Lynch syndrome

What is Lynch syndrome?

Lynch syndrome, previously known as Hereditary Non-polyposis Colorectal Cancer (HNPCC), is an inherited cancer predisposition syndrome which gives people an increased chance of developing certain cancers across their lifetime, often at a younger age than the general population.

People with Lynch syndrome have a significantly higher risk of developing colorectal (bowel) and endometrial cancers. Other cancers seen less frequently in Lynch syndrome include:

• Ovarian cancer
• Stomach cancer
• Hepatobiliary cancer (liver/gallbladder)
• Urinary tract cancer
• Kidney cancer
• Pancreatic cancer
• Brain cancer
• Skin cancer
• Small bowel cancer

Recent studies suggest there may also be an increased risk of developing prostate cancer with some of the genes. Personal risks may differ based on which gene is involved.

If you have been diagnosed with Lynch syndrome or are considering being tested, it is important that both you and your doctor are aware of your family’s history of these cancers.

The genes involved

Lynch syndrome is caused by a DNA change in one of the body’s mismatch repair (MMR) genes. These genes are MLH1, MSH2, MSH6, and PMS2.

Normally, a person will inherit two working copies of these genes, one from their mother and one from their father. When working correctly, these genes repair the mistakes that can occur when DNA is copied in preparation for cell division.

In Lynch syndrome, a person inherits one working copy and one non-working copy of these genes.

When the second working copy becomes defective in the organ at risk, through environmental exposures or other reasons, the repair system fails in that cell and a cancer is likely to develop.

How is it passed down in families?

Lynch syndrome is inherited, which means that a parent with Lynch syndrome has a 50% (1 in 2) chance of passing the non-working defective copy on to their children. Men and women have an equal chance of inheriting Lynch syndrome.

Lynch syndrome cannot skip a generation so if your children do not inherit Lynch syndrome, your grandchildren will not be affected either.

How do you know if your family has Lynch syndrome?

A general guide to identifying families who may carry Lynch syndrome is provided by the 3, 2, 1 rule (also known as the Amsterdam II criteria).

• 3 – Three or more family members (including you) have been diagnosed with a Lynch syndrome associated cancer
• 2 – Two consecutive generations or more are affected
• 1 – One affected family member is diagnosed with a Lynch syndrome associated cancer before 50 years of age

This criteria is an important diagnostic tool but can fail to identify some families with Lynch syndrome (for example, where family size is small or where knowledge of family cancer history is incomplete). 

Lynch Syndrome can also be present where there is no family history at all. Similarly, a strong family history of cancer, occurring at a younger than normal age does not necessarily mean that your family has Lynch syndrome.

It is best to speak to your doctor to find out if genetic counselling and testing would be suitable for you. 

Today, all colorectal and endometrial cancers should be tested for the signature mismatch repair deficiency which alerts us to the possibility of Lynch Syndrome.

Diagnosis

Step one

Step two

Step three

After diagnosis

Managing the risk

Once you have been diagnosed with Lynch syndrome it is important to develop a surveillance plan. This outlines the routine tests you should have, identifying what these tests are and how often they should be performed.

Sometimes your geneticist or genetic counsellor who helped you through the testing process will explain the required tests to you, or it may be your GP or clinician that helps you develop this plan.

The key thing is that you have a medical professional help you understand how best to protect yourself and make an appropriate plan for organising referrals and appointments, keeping track of your progress through surveillance.

Surveillance plans

The contents of your plan largely depend on the gene involved in the family, and to a lesser extent your family’s experience with cancer and the types of cancers that have been present. Your clinician, geneticist and/or surgeon can help you.

The surveillance plan for most families will follow the standard National guidelines. In Australia, the current guidelines recommend two specific things:

• Annual colonoscopy is recommended from age 25 (MLH1 or MSH2 gene variant) or age 30 (MSH6 or PMS2 gene variant), or 5 years younger than youngest colorectal cancer affected relative.
• Prophylactic total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO) to be considered after childbearing is complete or by 40 years of age for those with MLH1, MSH2 or MSH6 gene carriage.

In developing your surveillance plan, your clinician will consider your specific gene change and your family’s history of cancer and may include additional tests or preventative measures that are important to address your personal risk profile.

You may find the Prospective Lynch Syndrome Database’s risk calculator helpful while preparing your surveillance plan.

