Scientists have developed a blood test for breast cancer able to identify which patients will suffer a relapse after treatment, months before tumours are visible on hospital scans.

The test can uncover small numbers of residual cancer cells that have resisted therapy by detecting cancer DNA in the bloodstream.

Researchers at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust were able to track key mutations that cancer accumulates as it develops and spreads, without the need for invasive biopsy procedures.

They hope that by deciphering the DNA code found in blood samples, it should be possible to identify the particularly mutations likely to prove lethal to that patient – and tailor treatment accordingly.

The study is an important step towards use of ‘liquid biopsies’ to revolutionise breast cancer care – by changing the way cancer is monitored in the clinic and informing treatment decisions.

Researchers took tumour and blood samples from 55 breast cancer patients with early-stage disease who had received chemotherapy followed by surgery, and who had potentially been cured of their disease.

By monitoring patients with blood tests taken after surgery and then every six months in follow-up, the researchers were able to predict very accurately who would suffer a relapse.

Women who tested positive for circulating tumour DNA were at 12 times the risk of relapse of those who tested negative, and the return of their cancer was detected an average of 7.9 months before any visible signs emerged.

The researchers used a technique called ‘mutation tracking’ – developing a digital PCR test that was personalised to the mutations found in an individual patient’s cancer – to identify tumour DNA in the bloodstream.

Because the researchers at the ICR and The Royal Marsden were looking for mutations common to many types of breast cancers, they found the test could be applied to all breast cancer subtypes.

The research also showed how genetic mutations build up in the cancer as it develops over time, as the leftover cancer cells grow and spread.

This reinforces the importance of detecting recurrence early so patients can have treatment before the extra mutations emerge and make the disease harder to treat. Institute of Cancer Research

Many cancers include increased copies of the gene MET. But in which cases is MET driving the cancer and in which do these increased copies happen to ‘ride along’ with other molecular abnormalities that are the true cause of the disease? The answer influences whether a tumour will respond to drugs that inhibit MET, like crizotinib. A University of Colorado Cancer Center study sheds light on the best method to determine the threshold at which MET amplification becomes clinically relevant.

‘Generally, there are two ways that the number of copies of the MET gene can be increased: The tumour can make multiple copies of the entire chromosome on which it sits — chromosome 7 — or it can amplify just the MET region. In the first case, MET is unlikely to be the specific driver of the cancer’s biology, it may just be a ride along. But if the MET region is amplified separate from the rest of the chromosome, this would suggest that the MET gene is indeed the area of specific importance to the cancer,’ says Sinead Noonan, MD, investigator at the CU Cancer Center, senior thoracic oncology fellow at the CU School of Medicine, and the study’s first author.

The goal of the current study was to find evidence supporting the above hypothesis and to identify a group of MET-driven patients in which crizotinib would be effective.

To do so, Noonan worked with Marileila Garcia, PhD, CU Cancer Center investigator and professor of Oncology at the CU School of Medicine, who assessed the genetics of over 1,000 lung cancer patients. Using the low level criteria commonly used for defining an increase in MET copy number, independent of whether it was increased by increasing the overall number of copies of the chromosome or just that region of the chromosome, 14.4 percent of these samples were positive for MET copy number gain. The group then looked at another measure, comparing MET copy number to the number of chromosome 7 centromeres — the center point of the chromosome — which allowed them to see how specifically MET was amplified in comparison with the chromosome as a whole. When the low level criteria for defining an increase in MET copy number using the ratio of MET to centromere 7 was used, only 4.5 percent of these cases were positive.

Now the question was what ratio of MET to centromere 7, exactly, defined patients whose tumours were driven by this gene amplification and so would be most susceptible to MET inhibition via crizotinib.

‘There is almost always only one driver abnormality in any given tumour,’ Noonan says. But in 47 percent of the tumours defined by the minimal MET-to-centromere-7 ratio criteria, the group was able to identify other known genetic drivers, including mutations or gene rearrangements in EGFR, KRAS, BRAF, ALK, ERBB2, RET or ROS1.

‘Strikingly, as we looked at cases with higher and higher MET positivity, the degree of overlap with other known drivers decreased,’ Noonan says. In other words, as the MET-to-centromere-7 ratio increased, the group was less likely to find any other candidates for the cause of the cancer.

