Understanding hereditary colorectal cancer syndromes

Monica Araujo delves into common hereditary colorectal cancer syndromes and sheds light on their potential links to breast cancer.

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Colorectal cancer remains a significant global health concern, affecting millions of individuals each year. While many cases are sporadic, a considerable number have a hereditary component, emphasising the importance of understanding hereditary colorectal cancer syndromes.

Polyposis vs. non-polyposis syndromes

Hereditary colorectal cancer syndromes can be broadly categorised into two groups: polyposis syndromes and non-polyposis syndromes.

Polyposis syndromes

Polyposis syndromes are characterised by developing multiple precancerous polyps in the colon. Two prominent polyposis syndromes are familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). Other examples of polyposis syndromes include Peutz-Jeghers syndrome, juvenile polyposis syndrome, serrated polyposis syndrome and hereditary mixed polyposis syndrome.

• Familial adenomatous polyposis

FAP is primarily caused by mutations in the APC gene. Individuals with FAP develop hundreds to thousands of adenomatous polyps in the colon, significantly increasing their risk of colorectal cancer. Genetic testing can identify APC mutations, allowing for early intervention and monitoring.

• MUTYH-associated polyposis

Unlike FAP, MAP is associated with biallelic mutations (mutations in both genes, one from each parent) in the MUTYH gene. Although the number of polyps is typically fewer than in FAP, individuals with MAP still face an elevated risk of colorectal cancer. Recognising the genetic basis of MAP is crucial for implementing appropriate surveillance strategies.

Non-polyposis syndromes

Non-polyposis syndromes are characterised by a higher risk of colorectal and other cancers without the extensive polyp formation seen in polyposis syndromes.

Lynch syndrome is the most common form of genetically determined colon cancer predisposition, accounting for 2% to 4% of all colorectal cancer cases. Lynch syndrome is predominantly linked to mismatch repair (MMR) gene mutations, including MLH1, MSH2, MSH6, and PMS2. Mismatch repair proteins are crucial in repairing errors occurring during DNA replication. Deficient MMR function leads to the accumulation of DNA errors, increasing the risk of colorectal cancer. Lynch syndrome is also associated with an elevated risk of endometrial, ovarian, and other cancers.

Genetic basis of hereditary colorectal cancer syndromes

Understanding the genetic underpinnings of hereditary colorectal cancer syndromes is vital for effective diagnosis and management. While the primary focus of hereditary colorectal cancer syndromes is on colorectal cancer, certain genes and genetic mutations have been implicated in an increased risk of breast cancer and other cancers as well.

Hereditary cancer syndromes like PTEN hamartoma tumour syndrome, Peutz-Jeghers syndrome and Li-Fraumeni syndrome are associated with an increased risk of developing both colorectal- and breast cancer. The type of cancer and associated risk depends on the gene involved.

Importantly, there have been suggestions that there is an increased risk for breast cancer in women with Lynch syndrome. However, there isn’t enough evidence to support increased screening above average-risk breast cancer screening recommendations or those based on personal/family history of breast cancer.

Mutations that are known to be associated with an increased risk of developing colorectal cancer are most often inherited in an autosomal dominant manner. This means that a carrier of a mutation has one functional gene and one faulty gene. The faulty gene can be passed on to their children. The children of a mutation carrier have a 50% chance of inheriting their parent’s mutation and a 50% chance of not inheriting it. As a result, mutation carriers have a high risk (but not 100% risk) of developing cancer in their lifetime.

Genetic testing

Hereditary colorectal cancer syndromes pose unique challenges that necessitate early detection and intervention. Understanding the differences between polyposis and non-polyposis syndromes, recognising the genes and syndromes involved, and acknowledging potential links to breast cancer contribute to more comprehensive and personalised approaches to managing these conditions.

Genetic testing and genetic counselling play pivotal roles in empowering individuals with knowledge about their hereditary cancer risks, enabling proactive measures to mitigate those risks and enhance overall health outcomes.

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