The gene and hormone soup that enables women to breastfeed their newborns also can be a recipe for breast cancer, particularly when the first pregnancy is after age 30.

Researchers have now found that the gene DNMT1 is essential to maintaining breast, or mammary,  stem cells, that enable normal rapid growth of the breasts during pregnancy, as well as the cancer stem cells that may enable breast cancer. They’ve learned that the DNMT1 gene also is highly expressed in the most common types of breast cancer.

Conversely, ISL1 gene, a tumour suppressor and natural control mechanism for stem cells, is nearly silent in the breasts during pregnancy as well as cancer, said Dr. Muthusamy Thangaraju, biochemist at the Medical College of Georgia at Georgia Regents University.

“DNMT1 directly regulates ISL1,” Thangaraju said. “If the DNMT1 expression is high, this ISL1 gene is low.” They first made the connection when they knocked out DNMT1 in a mouse and noted the increase in ISL1. Then they got busy looking at what happened in human breast cancer cells.

They found ISL1 is silent in most human breast cancers and that restoring higher levels to the human breast cancer cells dramatically reduces the stem cell populations and the resulting cell growth and spread that are hallmarks of cancer.

When they eliminated the DNMT1 gene in a breast-cancer mouse model, “The breast won’t develop as well,” Thangaraju said, but neither would about 80 percent of breast tumours. The deletion even impacted super-aggressive, triple-negative breast cancer.

The findings point toward new therapeutic targets for breast cancer and potentially using blood levels of ISL1 as a way to diagnose early breast cancer, the researchers report. In fact, they’ve found that the anti-seizure medication valproic acid, already used in combination with chemotherapy to treat breast cancer, appears to increase ISL1 expression, which may help explain why the drug works for these patients, he said. The scientists are screening other small molecules that might work as well or better. Georgia Regents University and Health System

Normal skin contains an unexpectedly high number of cancer-associated mutations, according to a study. The findings illuminate the first steps cells take towards becoming a cancer and demonstrate the value of analysing normal tissue to learn more about the origins of the disease.

The study revealed that each cell in normal facial skin carries many thousands of mutations, mainly caused by exposure to sunlight. Around 25 per cent of skin cells in samples from people without cancer were found to carry at least one cancer-associated mutation.

Ultra-deep genetic sequencing was performed on 234 biopsies taken from four patients revealing 3,760 mutations, with more than 100 cancer-associated mutations per square centimetre of skin. Cells with these mutations formed clusters of cells, known as clones, that had grown to be around twice the size of normal clones, but none of them had become cancerous.

‘With this technology, we can now peer into the first steps a cell takes to become cancerous,’ explains Dr Peter Campbell, a corresponding author from the Wellcome Trust Sanger Institute. ‘These first cancer-associated mutations give cells a boost compared to their normal neighbours. They have a burst of growth that increases the pool of cells waiting for the next mutation to push them even further.

‘We can even see some cells in normal skin that have taken two or three such steps towards cancer. How many of these steps are needed to become fully cancerous? Maybe five, maybe 10, we don’t know yet.’

The mutations observed showed the patterns associated with the most common and treatable form of skin cancer linked to sun exposure, known as cutaneous squamous cell carcinoma, rather than melanoma, a rarer and sometimes fatal form of skin cancer.

‘The burden of mutations observed is high but almost certainly none of these clones would have developed into skin cancer,’ explains Dr Iñigo Martincorena, first author from the Sanger Institute. ‘Because skin cancers are so common in the population, it makes sense that individuals would carry a large number of mutations. What we are seeing here are the hidden depths of the iceberg, not just the relatively small number that break through the surface waters to become cancer.’

Skin samples used in this study were taken from four people aged between 55 and 73 who were undergoing routine surgery to remove excess eyelid skin that was obscuring vision. The mutations had accumulated over each individual’s lifetime as the eyelids were exposed to sunshine. The researchers estimate that each sun-exposed skin cell accumulated on average a new mutation in its genome for nearly every day of life.