A group completely free from overlap with other known cancer drivers was only found in the group in which MET overbalanced centromere 7 by 5 times. Using the other common method of simply counting MET, independent of the ratio, it was impossible to find a group without additional known genetic driver.

‘I think these data really help to solidify MET-to-centromere ratio as the better measure for defining a lung cancer driven by MET copy number,’ says D. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research at the CU Cancer Center and the senior author of the study. ‘While the highest ratio only occurs in 0.34 percent of cases, it has clearly been associated with responses to crizotinib approaching 70 percent. However, responses have also been seen at lower ratios. Overall, if we look across all levels of MET-ratio positive cases but exclude those with other identifiable drivers we can identify a group representing 2.4 percent of adenocarcinomas which is ripe for further investigation as potential MET-sensitive subtypes of lung cancer.’ ScienceDaily

Gastric cancer poses a significant health problem in developing countries and is typically associated with late-stage diagnosis and high mortality. A new study points to a pivotal role played by the biomarker microRNA (miR)-506 in gastric cancer. Patients whose primary gastric cancer lesions express high levels of miR-506 have significantly longer survival times compared to patients with low miR-506 expression. In addition, miR-506 suppresses tumour growth, blood vessel formation, and metastasis.

‘Epithelial-to-mesenchymal transition (EMT) is an important process that enables cancer cells to invade their surroundings and to metastasize,’ explained lead investigator Xin Song, MD, PhD, of the Cancer Research Institute of Southern Medical University (Guangzhou, China) and Cancer Biotherapy Center of The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province, Kumming, China). ‘Our study presents evidence that miR-506 is a potent inhibitor of EMT.’

Mesenchymal cells play an important role in normal tissue repair as well as in pathological processes such as tissue fibrosis, tumour growth, and cancer metastasis. Polarized epithelial cells undergo biochemical changes to give rise to mesenchymal cells through EMT. The transformed cells have the ability to migrate away from the epithelial layer, invade other tissues, and resist apoptosis (normal programmed cell death). EMT is a key step during normal embryogenesis, but it is also now recognized to be involved in cancer pathophysiology. Changes in the expression of specific microRNAs, a class of small noncoding RNAs that regulate gene expression, are one of several mechanisms that may initiate an EMT.

Researchers examined the expression of one of these microRNAs, miR-506, which was in turn identified as a useful marker for stratifying gastric cancer patients. The researchers used quantitative real-time PCR in a blinded manner to detect miR-506 in human gastric cancer samples taken from 84 patients who had undergone cancer surgery. When samples were divided into groups with miR-506 levels above and below the mean, survival was found to be significantly longer in patients with high miR-506 expression. For example, at 60 months, cumulative survival was approximately 80% in the high miR-506 expression group compared to approximately 30% in the low-expression group.

The investigators next examined miR-506 expression in cells from seven gastric cancer cell lines. They found that gastric cancer cells had lower levels of miR-506 than normal stomach tissue. Further analysis of cell growth in vitro showed that miR-506 levels were lowest in the cell lines that had the highest invasive activity (SGC-7901 cells), and the highest levels were seen in cell lines with the lowest invasive activity (BGC-823 cells), thus supporting the hypothesis that miR-506 acts as a suppressor of cell metastasis. Lending greater strength to this hypothesis, inhibitors of miR-506 counteracted the downstream activity of miR-506, such as increasing the invasiveness and mobility of BGC-823 cells.

Further experiments showed that miR-506 inhibits new blood vessel growth (angiogenesis), with miR-506 overexpression suppressing vascular tubule development in SGC-7901 cells and miR-506 inhibitors promoting the formation of a tubular vessel network in BGC-823 cells. They also showed that miR-506 overexpression was associated with decreased expression of matrix metalloproteinase-9 and -2, and provided evidence that miR-506 may be targeting the proto-oncogene ETS1. ‘These findings indicate that miR-506 is necessary and sufficient for angiogenesis suppression during gastric cancer progression,’ commented Dr. Song.

‘In summary, cancer is a complex disease and controlling cancer development and progression requires system level and integrative approaches. Our study suggests that miR-506 acts as a tumour suppressor in gastric cancer. Additional studies will be needed to explore the potential clinical utility of miR-506 as a potential biomarker for gastric cancer prognosis and as a new potential therapeutic target,’ added Dr. Song. EurekAlert

An international team that includes researchers at Sahlgrenska Academy has found a new genetic cause of osteoporosis. The findings set the stage for eventually curing the disease.

