An international scientific collaboration led by Baylor College of Medicine has revealed clues about genetic alterations that may contribute to a rare form of kidney cancer, providing new insights not only into this rare cancer but other types as well.

The collaboration – part of The Cancer Genome Atlas initiative which is funded by the National Institutes of Health – completed the sequence completed the sequence of chromophobe renal cell carcinoma and have published the results.

“The Cancer Genome Atlas is a federally funded national effort that has already completed the sequence of many major types of cancer (breast, lung, ovarian, for example), but this project is now branching out to sequence more rare types of cancer,” said Dr. Chad Creighton, associate professor of medicine and a biostatistician in the NCI-designated Dan L. Duncan Cancer Center at Baylor and the lead and corresponding author on the report. “The idea is that with a better understanding of these more rare types of cancers, we gain new insight that might be relevant to how we study other types of cancer. The findings in this study are a perfect example of that.”

Chromophobe renal cell carcinoma is a rare type of kidney cancer, with approximately 2,000 new cases diagnosed each year in the United States. A majority of patients survive the disease.

“Although most patients are reassured when the pathology of their kidney tumour comes back as chromophobe, we all have cared for patients who developed and died from metastatic chromophobe kidney cancers,” said Dr. Kimryn Rathmell, associate professor of haematology and oncology in the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill and a co-senior author on the study. “This report is incredibly exciting for physicians who care for these patients because all of the treatment plans we have had to this point have been based on the biology of the more common kidney cancer type, as if chromophobe must be a close relative of that disease.”

The project shows with no uncertainty that chromophobe renal cell carcinoma represents a distinct cancer entity, and reveals exciting biology inherent to the disease that we hope in the future will allow new therapies to be developed specifically for the chromophobe type of kidney cancer, Rathmell said.

The team sequenced 66 tumor samples at Baylor’s Human Genome Sequencing Center. Other types of data were collected on these samples and integrated with the sequencing, including gene expression and epigenetic data. In addition to sequencing known genes, DNA from mitochondria and from the entire genome was also sequenced.

“Instead of just looking specifically at the exome, we also analysed the entire genome, something not typically done in these genomic studies,” said Creighton. The exome, the part of the genome used to make proteins, constitutes only 1 percent of the total genome, where the other 99 percent is often ignored in studies.

With whole exome analysis, scientists are just looking within the boundaries of known genes, to see which are broken and may have caused the disease, he explained.

“However, when you look outside of the genes, there is much more going on,” said Creighton. “For example, gene regulatory features of the genome can be altered.”

From whole genome analysis, the team observed a significant amount of structural rearrangements or breakpoints involving the promoter region of a gene called TERT, which encodes for the most important unit of the telomerase complex.

Telomerase represent the “clock” of the cell, Creighton said. “This plays a critical role in cell division, and with many cancer cells, telomerase levels are really high and time never really runs out, which allows the cell to never die. “

It was the promoter region, not the actual gene, that was affected, Creighton clarified. “Since there isn’t a breakdown in the actual gene, this malfunction is not picked up in whole exome analysis.”

The study also raised intriguing questions about the roles of mitochondrial DNA alterations and of the cell of origin involved in cancer initiation, the authors noted.

This could signify new approaches for how scientists should conduct molecular studies of cancer, he said. “We need to survey the regulatory regions for other cancer types as well.” Baylor College of Medicine

Prostate cancer is a leading cause of cancer-related death in men in the United States. The development and progression of the disease depend on the actions of male sex hormones called androgens, which bind to the androgen receptor to activate signalling pathways involved in cell growth and survival. Therefore, there is a strong need to identify novel drug targets to alter androgen-receptor signalling and treat this often deadly disease.

