Researchers have identified genetic mutations affecting the
immune system which may lead to the development of a more than one
bowel tumour at the same time.
Understanding how these cancers develop could improve targeting
of therapies.
Most people with colorectal cancer will develop one primary
tumour, which may then multiply and spread. However, in around two
to five percent of colorectal cancer cases, two primary tumours
will originate and develop independently, known as synchronous
colorectal cancer.
The study, led by researchers from King's College London,
investigated whether the synchronous tumours had the same or
different mutations and what genetic alterations could be
predisposing people to develop more than one colorectal tumour.
They analysed 20 synchronous colorectal cancers from 10 patients,
and compared their genetics to people with only one colorectal
cancer and to healthy people.
The genetic analysis found the synchronous tumours were not
related to each other - they contained a variety of different
genetic mutations that had led to cancer. This genetic variation
makes synchronous colorectal cancers more difficult to treat,
because therapies targeted at specific genetic aberrations in a
person's cancer may not work if the other tumour has different
genetic mutations.
Researchers also found synchronous colorectal cancer patients
had a higher occurrence of inherited damaging mutations in
immune-related genes. Three-quarters of synchronous colorectal
cancer patients were found to have rare damaging mutations in genes
related to immune system function.
These patients had differences in the composition of their gut
immune cells, which could lead to inflammation in the gut. The
study authors conclude that synchronous colorectal cancer patients
have inherited damaging alterations of immune-related genes, which
may cause an inflammatory environment in the gut and increase the
frequency of independent cancer-initiating events.
Dr Francesca Ciccarelli, of King's College London, said:
"Between two and five percent of all bowel cancer patients develop
more than one primary tumour, called synchronous tumours. Prior to
this study, it was unclear whether these multiple tumours started
because of the same faulty genes. Now we know that these tumours
are as different as cancers from two different people and patients
inherit mutations in genes of the immune system that potentially
have damaging effect. These mutations are usually very rare in
healthy people, but they occur at a much higher frequency in this
patient group.
"Currently, colorectal cancer patients with synchronous tumours
receive the same type of treatments as other cancer patients, but
we now know that each of their multiple cancers are likely to
respond to therapy and develop resistance in a different way.
Therefore, their treatment should be tailored accordingly. This is
an extreme example of precision medicine - normally, precision
medicine targets a therapy to match a patient's cancer mutation,
but in the case of multiple tumours in one patient we need to give
the right drug to the right cancer in order to maximise the
response.
"We still do not know whether the damaging mutations in immune
system genes of these patients have a direct effect on the
composition of the gut immune cells. To unravel this aspect, we
will do further studies to profile the gene expression pattern of
these cells and, in case we find differences with healthy people,
this can be used as a biomarker to predict the development of
synchronous tumours."
Dr Matteo Cereda, also of King's College London, said: "These
patients also have an abnormal composition of immune cells of the
gut and in the tumours. Our hypothesis is that these individuals
develop multiple tumours because they have an abnormal immune and
inflammatory response that favours tumour initiation."
Dr Ciccarelli has been seconded to the Francis Crick Institute
(starting in November) to continue work in this area. She added:
"This multidisciplinary study involved computational biologists,
geneticists, clinicians and immunologists. The collaboration with
colleagues from different backgrounds was key to understanding the
results and putting them into a meaningful context for patients.
This is the type of collaborative project that we will continue to
carry out at the Crick - collaboration is one of the most powerful
ways to tackle complex health problems such as cancer."
The paper, Patients with genetically heterogeneous synchronous colorectal
cancer carry rare damaging germline mutations in immune-related
genes, is published in Nature Communications.