Analysis of 607 small cell lung cancer (SCLC) lung tumours and neuroendocrine tumours (NET) identified common molecular markers among both groups that could reveal new therapeutic targets for patients with similar types of lung cancer, according to research.

This study examined the clinical specimens of 607 total cases of SCLC tumours (375) and lung NET (232), which included carcinoid, atypical carcinoid and large-cell neuroendocrine tumors. Biomarker testing was achieved through a combination of DNA sequencing (Next-Generation Sequencing (NGS) or Sanger-based); immunohistochemistry (IHC) to identify which proteins are present; and in situ hybridization (ISH) testing, a form of gene amplification, to determine if any of the markers that can cause cancer cells to grow or to become resistant to treatment are present.

Sequencing data were obtained from 201 total specimens (SCLC=115, NET=86). The 115 SCLC tumors harboured a wide spectrum of gene markers. Sequencing revealed mutations in p53 (57 percent), RB1 (11 percent), ATM, cMET (6 percent), PTEN (6 percent), BRAF (3 percent), SMAD4, KRAS (3 percent), ABL1, APB, CTNNB1, EGFR, FBXW7, FGFR2 (2 percent), HNF1A, HRAS, JAK3 (2 percent), MLH1 and PIK3CA (1 percent).

Multiple genes of interest were found in the NET group of 86 tumours, including 66 pulmonary neuroendocrine carcinomas and 20 carcinoid tumours. Among the neuroendocrine tumours, mutations were seen in p53 (44 percent), FGFR2 (9percent), ATM (9 percent), KRAS (6 percent) and PIK3CA (4 percent) as well as EGFR (2 percent) and BRAF (4 percent). Analysis of the carcinoid tumours revealed fewer markers, with notable mutations in p53 (11 percent), HRAS (11 percent), and BRAF (6 percent).

EGFR amplification was verified for 11 percent (5) of the 46 SCLC tumours tested. No SCLC tumours displayed amplification of cMET or HER2. The neuroendocrine tumours exhibited amplification of EGFR (13 percent), cMET (3 percent), and HER2 (4 percent) amplification, while the carcinoid tumours only showed amplification in EGFR (8 percent).

The overexpression of cKIT (64 percent vs. 37 percent), RRM1 (54 percent vs. 28 percent), TOP2A (91 percent vs. 48 percent), TOP01 (63 percent vs. 43 percent), and TS (46 percent vs. 25 percent) was found more frequently in SCLC tumours compared to lung NET, respectively (p=0.0001 for all). Low expression of PTEN was more often identified in SCLC tumours compared to lung NET (56 percent vs. 36 percent; p=0.001).

Molecular profiling of these lung cancer subtypes is not routinely performed, however, numerous mutations were found to be in common with non-small cell lung cancer tumours. Specifically, an EGFR mutation was noted in one small cell lung cancer specimen and one neuroendocrine specimen, an ALK rearrangement was detected in a neuroendocrine tumor, and HER2 amplification was seen in a neuroendocrine specimen.

“Even cancers that appear to be very similar can be dramatically different at the molecular level, and these differences may reflect unique vulnerabilities that could positively impact therapeutic options and decisions,” said Stephen V. Liu, MD, senior study author and Assistant Professor of Medicine in the Division of Hematology/Oncology at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. “We are pleased that this research confirms these rarer subtypes; it calls for additional investigation on a larger scale. Once confirmed, molecular profiling of small cell tumours and NET could become standard, as it is currently for non-small cell lung cancers, which will be especially important as more molecularly targeted chemotherapy agents are developed.” ASTRO

Highlighting a potential target in the treatment of multiple sclerosis (MS) and Alzheimer’s disease, new research suggests that triggering a protein found on the surface of brain cells may help slow the progression of these and other neurological diseases.

Working with mice, two research teams at Washington University School of Medicine in St. Louis independently linked the protein to the ability to clear debris from the brain. Such waste builds up both as a by-product of daily mental activities and as a result of misdirected immune system attacks on brain cells. If too much debris is present in the brain for too long, it can contribute to neurological disease.

In one study, scientists showed that Alzheimer’s brain plaques build up more slowly in mice that have a defective version of the TREM2 protein. In another, researchers showed that mice lacking the same protein had trouble cleaning up debris in the brain produced by damage to a protective coating on nerve cells. The problem is thought to occur in MS and other neurological disorders.

“We’ve been very interested in identifying ways to control naturally occurring mechanisms that help clean and repair the brain, and these new studies provide clear evidence that TREM2 could be just such a target,” said Laura Piccio, MD, PhD assistant professor of neurology and senior author of one of the studies.

Scientists are looking for ways to activate the protein to slow or prevent  damage caused by neurological disorders.

Previous studies have linked rare forms of the TREM2 gene to early-onset dementia and increased risk of Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

Scientists knew the protein was found on brain cells called microglia, which help maintain and repair the central nervous system. The new studies are among the first to provide clear evidence that the protein plays an integral role in at least some of these processes.

