While lifestyle and environmental factors play a significant role in the development of bowel cancer, there can also be a hereditary component in a small number of cases. Understanding these underlying genetic causes is essential for early diagnosis and intervention, especially in individuals with a strong family history of the disease.
At Combat Medical, where we specialise in advanced therapeutic technologies such as HIPEC (Hyperthermic Intraperitoneal Chemotherapy) and HIVEC (Hyperthermic Intra-Vesical Chemotherapy), the relevance of genetic predisposition is vitally important in informing both treatment decisions and long-term patient management strategies.
Familial Risk and Genetic Syndromes
Having a first-degree relative – whether that be a parent, sibling, or child – diagnosed with bowel cancer significantly increases an individual’s lifetime risk of developing the disease. This risk becomes more pronounced if the relative was diagnosed before the age of 50 or if more than one first-degree relative is affected. While most bowel cancers are sporadic, an estimated 5% are due to inherited mutations, and identifying these patients early on can be a clinical turning point.
These inherited conditions present an opportunity to pivot from reactive to proactive medicine. Identifying genetic syndromes can guide preventative measures, such as prophylactic surgery, enhanced surveillance, or consideration of emerging therapies like HIPEC in selected high-risk patients.
Here are the key hereditary syndromes and their clinical implications:
Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer – HNPCC)
Lynch syndrome is the most common inherited cause of colorectal cancer, implicated in approximately 3% of all bowel cancer cases in the UK. It results from mutations in DNA mismatch repair (MMR) genes – most commonly MLH1, MSH2, MSH6, and PMS2.
Clinical Characteristics and Risk Profile:
- Lifetime risk of colorectal cancer is estimated between 40% and 80%.
- Particularly aggressive and often presents before age 50.
- Associated with other cancers: endometrial, ovarian, gastric, and urothelial.
- Often right-sided in the colon and may occur synchronously or metachronously.
Clinical Implications:
For clinicians, early identification of Lynch syndrome through family history or universal screening of all colorectal tumours for microsatellite instability (MSI) or MMR deficiency is essential. Patients with Lynch syndrome benefit from early and more frequent colonoscopic surveillance – often beginning between ages 20 and 25, or 2-5 years earlier than the youngest affected relative.
The surgical decision-making process may also differ. Extended colectomy may be favoured over segmental resection in some cases due to the high risk of metachronous cancers. HIPEC is being studied as a preventative and therapeutic option in peritoneal metastasis associated with Lynch-related colorectal cancers.
Familial Adenomatous Polyposis (FAP)
FAP is a rare but highly penetrant inherited syndrome resulting from mutations in the APC gene. Although it accounts for less than 1% of all colorectal cancers, its impact is profound due to the almost certain progression to cancer without intervention.
Clinical Characteristics and Risk Profile:
- Development of hundreds to thousands of adenomatous polyps in the colon and rectum.
- Nearly 100% lifetime risk of colorectal cancer if left untreated.
- Typically develops in teenage years; colorectal cancer often manifests by the 40s.
Clinical Implications:
Colectomy is generally recommended in late adolescence or early 20s. Surveillance begins in the early teens. While total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is common, decisions must be tailored to polyp burden, rectal involvement, and patient preference.
FAP patients require lifelong upper gastrointestinal surveillance due to the associated risk of duodenal and periampullary cancers. Additionally, desmoid tumours, particularly intra-abdominal ones, can complicate surgical management, making a case for individualised care protocols.
Other Inherited Syndromes: Clinical Rarity, But High Risk
Though rare, several other hereditary syndromes carry significant colorectal cancer risks and demand clinical vigilance.
MUTYH-Associated Polyposis (MAP):
- Autosomal recessive inheritance.
- Polyposis similar to attenuated FAP.
- Lifetime risk of colorectal cancer ranges from 50% to 90% without surveillance.
Peutz-Jeghers Syndrome (PJS):
- Characterised by mucocutaneous pigmentation and hamartomatous polyps.
- Lifetime risk of colorectal cancer is around 40%, along with increased risks for pancreatic, breast, and ovarian cancers.
- Surveillance includes regular colonoscopy, upper endoscopy, and pancreatic imaging.
Juvenile Polyposis Syndrome (JPS):
- Involves multiple hamartomatous polyps throughout the GI tract.
- Approximately 68% cumulative risk of colorectal cancer by age 60.
- Requires endoscopic surveillance and possible surgical intervention based on polyp burden and dysplasia.
PTEN Hamartoma Tumour Syndrome:
- Includes Cowden syndrome and other phenotypes.
- Lifetime colorectal cancer risk is estimated between 9% and 20%.
- Clinical features may also include thyroid and breast neoplasms, mandating multidisciplinary surveillance strategies.
The Role of HIPEC and Future Directions
While these inherited syndromes demand robust surveillance and early surgical interventions, emerging adjunct therapies like HIPEC hold promise in managing peritoneal metastasis, particularly in Lynch syndrome and FAP-related colorectal cancers.
At Combat Medical, our commitment lies in refining intraoperative chemotherapy protocols, utilising hyperthermia and targeted agents to maximise cytotoxic efficacy while minimising systemic toxicity.
This treatment modality may not only provide therapeutic value in established metastasis but could also serve a prophylactic role in ultra-high-risk genetic populations where conventional surgery and surveillance may not be enough.
