of chemotherapy and radiation therapy.
Experts from organizations like ASCO, NCCN, and ESMO recommend additional treatment (adjuvant therapy) in certain situations. This applies particularly to stage II high-risk patients and all stage III patients. Within 6 to 8 weeks after surgery, the patient may receive chemotherapy, upon recovery.
There are several chemotherapy options. FOLFOX is a combination of the drugs 5-fluorouracil, leucovorin, and oxaliplatin. It is usually the first choice for advanced disease, and studies have shown it to be more effective than older treatments. FOLFIRI, another combination of drugs including 5-fluorouracil, leucovorin, and irinotecan, is the second most effective treatment and can be used first or second line.
In cases of advanced colorectal cancer, doctors sometimes add monoclonal antibodies (like bevacizumab, cetuximab, and panitumumab) to the chemotherapy regimen. These drugs have shown a clear benefit for patients with tumors on different sides and can be considered for initial treatment.
Studies have shown that the choice of chemotherapy drugs can be influenced by the specific genetic characteristics of the patient’s cancer.
Radiation therapy before surgery is advisable for stage II and III rectal cancer, or if the tumor can’t be completely removed through surgery. But for metastatic cancers that have spread to other parts of the body, radiation therapy is typically used as a palliative approach.
Surgery for HCCR depends on a variety of factors, including the patient’s age and their willingness to go through intensive follow-up. Alone or combined with ileorectal anastomosis (a procedure that reconnects the small intestine and the rectum), total abdominal colectomy (removal of the entire colon) is usually the preferred option.
In a subtype of hereditary CRC called familial adenomatous polyposis (FAP), preventive removal of the colon is an important option to keep in mind. In this case, the timing of the operation and safe surgical techniques are crucial concerns. The comprehensive assessment of a patient’s family history of cancer should guide surveillance and surgical plans.
What else can A Review of Hereditary Colorectal Cancers (Familial Colon Cancer) be?
Gardner syndrome is a type of familial adenomatous polyposis (FAP), a genetically inherited disorder. Its key features include many intestinal polyps along with various other issues like bone tumors (osteomas), thyroid cancer, eye abnormalities, and dental issues like extra or unusual teeth. This condition comes with a significant risk of developing colon cancer.
Muir-Torre syndrome (MTS) is a unique subtype of Lynch syndrome. MTS is marked by skin tumors and internal cancers, with colon cancer being the most prevalent.
Turcot syndrome (TS) is associated with brain tumors. It’s separated into two types: TS type I (with large but fewer intestinal polyps that might become malignant and brain tumors like glioblastoma or astrocytoma) and TS type II brings a risk for medulloblastoma and it often happens with familial adenomatous polyposis. Tumors may also form in the spinal cord producing spinal cord compression symptoms.
Juvenile polyposis coli (JPC) is a rare disorder, showcasing many juvenile hamartomatous polyps in the gastrointestinal tract. The disease comes with a 20% lifetime risk of colorectal cancer (CRC). Symptoms of JPC include rectal bleeding, anemia, abdominal pain, intestinal complications, diarrhea, and rectal prolapse, as well as the possible loss of polyps. There could also be growth issues and swelling among other signs.
Peutz-Jeghers Syndrome (PJS) is known for pigmentation spots and multiple gastrointestinal polyps. Symptoms primarily include dark patches, abdominal pain, and anemia. These polyps could lead to gastrointestinal cancer of the colorectal, pancreatic, and gastric organs, as well as numerous non-gastrointestinal cancers like breast, uterus, cervix, ovary, testicular, and lung cancers. The risk of CRC in a lifetime is 39%. Regular follow-ups are essential for patients with PJS due to the high cancer risk and relapse chances.
Hamartoma tumor syndrome is also known as PTEN hamartoma tumor syndrome (PHTS). It links with various benign diseases like enlarged head size (macrocephaly), Hashimoto’s thyroiditis (a type of thyroid disease), skin and mucous membrane growths, colon polyps, and vascular malformations, as well as cancers including breast, thyroid, kidney, endometrial, and colon. It can also cause autism and other conditions.
Cowden syndrome (CS) is defined by many hamartomas that can appear in any organ, along with macrocephaly (enlarged head), skin lesions, and an elevated risk of breast and thyroid cancers, ovarian and colon cancer. The risk of CRC in a lifetime is 13%.
Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a congenital disorder usually defined by hamartomatous intestinal polyps, lipomas (benign fatty tumors), macrocephaly, and pigmentation changes in the genitalia. Patients with BRRS and a PTEN mutation have the same risk of developing cancer as patients with CS.
Proteus syndromes (PS) are disorders characterized by the progressive and excessive growth of the skeleton, skin, fat tissue, and central nervous system, with a few hamartomatous polyps. Common complications include extensive brain anomalies, lung disease, blood clots in the lungs (pulmonary embolism) and deep vein thrombosis. The tumors are typically benign, though rare cases of malignant tumors have been reported.
Solamen syndrome is defined by Segmental Overgrowth, Lipomatosis, Arteriovenous Malformation, and Epidermal Nevus. Patients with this syndrome usually carry germline mutations in phosphatase and PTEN homologs.
Surgical Treatment of A Review of Hereditary Colorectal Cancers (Familial Colon Cancer)
The type of inherited colorectal cancer the patient has is a key factor in planning surgical treatment. If a patient has either attenuated or familial adenomatous polyposis, which involves a large number of rectal adenomas, the recommended treatment is a proctocolectomy with ileostomy or ileal-pouch anal anastomosis. This is essentially a surgical procedure to remove the colon and rectum and to create a new way for the body to expel waste. The specific timing of this treatment, however, should be decided on a case-by-case basis.
If it’s possible to remove all the patient’s rectal adenomas that are larger than 5 mm using less invasive endoscopic surgery, then an alternative to the more invasive surgeries may work for them. This alternative is a procedure called total colectomy with ileorectal anastomosis, which removes the colon but leaves the rectum intact.
If a patient has experienced more than 20 adenomas in their lifetime, another type of inherited colorectal cancer called MUTYH-associated polyposis should be considered. In this case, the patient should be advised to have an annual colonoscopy. During the colonoscopy, any polyps can be removed in a process called a polypectomy.
What to expect with A Review of Hereditary Colorectal Cancers (Familial Colon Cancer)
According to Lee’s study, individuals with a non-hereditary type of colorectal cancer (CRC), who also have a family history of the disease, showed better survival rates. However, these individuals experienced recurrence rates similar to those without a family history of CRC.
People who have survived CRC, between 5 and 10 years from their diagnosis, generally reported good health-related quality of life. However, they experienced significantly lower social functioning and more problems such as shortness of breath, constipation, diarrhea, and financial issues compared to individuals without the disease. This tendency was especially noted among younger subjects.
Possible Complications When Diagnosed with A Review of Hereditary Colorectal Cancers (Familial Colon Cancer)
Severe complications that occur during a colonoscopy, like perforation or hemorrhage, represent the most dangerous risks associated with colorectal cancer screening programs. These immediate complications occurred in 3.3% of cases. Yet, certain factors can contribute to the increased risk of these early and late complications. These include a history of colon disease, the use of anticoagulation medicine, a history of pelvic surgery or abdomen radiation, or a history of perforation.
The elderly, particularly those over 65 years with severe health problems, can experience serious complications after a complete removal of the colon, known as a total colectomy. Systemic complications were found in 22% of these cases. Meanwhile, surgical complications were reported in 8% of cases and included anastomotic leakage (leakage from the junction where two parts are surgically joined), severe wound infections, and bleeding after surgery.
Factors that Increase Risk of Complications During Colonoscopy and After Colectomy:
- History of colon disease
- Use of anticoagulation medicine
- History of pelvic surgery or abdomen radiation
- History of perforation
- Being older than 65 years especially with other health issues
Common Complications After Total Colectomy:
- Anastomotic leakage
- Severe wound infections
- Bleeding after surgery
Preventing A Review of Hereditary Colorectal Cancers (Familial Colon Cancer)
There is a crucial need to enhance public understanding about colorectal cancer (CRC), especially among young people. We also need to encourage young patients who are eligible for screening to get tested more regularly and make sure they understand the importance of getting symptoms checked early. This is a key way to reduce the impact of CRC on younger individuals.
It is also advised to adopt healthy lifestyle and dietary habits from early life to reduce the risk of developing CRC. This is considered one of the most essential strategy to prevent the initiation of colorectal cancer.