In Alzheimer’s disease, amyloid beta, a by-product of brain metabolism that is normally cleared from the brain, builds up to form plaques. Researchers in the laboratories of Marco Colonna, MD, the Robert Rock Belliveau MD Professor of Pathology, and John Cirrito, PhD, associate professor of neurology, bred mice lacking the gene with mice genetically engineered to have an Alzheimer’s-like condition.

First author Yaming Wang, PhD, a postdoctoral research scholar, monitored the build-up of amyloid plaques in the mice offspring as they aged and found that the absence of the gene significantly accelerated the accumulation of the plaques.

“We found that microglia cluster around amyloid plaques when TREM2 is present, presumably because the cells are getting ready to absorb the plaques and break them down,” said Colonna. “When TREM2 is absent, this clustering does not occur.”

In MS, misdirected immune cell attacks damage myelin, a protective coating on nerve cells, leaving myelin fragments in brain tissue. Failure to promptly remove this debris can worsen damage caused by the condition and inhibit repair mechanisms.

For the MS study, Piccio and colleagues at the John L. Trotter MS Center at Washington University School of Medicine and Barnes-Jewish Hospital gave a compound called cuprizone to mice that lacked the TREM2 gene. Cuprizone causes loss of myelin in a manner somewhat similar to that seen in people with MS.

“When we give normal mice this chemical, they can clear most of the myelin fragments from the brain,” Piccio said. “But when we gave cuprizone to mice that did not have the gene and looked at their brains four, six and 12 weeks later, we could still see evidence of damaged myelin.”

Motor coordination in these mice also was significantly more impaired after cuprizone exposure. This may reflect enhanced damage to brain cells resulting from the lingering presence of damaged myelin in the brain.

Colonna and his colleagues showed that TREM2 detects molecules associated with amyloid beta and with damaged neurons. They believe that the protein helps keep microglia from self-destructing as debris is cleared from the brain.

“This is a mechanism that is very common in immune cells,” he explained. “When a signal activates immune cells and they start attacking an invader or working to repair an injury, they start using energy very rapidly. If the cells do not receive a second signal confirming the need for their services, this increased energy usage will kill them.” University of Washington in St. Louis

Age-related loss of the Y chromosome (LOY) from blood cells, a frequent occurrence among elderly men, is associated with elevated risk of various cancers and earlier death.

This finding could help explain why men tend to have a shorter life span and higher rates of sex-unspecific cancers than women, who do not have a Y chromosome, said Lars Forsberg, PhD, lead author of the study and a geneticist at Uppsala University in Sweden.

LOY, which occurs occasionally as a given man’s blood cells replicate – and thus takes place inconsistently throughout the body – was first reported nearly 50 years ago and remains largely unexplained in both its causes and effects. Recent advances in genetic technology have allowed researchers to use a blood test to detect when only a small fraction of a man’s blood cells have undergone LOY.

Dr. Forsberg and colleagues studied blood samples from 1,153 elderly men aged 70 to 84 years, who were followed clinically for up to 40 years. They found that men whose samples showed LOY in a significant fraction of their blood cells lived an average of 5.5 years less than men whose blood was not affected by LOY. In addition, having undergone LOY significantly increased the men’s risk of dying from cancer during the course of the study. These associations remained statistically significant when results were adjusted for men’s age and other health conditions.

“Many people think the Y chromosome only contains genes involved in sex determination and sperm production,” said Jan Dumanski, MD, PhD, co-author on the study and a professor at Uppsala University. “In fact, these genes have other important functions, such as possibly playing a role in preventing tumours.” When LOY takes place, Y chromosome genes are not expressed, and this tumour prevention would be reduced.

Interestingly, LOY in blood cells is associated with many different cancers, including those outside of the blood system. This may be because Y chromosome genes enable blood cells to assist with immunosurveillance, the process by which the immune system detects and kills tumour cells to prevent cancer.

“Our hypothesis is that LOY disrupts the immunosurveillance normally conducted by blood cells, allowing tumours to grow unchecked and develop into cancer,” Dr. Forsberg said.

These findings suggest a new approach to early detection of cancer risk in men: a blood test to assess LOY. “LOY is not very dangerous in a small fraction of blood cells, but becomes increasingly predictive of cancer as more cells lose their Y chromosome,” Dr. Forsberg explained. “This takes years, so you’d have a window of time to do something to reduce your risk.”

The researchers are currently exploring LOY in more detail, including the effects of various lifestyle factors and other health conditions. They are also examining the frequency and consequences of LOY in different types of cells and throughout the life course. The American Society of Human Genetics

Ovarian cancer is notoriously difficult to diagnose and treat, making it an especially fatal disease. Researchers at University of California, San Diego School of Medicine and Moores Cancer Center have now identified six mRNA isoforms (bits of genetic material) produced by ovarian cancer cells but not normal cells, opening up the possibility that they could be used to diagnose early-stage ovarian cancer. What’s more, several of the mRNA isoforms code for unique proteins that could be targeted with new therapeutics.

