Newly identified genetic markers classify previously undetermined glioblastoma tumors

June 5, 2018, Duke University
Newly identified genetic markers classify previously undetermined glioblastoma tumors
SMARCAL1 mutations identified in this study were found to be involved in how cancer cells become immortal by keeping their telomeres long through a process known as alternative lengthening of telomeres (ALT). Shown is a SMARCAL1-mutant cancer cell line ex. Credit: Duke University

Most glioblastoma tumors are marked by one or two broad mutation patterns, but about 20 percent of the lethal brain tumors have biomarkers that cannot be identified. 

Now scientists at Duke Cancer Institute have identified for the vast majority of the remaining 20 percent of uncharacterized tumors, which tend to be especially lethal. The findings indicate that these mutations involve a previously unknown disruption of the cell's normal mortality that is governed by components called telomeres.

Telomeres are pieces of DNA that protect the ends of chromosomes. Under normal circumstances, they become shorter with age and eventually trigger a series of events that leads to a cell's natural death. Some cause them to remain long however, so cells never die, leading to immortal cells and growth. 

"The mutations we identified could be targeted for new therapies that would benefit these patients, who typically have the worst prognosis," said lead author Bill Diplas, an M.D./Ph.D. candidate and member of the Hai Yan Laboratory in the Duke Department of Pathology.

Diplas, Yan and colleagues in the Preston Robert Tisch Brain Tumor Center at Duke published their findings May 25 in the journal Nature Communications.

The researchers used gene sequencing to characterize the genetic landscape of glioblastoma tumors that did not appear to carry the two common mutations that are evident in 80 percent of these brain tumors. 

The researchers identified new mutations that reveal these tumors are actually made up of two distinct subgroups related to their unique mechanisms of maintenance. This includes a subgroup driven by rearrangements in the promoter of telomerase reverse transcriptase, known as TERT, and a subgroup with mutations in two additional genes, named SMARCAL1 and ATRX. 

The findings establish a previously unrecognized connection between a mechanism of telomere maintenance known as alternative lengthening of telomeres (ALT) and mutations in SMARCAL1 in cancer.

The alterations for telomere maintenance identified by the Duke researchers are present in other tumor types as well, potentially providing a new target for drug therapies.

"Tumor cell telomere maintenance is a very promising area for drug research," Yan said. "But it's extremely important to understand what's driving the cell's immortality. Cancer cells can possibly switch from one mechanism to another when they are targeted, so understanding the different genetic pathways can help develop therapies that address this resistance."

The authors also found that there were an increased number of mutations in the gene BRAF among younger patients with this tumor type. This is significant because the resulting mutant protein can be targeted by several FDA-approved drugs.

Explore further: Immortality gene mutation identifies brain tumors, other cancers

More information: Bill H. Diplas et al. The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma, Nature Communications (2018). DOI: 10.1038/s41467-018-04448-6

Related Stories

Immortality gene mutation identifies brain tumors, other cancers

March 18, 2013
Newly identified mutations in a gene that makes cells immortal appear to play a pivotal role in three of the most common types of brain tumors, as well as cancers of the liver, tongue and urinary tract, according to research ...

Unraveling the mystery of why cancer cells survive and thrive

January 30, 2017
Some cancer cells have a trick up their sleeve to avoid cell death: boosting maintenance of telomeres, the protective "end caps" on chromosomes, and a research team led by Jackson Laboratory (JAX) Professor Roel Verhaak reports ...

Two genes linked to why telomeres stretch in cancer cells

June 30, 2011
Scientists at Johns Hopkins have provided more clues to one of the least understood phenomena in some cancers: why the "ends caps" of cellular DNA, called telomeres, lengthen instead of shorten.

How two telomere proteins interact with each other and the functional effects of cancer-associated mutations

April 11, 2017
Scientists at The Wistar Institute have unveiled part of the protein complex that protects telomeres—the ends of our chromosomes. The study, published online in Nature Communications, explains how a group of genetic mutations ...

Researchers uncover more genetic links to brain cancer cell growth

December 2, 2016
Two recently discovered genetic differences between brain cancer cells and normal tissue cells—an altered gene and a snippet of noncoding genetic material—could offer clues to tumor behavior and potential new targets ...

Researchers find a pathway that leads to resistance of aggressive brain tumor treatment

February 16, 2018
Glioblastoma multiforme is one of the most common and deadly brain tumors. Despite the initial responsiveness to state-of-the-art therapies, tumors virtually always become resistant and eventually recur. Researchers at Dartmouth's ...

Recommended for you

Researchers create novel combination as potential therapy for high-risk neuroblastoma

June 18, 2018
Researchers at VCU Massey Cancer Center in Richmond, Virginia, have identified a promising target to reverse the development of high-risk neuroblastoma and potentially inform the creation of novel combination therapies for ...

Study suggests well-known growth suppressor actually fuels lethal brain cancers

June 18, 2018
Scientists report finding a potentially promising treatment target for aggressive and deadly high-grade brain cancers like glioblastoma. But they also say the current lack of a drug that hits the molecular target keeps it ...

Standard myelofibrosis drug can awaken 'dormant' lymphoma

June 18, 2018
Most patients with myelofibrosis, a rare chronic disorder of the haematopoietic cells of the bone marrow, benefit from drugs from the JAK2 inhibitor class: symptoms are relieved, survival extended and general quality-of-life ...

Genomics offers new treatment options for infants with range of soft tissue tumors

June 18, 2018
The genetic causes of a group of related infant cancers have been discovered by scientists at the Wellcome Sanger Institute, the University of Wuerzburg and their collaborators. Whole genome sequencing of tumours revealed ...

Breast cancer researcher warns against online genetic tests

June 18, 2018
We have never been so fascinated by the secrets inside our cells.

Non-coding DNA reveals a route by which advanced prostate cancer resists treatment

June 15, 2018
Two research teams converge on epigenetic switches that feed treatment-resistant metastatic prostate tumors. This research highlights the value of exploring gene regulation and large-scale structural changes in the cancer ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.