Information for health professionals

Lynch syndrome is extremely under‐diagnosed. Although Lynch syndrome is identified in approximately 3% of all colorectal cancers (CRCs), it is estimated that roughly 90% of Lynch syndrome carriers are unaware of their Lynch syndrome status.

These carriers are therefore unaware of their increased cancer risk and surveillance needs and cannot alert their families.

Clinical Criteria for Diagnosis

Lynch syndrome may be indicated where the family history of cancer meets the Amsterdam II Criteria (see above) or the individual meets Bethesda Criteria (see below).

Today, however, all cancers of the bowel and endometrium should be tested for the signature of Lynch syndrome as there may not be a family history nor early aged onset of the cancer.

A cancer family history is an important diagnostic tool, however using these criteria may fail to identify some families with Lynch syndrome; particularly where family size is small or where knowledge of family cancer history is incomplete.

It’s important to consider these limitations and take a conservative approach to assessing a family history.

The Bethesda Criteria provide guidance to identify an enhanced risk of Lynch syndrome. These criteria are: 

• A Uterine cancer under age 50, or
• A Colorectal cancer (CRC) under age 50, or
• Synchronous or metachronous CRC (or other Lynch cancer) regardless of age, or
• A CRC with MSI‐H negative histology under age 60, or
• A CRC and one first degree relative also has/had a CRC (or other Lynch cancer) with one of the cancers being diagnosed under age 50, or
• A CRC with two or more first or second degree relatives with CRC (or other Lynch cancers) regardless of age.

A diagnosis of LS is a life changing experience for a patient, and they may take time to adjust to the diagnosis. Consider counselling or referrals for ongoing support.

Referral pathways

If a patient meets the above listed criteria, or has the Lynch syndrome signature of mismatch repair deficiency in their colorectal or endometrial cancer at any age, they should be referred immediately to a Family Cancer Clinic.

Our Familial cancer online training and resources will help you learn more about referring patients to familial cancer centres, and our GP referral guide for Lynch syndrome risk assessment provides more information on Lynch syndrome specifically.

Some centres will perform a 'reflex' second test on the cancer (methylation or V600E BRAF testing) to filter out cases where this signature is not due to Lynch syndrome, but due to a development only in the tumour that mimics Lynch syndrome.

These tumours are called sporadic mismatch repair deficient cancers and those patients do not need to be referred to a Familial Cancer Clinic.

A diagnosis of Lynch syndrome may affect childbearing decisions. A referral to a fertility specialist for discussions on predictive testing and assisted conception may also be required.

Surveillance

Lynch syndrome cancers may be more aggressive and often occur at an earlier age than in the general population. It is therefore essential for individuals with Lynch syndrome to follow a targeted surveillance regime.

Most Familial Cancer Clinics have associated Risk Management Services which help keep track of, and arrange, surveillance procedures when needed according to guidelines.

General practitioners and practice nurses can play a key part in assisting patients with Lynch syndrome to co-ordinate their surveillance regime.

In Australia, the NSW Cancer Institute produce evidence-based cancer treatment protocols for Lynch syndrome. These guidelines are updated every two years as a minimum or more frequently if there are major updates in evidence.

For those in NSW, enrolment to the state Hereditary Cancer Registry is strongly advised, as they provide a screening reminder service as well as other information and services. In other states, hospital based registries perform similar functions.

Other factors

Cancer risk for Lynch syndrome carriers is also influenced by familial and environmental factors and surveillance recommendations have changed extensively since the first Lynch syndrome patients were identified.

A patient’s surveillance regime must therefore be considered in conjunction with their family history of cancer, environmental factors and continually evolving Australian and global best practice. 

There is strong evidence that aspirin prevents colorectal and other Lynch Syndrome cancers. Aspirin chemoprevention is advised from the commencement of colonoscopic surveillance.

International recommendations for best practice may be considered where the patient’s family history or other factors are relevant. These include:

• Gastric cancers: Biennial upper GI endoscopy from age 30, especially if there is a family history of gastric cancer or the family is of East of South East Asian descent
• Renal cancers: Urine cytology with or without urinalysis starting at age 30 -36, especially for males with MSH2 Lynch Syndrome

Family cancer clinics provide evidence based and personalised risk estimates and screening advice.

Other resources