DNA sequencing can help to identify 'driver' mutations in cancer

A recent study revealed that an effective DNA sequencing technology can not only help to identify the mutations undergone in the root of the tumor of a patient that is important for incorporating the treatment of cancer but the technology can now help to get the genetic map of evolution of the disease that can help the doctors to monitor the response to the treatment.

"We're finding clinically relevant information in the tumour samples we're sequencing for discovery-oriented research studies," said Elaine Mardis, PhD, co-director of The Genome Institute at the School of Medicine.

"Genome analysis can play a role at multiple time points during a patient's treatment, to identify 'driver' mutations in the tumour genome and to determine whether cells carrying those mutations have been eliminated by treatment." She added.

These findings can help us to guide for deciding future designs of clinical trials for cancer which will be based on the results of the sequencing, said Mardis, affiliated with the Siteman Cancer Center at the School of Medicine and Barnes-Jewish Hospital.

Mardis and her colleagues have sequenced the entire DNA - the genome - of tumour cells of over 700 cancer patients till date. Thus, by comparing the sequences of the tumour cells with the healthy ones, the elementary mutation occurred in the patient’s cancer can be identified.

Moreover, the information extracted from the sequencing of whole genome is driving the scientists to classify the tumours again on the basis of their genetic makeup instead of their location in the body as earlier.

Mardis and her colleagues have found that, patients with breast cancer, there are various driver mutations in the genes that were not associated with breast cancer tumours earlier.

In addition to that, variety of genes has been identified linked to prostate, colorectal, lung or skin cancer, as well as leukaemia and other cancers. Drugs targeting mutations in these genes that includes imatinib, ruxolitinib and sunitinib, while not approved for breast cancer, are already present in the market for other type of cancers.

"We are finding genetic mutations in multiple tumour types that could potentially be targeted with drugs that are already available," Mardis said.

However, it may require a standard change for the oncologists across the world to evaluate the potential benefits of customized cancer therapy.

While present clinical trials typically involve assigning the treatment therapy to a cancer patient randomly, the new approach of individualized treatment will choose the drugs on the basis of detected mutations in each patient's tumour.

"Having all treatment options available for every patient doesn't fit neatly into the confines of a carefully designed clinical trial," Mardis acknowledged.

"We're going to need more flexibility." She added.

The time of developing the mutation during the course of cancer is also important to decide the treatment.

In a recent study, Mardis and her team mapped the genetic evolution of leukaemia and they found some clues to suggest that personalized cancer drugs should target at mutations that develop during the early stage of the disease.

They used the "deep digital sequencing," an advance technique developed at The Genome Institute, and sequenced individual mutations in patient’s tumour samples for more than 1,000 time each.

This provided a layout of the frequency of each mutation taking place in a patient's tumour genes that allowed the researchers to map the genetic evolution of cancer cells with the progression of the disease.

It was seen that, with the evolution of cancer, tumours acquire new mutations but the original cluster of mutations of initial stage was retained.

These findings suggest that the drugs targeting the cancer can be more effective if focused towards the genetic changes occurring at the initial stage of cancer.

Drugs targeting the mutations detected during the evolved and later stages of cancer may not be that effective as they would not be able to kill all the tumour cells.

Mardis said that sequencing the entire genome of cancer cells is very essential in order to predict a clear picture of the evolution of the cancerous cells. If the sequencing of a small part of genomes involved is done, it is not possible for the researchers to track the frequency of mutations over time. Moreover, only 1 to 2 percent of the genomes consist of genes.

In another study at Washington University, the researchers did a phase III clinical trial of post-menopausal women with estrogen-receptor positive breast cancer, and shown that sequencing can really help to predict that which women is likely to respond to treatment with aromatase inhibitors.

Interestingly, when the sequencing of patient’s breast tumours was done before and after aromatase inhibitor therapy, the researchers identified substantive genomic changes occurring in the responsive patients. In addition to that, the patients who were unresponsive to the therapy, the changes remained largely unchanged by the therapy.

In addition, the researchers have also identified a number of mutations in the breast tumours that have complimentary small-molecule inhibitor drugs targeting the defective proteins.

Moreover, the outputs of the findings predict that that for women who are unresponsive to the aromatase inhibitors, treatment options may include a combination of conventional chemotherapy along with the indicated small-molecule inhibitor.

-With inputs from ANI