In a world first, Australian researchers have mapped the entire genome of a prostate tumour, providing a new lens through which to view this disease.
They mapped the most commonly diagnosed grade of prostate cancer. It was a tumour that scored 7 on the standard Gleason score and is clinically known to be highly unpredictable.
This mapping, using a biopsy sample taken from a patient, was a long and slow process.
It required the researchers to get DNA out of tissue without destroying it. Previously this had not been achieved in humans.
The results of their study of this single tumour are published in the journal Oncotarget that is aimed at doctors and scientists.
Prostate cancer is the most commonly diagnosed cancer in Australian men and this work is proof of principle that next-generation mapping can provide insights into its subtypes.
The information gained by such mapping could be used to characterise an individual’s tumour and reveal previously unrecognised information so treatment can be more targeted.
Conducted at Sydney’s Garvan Institute of Medical Research, the mapping revealed previously undetected levels of DNA changes linked to the disease.
Very little understood
It uncovered 10 times more large-scale DNA rearrangements than have previously been detected in prostate cancer and identified 15 new potential drivers of this cancer.
“Although we’ve been researching prostate cancer for many years, very little is understood about what drives these tumours,” says study leader, Professor Vanessa Hayes, Head of Garvan’s Human Comparative and Prostate Cancer Genomics Laboratory.
“One of the biggest clinical challenges is distinguishing which cancers are going to spread and become life-threatening, and which patients could be spared harsh treatment they might not need.
“To have any hope of targeting treatment in this way, we first need to understand the genetic drivers of each individual tumour. “
The researchers used new mapping technology in tandem with whole genome sequencing to uncover the most complete picture to date of the prostate cancer genomic landscape.
While genomic sequencing is a close up exercise which reads each letter of a genetic code, mapping takes a few steps back and provides a bigger picture. It gives a bird’s eye view, orientating the sequence in its context.
She says prostate cancer has unique features.
“From previous genome sequencing studies we know it has very few small genetic changes, but rather, is more likely driven by large complex rearrangements of DNA within the genome. “
“This is different to most cancers, which are driven by small DNA mutations in a number of key genes.”
“Until now, we had no way of observing these DNA rearrangements or structural variants in prostate cancer.”
Professor Hayes says the synergy with whole genome sequencing was very important.
“We could not have done this with sequencing technology alone. Whole genome sequencing is invaluable in identifying small DNA mutations, but it may not detect when a gene has been completely deleted, transferred to another chromosome, or multiplied many times - which is what we see here.”
“Using next-generation mapping, we saw huge amounts of large-scale rearrangements, and genome sequencing then enabled us to identify the genes affected by these rearrangements.”
“Several cancer-promoting genes were multiplied many times, increasing their potency, and potentially driving this prostate tumour.”
“Whole genome sequencing opened a huge number of doors for our understanding of prostate cancer – next-generation mapping just doubled the number of doors,” says Prof Hayes.
Her team was first in Australia to obtain next-generation mapping technology, and first in the world to apply it to understanding an individual tumour.
“I believe that in the future this technology will complement next generation sequencing as a key to personalised medicine for prostate cancer.”
The study was performed as part of the Prostate Cancer Metastasis (ProMis) program, an Australian-led international initiative. Since it began, mapping technology has improved and is now faster.
The Garvan team has since mapped a further four tumours which will be the subject of another paper. Professor Hayes says this new work confirms the significance of these large DNA changes detected in the first study.
When it comes to mapping technology for cancer in humans, Australia is a world leader.
“This is a very promising research breakthrough,” says Professor Allan Spigelman, Director of Cancer Genetics at Sydney’s St Vincents’ Hospital.
“In time, it will complement some current treatment options that are based on genetic testing of blood samples. Using prostate cancer tissue genetic analysis may hopefully lead to even more precise and targeted treatments.”
Professor Spigelman, who conducts cancer genetics services across NSW, say at present men with prostate cancer can have genetic testing to see if they have a good chance of responding to particular medication.
“Current cancer gene testing of blood samples target DNA repair genes such as BRCA2.”
“Detection of a mutation here opens up novel drug treatments to which those carrying mutations in that gene respond best.”