Sanford-Burnham researchers have discovered that a protein called NWD1 affects androgen-receptor signalling to control the growth of prostate cancer cells. ‘A very limited number of proteins have been shown to specifically and exclusively affect androgen-receptor signalling, so our findings represent a major advance in the field,’ said lead study author Ricardo Correa, Ph.D., staff scientist at Sanford-Burnham. ‘NWD1 could represent a new biomarker for predicting patient prognosis as well as a therapeutic target for a novel class of prostate cancer drugs.’
High levels of androgens are critical for the growth of prostate cancer cells in early disease stages, and one major type of therapy focuses on inhibiting androgens. But over time, prostate cancer cells often respond to hormone therapy by expressing high levels of the androgen receptor, allowing these castration-resistant cells to grow even when androgen levels are low. Castration-resistant prostate cancer is an advanced form of the disease associated with poor survival rates. However, both early and advanced stages of prostate cancer depend on androgen-receptor signalling, highlighting the value of targeting this pathway for treating a broad range of patients.

While searching for novel modulators of androgen-receptor signalling, Correa and his team became interested in the nucleotide-binding domain and leucine-rich repeat (NLR) family of proteins. These proteins are involved in recognising pathogens and cell-injury signals and activating immune-defence pathways, but they have also been implicated in a variety of cancers. In particular, the researchers were intrigued by an NLR-related protein called NWD1, which was previously identified in zebrafish but had not yet been analyzed in humans.

In the new study, Correa and his colleagues found that the expression of the human NWD1 gene was very high in prostate tissue and other parts of the male reproductive system. Moreover, NWD1 expression was higher than normal in human prostate cancer cell lines, especially in castration-resistant and highly metastatic cell lines. Similarly, NWD1 protein levels were higher than normal in advanced-stage and castration-resistant prostate tumour tissue from patients.

Taken together, the findings suggest that NWD1 could be a potential prostate cancer biomarker because high levels of the protein are associated with malignant progression. ‘We believe that NWD1 could represent a promising biomarker because changes in NWD1 expression happen at stages where the levels of prostate-specific antigen (PSA), a protein that is widely used to screen men for prostate cancer, are not very accurate in the clinic,’ Correa said.
In addition to its potential use for predicting patient prognosis, NWD1 could represent a promising therapeutic target. When the researchers inhibited the activity of the NWD1 gene in prostate cancer cells, they noticed a drop in androgen-receptor levels as well as a decrease in cell growth and survival. On the other hand, an increase in NWD1 activity led to a rise in androgen-receptor levels in these cells.

Their experiments also shed light on the molecular mechanisms by which NWD1 affects androgen-receptor signalling. NWD1 silencing fed the activity of cancer-related genes such as PDEF (prostate-derived epithelial factor), which is known to bind to androgen receptors and belongs to a family of proteins that regulate cell growth and survival. Moreover, a protein called sex-determining region Y (SRY), which controls sex determination during fetal development, affected the activity of the NWD1 gene. Thus, the findings not only reveal a novel molecular pathway involved in prostate cancer, but also suggest that drugs targeting NWD1 could eventually become a new class of treatments for the disease. Sanford-Burnham

UCLA researchers led by Dr. Brigitte Gomperts have discovered the inner workings of the process thought to be the first stage in the development of lung cancer. Their study explains how factors that regulate the growth of adult stem cells that repair tissue in the lungs can lead to the formation of precancerous lesions.

Findings from the three-year study could eventually lead to new personalized treatments for lung cancer, which is responsible for an estimated 29 percent of U.S. cancer deaths, making it the deadliest form of the disease.

The study collaborated with Manash Paul and Bharti Bisht, postdoctoral scholars and co-lead authors of the study.

Adult stem cells in lung airways are present specifically to repair the airways after injury or disease caused by smoking, pollution, viruses or other factors. Gomperts and her team found that this reparative process is tightly regulated by molecules called reactive oxygen species, or ROS.

Recent research has shown that low levels of ROS are important for signalling the stem cells to perform important functions — such as repairing tissue damage — while high levels of ROS can cause stem cells to die. But the level of ROS needed for repair to be initiated has remained a subject of debate among researchers.

The UCLA study found that the dynamic flux of ROS from low to moderate levels in the airway stem cells is what drives the repair process, and that the increase in ROS levels in the repairing cell is quickly reduced to low levels to prevent excessive cell proliferation.

