A multidisciplinary team at Yale, led by Yale Cancer Center members, has defined a subgroup of genetic mutations that are present in a significant number of melanoma skin cancer cases. Their findings shed light on an important mutation in this deadly disease, and may lead to more targeted anti-cancer therapies.

The role of mutations in numerous genes and genomic changes in the development of melanoma — a skin cancer with over 70,000 new cases reported in the United States each year — is well established and continues to be the focus of intense research. Yet in approximately 30% of melanoma cases the genetic abnormalities are unclear. To deepen understanding of melanoma mutations, the Yale team conducted a comprehensive analysis using whole-exome sequencing of more than 200 melanoma samples from patients with the disease.

The multidisciplinary team — drawing on their expertise in genetics, cancer, computational biology, pharmacology, and other disciplines — also tested the response of tumour cells with specific mutations to anti-cancer drugs.

The researchers confirmed that a gene known as NF1 is a “major player” in the development of skin cancer. “The key finding is that roughly 45% of melanomas that do not harbour the known BRAF or NRAS mutations display loss of NF1 function, which leads to activation of the same cancer-causing pathway,” said Dr. Michael Krauthammer, associate professor of pathology and the study’s corresponding author.

Additionally, researchers observed that melanoma patients with the NF1 mutation were older and had a greater number of mutations in the tumours. These include mutations in the same pathway, collectively known as RASopathy genes.

Yet mutations in NF1 are not sufficient to cause skin cancer, said Ruth Halaban, senior research scientist in dermatology, a member of Yale Cancer Center, and lead author of the study. “Loss of NF1 requires more accompanying changes to make a tumour,” she explained. “Our study identified changes in about 100 genes that are present only in the malignant cells and are likely to be causative. This panel of genes can now be used in precision medicine to diagnose malignant lesions and can be applied to personalized cancer treatment.”

By testing the response of the melanoma samples to two cancer drugs, the researchers also determined that, in addition to loss of NF1, multiple factors need to be tested to predict the response to the drugs. “It opens the door to more research,” said Halaban, who is also principal investigator at Yale SPORE in Skin Cancer.
Yale University

Study identifies ‘major player’ in skin cancer genes
A multidisciplinary team at Yale, led by Yale Cancer Center members, has defined a subgroup of genetic mutations that are present in a significant number of melanoma skin cancer cases. Their findings shed light on an important mutation in this deadly disease, and may lead to more targeted anti-cancer therapies.

The role of mutations in numerous genes and genomic changes in the development of melanoma — a skin cancer with over 70,000 new cases reported in the United States each year — is well established and continues to be the focus of intense research. Yet in approximately 30% of melanoma cases the genetic abnormalities are unclear. To deepen understanding of melanoma mutations, the Yale team conducted a comprehensive analysis using whole-exome sequencing of more than 200 melanoma samples from patients with the disease.

The multidisciplinary team — drawing on their expertise in genetics, cancer, computational biology, pharmacology, and other disciplines — also tested the response of tumour cells with specific mutations to anti-cancer drugs.

The researchers confirmed that a gene known as NF1 is a “major player” in the development of skin cancer. “The key finding is that roughly 45% of melanomas that do not harbour the known BRAF or NRAS mutations display loss of NF1 function, which leads to activation of the same cancer-causing pathway,” said Dr. Michael Krauthammer, associate professor of pathology and the study’s corresponding author.

Additionally, researchers observed that melanoma patients with the NF1 mutation were older and had a greater number of mutations in the tumours. These include mutations in the same pathway, collectively known as RASopathy genes.

Yet mutations in NF1 are not sufficient to cause skin cancer, said Ruth Halaban, senior research scientist in dermatology, a member of Yale Cancer Center, and lead author of the study. “Loss of NF1 requires more accompanying changes to make a tumour,” she explained. “Our study identified changes in about 100 genes that are present only in the malignant cells and are likely to be causative. This panel of genes can now be used in precision medicine to diagnose malignant lesions and can be applied to personalized cancer treatment.”

By testing the response of the melanoma samples to two cancer drugs, the researchers also determined that, in addition to loss of NF1, multiple factors need to be tested to predict the response to the drugs. “It opens the door to more research,” said Halaban, who is also principal investigator at Yale SPORE in Skin Cancer. Yale University

This month in Breast Cancer Research and Treatment, Khalil and his colleagues at Case Western Reserve University proved the power of persistence; from a pool of more than 30,000 possibilities, they found 38 genes and molecules that most likely trigger HER2+ cancer cells to spread.