Osteoporosis is a common condition that leads to fractures with half of all women experiencing a fracture during their lifetime.

The discovery of a genetic variant has permitted researchers to link a particular gene to bone density and fractures. Follow-up studies have described the mechanisms by which the protein coded by the gene affects bone density.

Sahlgrenska Academy Professor Claes Ohlsson, who participated in the study, says, “Given that the EN1 gene has never been associated with osteoporosis before, we have a brand new pathway for developing drugs that can inhibit the condition.”

Directed by Canadian scientists, the international study initially examined highly detailed genetic data from 10,000 individuals and subsequently replicated the EN1 discovery in 500,000 others. The inclusion of so many subjects allowed the researchers to establish correlations between rare genetic changes and pathological conditions.

 “The study is clear evidence that uncommon genetic variants can have a significant impact on widespread diseases,” Professor Ohlsson says. “We have discovered a new mechanism for regulating bone density and fractures.” Sahlgrenska Academy, University of Gothenburg

A  few  years  ago,  Javier  Benítez, director  of  the Human Genetics Group at the CNIO,  received a  call  from Pablo  García  Pavía,  from  the  Cardiology  Unit  of  the  Puerta  de  Hierro University Hospital. This cardiologist was treating two brothers with a rare form of cancer, cardiac angiosarcoma (CAS). Could the experts in genetics do  something?  “At  that  time  we  tried  a  few  ideas,  but  unsuccessfully,”says Benítez. We have had to wait for modern genome analysis techniques to  discover  the  brothers’  genetic  problem.  The  finding  opens  a  way  to identify  CAS  families  who  are  carriers  of  a  mutation  in  the  gene
responsible  for  the disease. Family members  could  then  benefit  from an early diagnosis and the appropriate treatment.

Researchers  in  Benítez’s  group  recently  revaluated  the  case  of  the
brothers  with  CAS.  After  sequencing  their  exome  —  the  part  of  the
genome  that  is  translated  into  protein  and  therefore  the  one  that  most
influences the state of the organism, they  found that the cause of the
illness was a mutation in a gene called POT1.

The  identification  of  this  gene  led  them  directly  to  another  CNIO  group,
the  Telomere  and  Telomerase  Group,  headed  by  María  Blasco.  POT1  is
one of the proteins that comprise the protective shield around telomeres
—  the  structures  that  protect  the  tips  of  chromosomes —  and  it  has
recently  been  identified  as  responsible  for  other  forms  of  hereditary
cancer: melanoma  and  familial  glioma.  Blasco’s  group  is  not  only  one  of
the leading groups in  the field of  telomeres, but has also participated —
together with the groups headed by Carlos López-Otín and Elías Campo —
in  the  first  description  of  the mutation  of  this  gene  in  human  cancer
(chronic lymphocytic leukaemia).

Cardiac  angiosarcoma  is  a  rare  but  malignant  disease.  In  the  case  of
hereditary  CAS,  the  median  survival  expectancy  is  only  four  months
because  the  disease  is  diagnosed  at  an  advanced  stage.  Until  now,  no
related gene has been identified.

CNIO researchers also observed that hereditary CAS occurs in families with
a  high  incidence  of  other  types  of  cancer.  This  is  similar  to  what  is
observed in people affected by the so-called Li-Fraumeni syndrome, which
is caused by a mutation in the tumour suppressor gene — nicknamed the
genome  guardian — P53.  However,  POT1, but  not  P53, was  found
mutated in the families affected by CAS.

The  discovery  of  the  new  mutation  proved  to  be  even  more  significant
from  a  clinical  perspective,  given  that  it  identified  carriers  at  risk  of
developing cardiac angiosarcoma and possibly other tumours.

As  Benítez  explained,  “in  the  past,  we  simply  didn’t  have  anything  that
could  help  in  identifying  these  people  at  risk,  because  there  were  no
markers  for  familial  CAS  or  for  families  with  a  syndrome  similar  to  Li-
Fraumeni  without  P53  mutations.  This  study  uncovers  one  of  the  genes
that explains the high incidence of cancer in some of them.”

“The translation of these results into the clinic is immediate,” says Blasco.
“In fact, we are already helping families that carry this mutation.” CNIO