“We were inspired by many studies aimed at using DNA to detect cancer,” said first author Christian Barrett, PhD, bioinformatics expert and project scientist in the UC San Diego School of Medicine Institute for Genomic Medicine. “But we wondered if we could instead develop an ovarian cancer detection test based on tumour-specific mRNA that has disseminated from cancer cells to the cervix and can be collected during a routine Pap test.”

While DNA carries all the instructions necessary for life, its actual sequence contains much more than just the genes that code for proteins. In contrast, mRNAs are complementary copies of just the genes. They carry the recipe for every protein that the cell will produce from the nucleus to the cytoplasm, where cellular machinery can read the recipe and build the corresponding proteins. According to the authors of this study, the advantage of using cancer mRNA for diagnosis rather than DNA is sheer number — a cancer cell might harbour just one or a few copies of a DNA mutation, but mRNA variants can occur in hundreds to thousands of copies per cell.

To determine if mRNAs can be used to distinguish ovarian cancer cells from normal cells, the team developed a custom bioinformatics algorithm and used it to mine two large public databases of genetic information — The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) program, both sponsored by the National Institutes of Health. TCGA is a catalog of RNA and DNA from 500 tumors covering many cancer types, while GTEx is a database of RNA and DNA from normal tissue samples. From these, the researchers were able to analyze mRNA sequence data from 296 ovarian cancers and 1,839 normal tissue samples.

Using this bioinformatics approach, the researchers identified six mRNA isoform molecules that have the tumour specificity required for an early detection diagnostic of ovarian cancer. They also validated their digital results in the real world using RT-quantitative PCR, a gene amplifying technique, to detect the same ovarian cancer-specific mRNA molecules in lab-grown cells.
Beyond their diagnostic potential, some of the mRNA isoforms identified in this study could also act as new therapeutic targets. These mRNA isoforms are predicted to encode proteins with unique amino acid sequences, which might allow them to be specifically targeted with certain therapeutics, such as monoclonal antibodies or T-cell-based vaccines. What’s more, the ovarian cancer-specific mRNA isoforms themselves could also be targeted with new therapeutic drugs.

“Our experimental findings were made in a laboratory and were performed on ovarian cancer cells from cell lines,” said study co-author Cheryl Saenz, MD, a clinical professor of reproductive medicine who specializes in treating gynaecologic cancers. “Clinical trials will need to be conducted on women to confirm the presence of these markers in women that we know have cancer, as well as to document the absence of the markers in women that do not have ovarian cancer.” University of California – San Diego Health System

The field of medical genetics is swiftly evolving. It’s a period of rapid scientific discovery, new technologies and subsequent translation into medical practice, public policy and public health. But what role should the Medical Genetics specialist have since genetics impacts all patients and specialties in some way? In an effort to clearly define the changing role of the specialty of Medical Genetics and the distinction between Medical Geneticists and other genetics healthcare professionals, the American College of Medical Genetics and Genomics (ACMG) has released a new ‘Scope of Practice of the Specialty of Medical Genetics’ document, revising its earlier 2008 Policy Statement. The ACMG is the specialty society for the American Board of Medical Genetics and Genomics diplomates and others, providing leadership and resources to facilitate the delivery of clinical and laboratory medical genetics services.

ACMG President Gerald Feldman, MD, PhD, FACMG said, ‘We wanted to clearly define the value that board-certified Clinical Geneticists and Clinical Laboratory Geneticists provide, from their roles performing genetic testing interpretation in the diagnostic laboratory to the medical genetics consultation. The ACMG Scope of Practice document also establishes how our specialty interacts with other members of the medical genetics healthcare team and where we find common ground with other medical specialists.’

Feldman explained the genesis of the new document, ‘The ACMG Board of Directors felt that it was critical to revise the original 2008 document to answer the who, what, where, when, why and how in the current era of genomic medicine, which involves other genetics health professionals, such as genetic counsellors, genetic nurses, and other lab professionals performing genetic and genomic testing.’
The Scope of Practice document is available at
www.acmg.net/docs/ACMG_SOP_GIM_AOP_072315.pdf. A Commentary from Dr.

The ‘ACMG Scope of Practice of the Specialty of Medical Genetics’ Policy Statement states that the specialty includes:
-Genetic consultations, in both inpatient and outpatient settings
-Genetic counselling
-Treatment of genetic diseases, involvement in clinical trials and natural history
studies leading to approval and use of new, orphan and other drugs
-Early detection and prevention of genetic diseases or their complications
-Performing genetic and genomic testing, interpreting such results and providing
these results to physicians to facilitate diagnosis, management and treatment
-Activities outside of direct patient care, including public health administration, health professional education and research. American College of Medical Genetics and Genomics