By narrowing what was once an overwhelming range of potential culprits to a relatively manageable number, Khalil and his team dramatically increased the chances of identifying successful treatment approaches to this particularly pernicious form of breast cancer. The HER2+ subtype accounts for approximately 20 to 30 percent of early-stage breast cancer diagnoses, which are estimated to be more than 200,000 new breast cancer diagnoses each year in this country, leading to approximately 40,000 deaths annually. Several cancer chemotherapy drugs do work well at early stages of the disease — destroying 95 to 98 percent of the cancer cells in HER2+ tumors.

“Eventually though, many of these patients develop resistance to the drugs, and the 2 to 5 percent of the remaining breast cancer cells begin to grow and cause tumours again,” said Khalil, assistant professor in the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine. “We want to develop a strategy to target the genes responsible for enhancing HER2 oncogenic activity and increase the chances of eliminating the tumour entirely at the early stages of the disease.”

In this study, Khalil, also a member of the Case Comprehensive Cancer Center, and colleagues chose an innovative approach that went beyond merely comparing gene expression in normal and in HER2+ cancer-affected breast tissue. Other scientists tried such a straightforward comparison but found themselves swamped by hundreds and even thousands of gene expression differences. Instead, Khalil designed a study where the offending genes would stand out. He and colleagues compared gene expression differences among HER2+ breast cancer tissues of uncontrolled HER2 activity with those having greatly diminished HER2 activity. Ultimately their work revealed 35 genes and three long intervening noncoding RNA (lincRNAs) molecules were most associated with the active HER2+ cells.

To obtain special breast cancer tissues in HER2-active and HER2-diminished states, Khalil collaborated with oncologist Lyndsay Harris, MD, who had served as correlative science principal investigator for a clinical trial of the drug trastuzumab, which involved Brown University, Yale University and Cedars-Sinai. Harris, now professor of medicine, CWRU School of Medicine, and director of the Breast Cancer Program, University Hospitals Seidman Cancer Center, obtained the preserved HER2+ breast cancer tissues for Khalil’s study from two intervals — before and then during the trastuzumab clinical trial. The drug works by disrupting HER2 activity, which in turn prevents this recalcitrant protein from launching uncontrolled cell growth.

From this collection of HER2+ breast cancer tissue, Khalil and colleagues got to work on determining which genes and other genetic components stood out. First, they applied RNA sequencing and then compared the sequences in tissues collected before trastuzumab curtailed HER2 activity with those collected later when HER2 activity declined sharply. Next, investigators grew the HER2+ breast cancer tissue cells in the laboratory and examined genes prominent in the cell culture (in vitro) model of the disease. Forty-four genes stood out during this portion of the investigation. Finally, Khalil and colleagues obtained publically available RNA-sequence data sets comparing HER2+ breast cancer with matched normal tissue and found that 35 of those 44 genes passed through this third filter.

“In our investigation, we essentially went from thousands of genes and narrowed it down to 35 genes,” Khalil said. “A lot of those genes made sense in terms of carcinogenesis. When they become upregulated because of increased HER2 activity, many of these genes are involved in increased transcription and increased cell proliferation, which are hallmarks of cancer cells.”

The investigators applied the same comparative analysis — RNA sequencing, growing cells in culture and inhibiting HER2 protein — to observe the role of lincRNAs. Khalil and colleagues only discovered this special group of RNA genes in humans in 2009, and scientists now are slowly unraveling the mystery of lincRNAs. For this study, investigators uncovered three standout lincRNAs that are modulated in activity when subjected to increased HER2 activity.

“For the first time, we have shown that these lincRNAs can also contribute to this HER2+ breast cancers,” Khalil said. “So we added another layer of complexity to the disease with lincRNAs. However, these lincRNAs could potentially open the door for RNA-based therapeutics in HER2+ breast cancer, a therapeutic strategy that has great potential but has not been fully tested in the clinic yet.” Case Comprehensive Cancer Center

Almost 90% of men with advanced prostate cancer carry genetic mutations in their tumours that could be targeted by either existing or new cancer drugs, a landmark new study reveals.

