It’s in Our Genes: Hereditary Cancer Syndromes
This article was originally published in Issue One of Discover: Cancer Research In Manchester. All articles are available to read on the MCRC website and a PDF version can be accessed through the links at the end of the page.
Cancer is a genetic disease that’s caused by changes in our DNA. 12% of all cancers are linked to an inherited gene change.
Most of the time, alterations in our DNA do no real damage. But sometimes, they happen in important genes allowing cells to grow out of control and turn into cancer. Generally these cancer causing changes happen by chance. However, environmental may have an impact, for example, we know that smoking and UV from the sun or artificial sources like sun beds can lead to cancer through by causing changes in our DNA.
A small proportion of people are at increased cancer risk because of changes in DNA that are in particularly important genes, and are part of a person’s genetic makeup and so can be inherited. Here individuals and at-risk family members have a higher than average risk of developing certain types of cancer compared to the general population.
Individuals with these hereditary cancer syndromes are often diagnosed with multiple cancers over their lifetime and, depending on the gene involved, may develop their first cancer in childhood. So, it is really important that we are able to identify individuals with these hereditary cancer predisposing gene alterations as early as possible when there is the opportunity to implement age appropriate strategies for cancer prevention and early detection.
There are more than 20 different hereditary cancer syndromes.
Not all hereditary cancer syndromes are routinely tested for in the clinic. However, genetic testing would be recommended for people diagnosed with specific cancers in childhood or those with a strong family history of certain cancers.
Here are two examples of some of the more common hereditary cancer syndromes:
Hereditary breast and ovarian cancer syndrome is the most common hereditary cancer syndrome. It is caused by alterations in the BRCA1 and BRCA2 genes and increases the risk of developing breast cancer by up to 70% and ovarian cancer by up to 45%.
Lynch syndrome is a hereditary cancer syndrome caused by alterations in one of four genes that are responsible for finding and correcting errors in DNA. Mutations causing Lynch syndrome increase the risk of getting bowel cancer at a young age, as well as womb, ovarian, stomach, prostate and other cancers.
Research led by Professor Emma Crosbie, Professor of Gynaecological Oncology at the University of Manchester, led to a change in national policy in 2023 meaning that all women with womb cancer are now screened for Lynch syndrome- helping to identify women who may then also be at increased risk of developing bowel cancer, earlier.
Groundbreaking studies
Dr Emma Woodward, a Consultant Clinical Geneticist at Manchester University NHS Foundation Trust and Honorary Senior Lecturer at The University of Manchester is doing pioneering research to improve risk prediction and early detection for people that have, or are at risk of developing, hereditary cancer syndromes.
She is involved in several groundbreaking studies, including the CanCYP, ATLAS and DONATION projects.
CanCYP
Patients with hereditary cancer syndromes often come to their doctors with pressing questions about their diagnosis, such as, “How likely is it that I will develop another cancer?”. CanCYP is an innovative, data-driven project aiming to provide more accurate and personalised answers to these common patient questions.
The CanCYP project will make use of existing clinical data from NHS patients about their genetics and medical history from sources such as the National Cancer Registration and Analysis Service (NCRAS) database.
In this initial study, the focus is on children and young people with known hereditary alterations in the RB1 and TP53 genes who have developed cancers and undergone treatment, as well as any family members with confirmed alterations.
RB1 and TP53 are important genes that regulate cell growth and death. When altered, these genes are known to cause retinoblastoma (a rare childhood eye cancer of the retina) and Li-Fraumeni syndrome that increases the risk of several cancers including breast cancers and sarcomas.
This data will be used to calculate personalised cancer risk predictions, which can then be used in the clinic. By providing these tailored predictions, CanCYP has the potential to transform how doctors manage a person’s risk focusing on strategies for prevention and early detection.
ATLAS
The risk of a patient with Li-Fraumeni syndrome (LFS) developing a cancer over their lifetime is extremely high, up to 90% by the age of 60. So, detecting cancers at an early stage is key.
Currently, early detection for LFS patients involves annual whole-body MRI scans, often starting in childhood. Whilst these scans are mostly effective at detecting cancers, they can be challenging for patients as they require them to travel to hospital and waiting for results can cause patients increased anxiety.
ATLAS is a cutting edge trial that aims to detect cancers earlier in patients with LFS using liquid biopsies.
Liquid biopsies are a unique type of blood test that can detect signs of cancer, such as DNA from cancer cells. The amount and genetic makeup of this cancer cell DNA, called circulating-free DNA (cfDNA) is known to change over time. So, the idea behind the ATLAS trial is that regular liquid biopsies, monitoring cfDNA levels and its makeup in the blood, could be an additional way to detect cancers early in patients with LFS.
The study is also interested in the methylation patterns of cfDNA, a modification of the DNA caused by the addition of chemical tags called methyl groups. As it is thought that distinct methylation patterns may point to a particular organ, helping to identify the origin of the cancer. This is important as it can help to indicate which organ needs to be scanned in detail.
DONATION
Changes in certain genes are known to play a role in causing cancer. However, a single alteration alone is not enough.
Cells must go through a series of changes, gaining multiple alterations over time to go from a normal cell to a cancer causing one. This process, called mutational evolution, happens very early, and causes precursor lesions to develop into cancer.
Unfortunately, these early changes are particularly difficult for researchers to study. It is especially difficult to study cancers that have hard to spot symptoms, such as pancreatic cancer, as these patients often go to their doctor later, when the cancer has already grown or spread.
The DONATION project aims to model the early mutational evolution that leads to pancreatic cancer, a notoriously hard to treat cancer caused by inherited mutations in 5-10% of cases.
The project will make use of samples from patients enrolled in the rapid autopsy programme, where donors undergo a post-mortem examination within six hours of their death.
Rapid autopsies provide a unique opportunity to study cancer, as samples can be collected from all the different parts of the body, including where the cancer has spread and importantly, unaffected tissues too.
The project will compare samples from patients with known hereditary alterations in genes such as BRCA1 and BRCA2 that are responsible for repairing damaged DNA, to samples from healthy donors and those with non-cancerous precursor lesions to try to understand the early changes that lead to the development of cancer.
These changes will also be modelled in the lab using pancreatic organoids, a 3D, cell-based model that mimics the structure and function of the pancreas.
The hope is that by understanding the early changes that lead to cancer, researchers can find a way to intervene and prevent the cancer from progressing to its untreatable late stages.
To find out more about topics related to Dr Woodward’s research, visit the National Cancer Institute, Macmillan and Genomics Education Programme websites.