Gomperts’ lab found that disrupting this normal regulation of ROS back to low levels is equivalent to pulling the brakes off of the stem cells: They will continue to make too many of themselves, which causes the cells not to mature and instead become precancerous lesions. Subsequent progressive genetic changes to the cells in these lesions over time can eventually allow cancerous tumours to form.

‘Low ROS is what keeps stem cells primed so that your body is poised and ready to respond to injury and repair,’ said Gomperts, who also is an associate professor in the department of paediatrics at UCLA. ‘Loss of this ROS regulation leads to precancerous lesions. Now, with this precancerous model in place, we can begin looking for what we call ‘driver mutations,’ or those specific changes that take the precancerous lesions to full-blown cancer.’

Gomperts said that because many different factors — including cigarette smoke, smog and inflammation — could potentially trigger an increase in ROS in the airway stem cells, researchers might eventually be able to customize treatments based on the cause. ‘There are likely multiple ways for a person to get to a precancerous lesion, so the process could be different among different groups of people. Imagine a personalized way to identify what pathways have gone wrong in a patient, so that we could target a therapy to that individual.’

The research’s ultimate goal is to develop a targeted strategy to prevent pre-malignant lesions from forming by targeting the biology of these lesions and University of California – Los Angeles

Researchers at UT Southwestern Medical Center and the Gill Center for Cancer and Blood Disorders at Children’s Medical Center, Dallas, have made significant progress in defining new genetic causes of Wilms tumor, a type of kidney cancer found only in children.

Wilms tumour is the most common childhood genitourinary tract cancer and the third most common solid tumour of childhood.

“While most children with Wilms tumour are thankfully cured, those with more aggressive tumours do poorly, and we are increasingly concerned about the long-term adverse side effects of chemotherapy in Wilms tumour patients. We wanted to know – what are the genetic causes of Wilms tumour in children and what are the opportunities for targeted therapies? To answer these questions, you have to identify genes that are mutated in the cancer,” said Dr. James Amatruda, Associate Professor of Pediatrics, Molecular Biology, and Internal Medicine at UT Southwestern and senior author for the study.

Collaborating with Dr. Amatruda on the study were UT Southwestern faculty members Dr. Dinesh Rakheja, Associate Professor of Pathology and Pediatrics; Dr. Kenneth S. Chen, Assistant Instructor in Pediatrics; and Dr. Joshua T. Mendell, Professor of Molecular Biology. Dr. Jonathan Wickiser, Associate Professor in Pediatrics, and Dr. James Malter, Chair of Pathology, are also co-authors.

Previous research has identified one or two mutant genes in Wilms tumours, but only about one-third of Wilms tumors had these mutations.

“We wanted to know what genes were mutated in the other two-thirds. To accomplish this goal, we sequenced the DNA of 44 tumours and identified several new mutated genes,” said Dr. Amatruda, who holds the Nearburg Family Professorship in Pediatric Oncology Research and is an Attending Physician in the Pauline Allen Gill Center for Cancer and Blood Disorders at Children’s Medical Center. “The new genes had not been identified before. The most common, and in some ways the most biologically interesting, mutations were found in genes called DROSHA and DICER1. We found that these mutations affected the cell’s production of microRNAs, which are tiny RNA molecules that play big roles in controlling the growth of cells, and the primary effect was on a family of microRNAs called let-7.”

“Let-7 is an important microRNA that slows cell growth and in Wilms tumours in which DROSHA or DICER1 were mutated, let-7 RNA is missing, which causes the cells to grow abnormally fast,” Dr. Amatruda said.

These findings have implications for future treatment of Wilms tumour and several other childhood cancers, including neuroblastoma, germ cell tumour, and rhabdomyosarcoma.

“What’s exciting about these results is that we can begin to understand what drives the growth of different types of Wilms tumours. This is a critical first step in trying to treat the cancer based on its true molecular defect, rather than just what a tumour looks like under a microscope,” Dr. Amatruda said. “Most importantly, we begin to think in concrete terms about a therapy, which is an exciting translational goal of our work in the next few years. UT Southwestern Medical Center