Scientists in the UK and the US have created a comprehensive map of the genetic mutations within lethal prostate cancers that have spread around the body, in a paper being hailed as the disease’s ‘Rosetta Stone’.

Researchers say that doctors could now start testing for these ‘clinically actionable’ mutations and give patients with advanced prostate cancer existing drugs or drug combinations targeted at these specific genomic aberrations in their cancers.

The study was led in the UK by scientists at The Institute of Cancer Research, London, in collaboration with researchers from eight academic clinical trials centres around the world.

Uniquely, doctors at The Royal Marsden NHS Foundation Trust and at hospitals in the US were able to collect large numbers of samples of metastatic cancers – cancers that had spread from the original tumour to other parts of the body.

Normally these samples are extremely hard to access, and this is the first study in the world to carry out in-depth analysis of metastatic prostate cancers that are resistant to standard treatments.

Researchers analysed the genetic codes of metastatic tumours from the bone, soft tissues, lymph nodes and liver of 150 patients with advanced prostate cancer.

Nearly two thirds of the men in the study had mutations in a molecule that interacts with the male hormone androgen which is targeted by current standard treatments – potentially opening up new avenues for hormone therapy.

Mutations in the BRCA1 and BRCA2 genes – most famous for their roles in breast cancer – were found in nearly 20% of patients. Recent work at the ICR and The Royal Marsden has shown that these patients can be treated effectively by drugs called PARP inhibitors.

Researchers also discovered new mutations, never detected before in prostate cancer, but which do occur in other cancers. These include mutations in the PI3K and RAF gene families which can also be targeted by existing drugs, either currently in trials or approved for use in the clinic.

The researchers also took blood tests to analyse patients’ own genomes, and found that 8% were born with DNA errors that predisposed them to prostate cancer. They said this could strengthen the case for genetic screening for people with a family history of the disease.

Institute for Cancer Research

Scientists at the University of British Columbia have discovered a gene that could be an important cause of obesity.

The gene, which encodes a protein called 14-3-3zeta, is found in every cell of the body. But when scientists silenced the gene in mice, it resulted in a 50 per cent reduction in the amount of a specific kind of unhealthy “white fat” – the kind associated with obesity, heart disease and diabetes. The fat reduction occurred despite the mice consuming the same amount of food. Mice that were bred to have higher levels of the 14-3-3zeta protein were noticeably bigger and rounder, having an average of 22 per cent more white fat when fed a high calorie diet.

Earlier this year, a consortium of scientists found over 100 regions on the human genome that correlate with obesity, likely through regulating the brain’s perception of hunger and the distribution of fat throughout the body. That study, however, did not identify the gene that encodes 14-3-3zeta, which controls the production of fat cells (known as adipogenesis) and the growth of those cells.

Discovery of this direct link between a protein and fat production, described in Nature Communications, points the way to a possible drug therapy. Scientists theorize that by suppressing the gene or blocking the protein, they could prevent fat accumulation in people who are overweight, or are on their way to becoming so.

“People gain fat in two ways – through the multiplication of their fat cells, and through the expansion of individual fat cells,” said Gareth Lim, a postdoctoral fellow in UBC’s Life Sciences Institute. “This protein affects both the number of cells and how big they are, by playing a role in the growth cycle of these cells.”

Lim and James Johnson, a professor of cellular and physiological sciences, began investigating the 14-3-3 family of proteins four years ago as it often shows up in the unhealthy fat tissue of obese people. This study not only identified zeta as the operative protein, but demonstrated a clear cause-and-effect between 14-3-3zeta and fat accumulation.

“Until now, we didn’t know how this gene affected obesity,” Johnson said. “This study shows how fundamental research can address major health problems and open up new avenues for drug discovery.”

Obesity is linked to increased risk of diabetes, heart disease, and some forms of cancer. Worldwide, obesity costs society $2 trillion each year. More than one in four Canadians are obese, and that number continues to grow, according to Statistics Canada. Alarmingly, the obesity rate is also increasing in children.

We don’t fully understand how fat cells are made, and its clear that this information would be useful in efforts to prevent obesity.

Find other stories about: 14-3-3zeta, Faculty of Medicine, James Johnson, obesity, Obesity gene University of British Columbia