‘These kinds of mutations accumulate over time – whenever our skin is exposed to sunlight, we are at risk of adding to them,’ explains Dr Phil Jones, a corresponding author from the Sanger Institute and the MRC Cancer Unit at the University of Cambridge. ‘Throughout our lives we need to protect our skin by using sun-block lotions, staying away from midday sun and covering exposed skin wherever possible. These precautions are important at any stage of life but particularly in children, who are busy growing new skin, and older people, who have already built up an array of mutations.’

Recent studies analysing blood samples from people who do not have cancer had revealed a lower burden of mutations, with only a small percentage of individuals carrying a cancer-causing mutation in their blood cells. Owing to sun exposure, skin is much more heavily mutated, with thousands of cancer-associated mutations expected in any adult’s skin.

The results demonstrate the potential of using normal tissue to better understand the origins of cancer. The Cancer Genomics group at the Sanger Institute will continue this work with larger sample numbers and a broader range of tissues to understand how healthy cells transition into cancerous cells. Sanger Institute

A gene essential to the production of pain-sensing neurons in humans has been identified by an international team of researchers co-led by the University of Cambridge. The discovery could have implications for the development of new methods of pain relief.

The ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception.
Pain perception is an evolutionarily-conserved warning mechanism that alerts us to dangers in the environment and to potential tissue damage. However, rare individuals – around one in a million people in the UK – are born unable to feel pain. These people accumulate numerous self-inflicted injuries, often leading to reduced lifespan.

Using detailed genome mapping, two teams of researchers collaborated to analyse the genetic make-up of 11 families across Europe and Asia affected by an inherited condition known as congenital insensitivity to pain (CIP). This enabled them to pinpoint the cause of the condition to variants of the gene PRDM12. Family members affected by CIP carried two copies of the variant; however, if they had only inherited one copy from their parents, they were unaffected.

The team looked at nerve biopsies taken from the patients to see what had gone wrong and found that particular pain-sensing neurons were absent. From these clinical features of the disease, the team predicted that there would be a block to the production of pain-sensing neurons during the development of the embryo – they confirmed this using a combination of studies in mouse and frog models, and in human induced pluripotent stem cells (skin cells that had been reset to their ‘master state’, which enables them to develop into almost any type of cell in the body).

PRDM12 had previously been implicated in the modification of chromatin, a small molecule that attaches to our DNA and acts like a switch to turn genes on and off (an effect known as epigenetics). The researchers showed that all the genetic variants of PRDM12 in the CIP patients blocked the gene’s function. As chromatin is particularly important during formation of particular specialised cell types such as neurons, this provides a possible explanation for why pain-sensing neurons do not form properly in the CIP patients.

‘The ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception,’ says Professor Geoff Woods from the Cambridge Institute for Medical Research at the University of Cambridge, who co-led the study. ‘Both are equally important to the development of new pain treatments – if we know the mechanisms that underlie pain sensation, we can then potentially control and reduce unnecessary pain.’

PRDM12 is only the fifth gene related to lack of pain perception to have been identified to date. However, two of the previously-discovered genes have already led to the development of new pain killers that are currently been tested in clinical trials. University of Cambridge

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

In a report of a proof-of-principle study of patients with colon and other cancers for whom standard therapies failed, researchers at the Johns Hopkins Kimmel Cancer Center say that mistakes in so-called mismatch repair genes, first identified by Johns Hopkins and other scientists two decades ago, may accurately predict who will respond to certain immunotherapy drugs known as PD-1 inhibitors. Such drugs aim to disarm systems developed by cancer cells to evade detection and destruction by immune system cells.

“This study gives us a solid clue about how immunotherapy may work in cancer and how to guide immunotherapy treatment decisions based on the genetic signatures of a cancer rather than class of cells or organ of origin,” says Luis Diaz Jr., M.D., an oncologist at the Johns Hopkins Kimmel Cancer Center.

“Defects in mismatch repair genes are found in a small percentage of many cancer types, and this type of biomarker for immunotherapy response could apply to tumours containing errors in other DNA repair genes, as well,” says Dung Le, M.D., an oncologist at the Johns Hopkins Kimmel Cancer Center. “Using a predictive biomarker can help us direct the use of immunotherapy drugs to patients who are more likely to respond, avoiding giving people expensive and time-consuming treatments that are not likely to work or delaying the use of other treatments.” John Hopkins Medicine