Germline mutations in certain genes are known to cause inherited cancer. Thus, individuals carrying mutations in the so-called breast cancer type I and II genes (BRCA1 and BRCA2) are highly prone to breast as well as ovarian cancers. In cancers, both gene mutations and aberrant regulation of genes (promoter inhibition by methylation of DNA) are known to play pivotal roles regulating cancer growth.
An issue of controversy has been whether aberrant promoter methylation in normal tissue may be a cancer risk factor. Researchers from Haukeland University Hospital in Bergen, Norway, and colleagues analysed for potential impact of normal tissue BRCA1 methylation on ovarian cancer risk. Analysing white blood cells from 934 patients and 1,698 healthy controls, they found BRCA1 methylation among 6.4% of patients diagnosed with ovarian cancer, contrasting 4.2% among controls. Importantly, elevated BRCA1 methylation was confined to patients diagnosed with so-called high-grade serous tumours, the most aggressive variant of ovarian cancer, which also is the variant associated with BRCA1 mutations. Among patients with high-grade serous cancers, methylation was detected among 9.6% of individuals, corresponding to an almost 3-fold increase in risk for individuals harbouring methylation (age-adjusted odds ratio of 2.91). As for non-serous or low-grade serous cancers, methylation frequency resembled controls (5.1% and 4.0%, respectively). In the same report, the researchers replicated these findings in an independent validation study in which they found methylation among 9.1% of patients with high-grade serous cancers versus 4.3% among controls.
According to the authors, it is important to note that white blood cell BRCA1 methylation was detected also among newborns and young adults, indicating that normal tissue BRCA1 methylation may occur as a prenatal event. These findings have significant implications to the understanding of normal tissue methylation and strongly indicate that events occurring before birth influence cancer risk later in life.
bioengineer.orgbioengineer.org/normal-tissue-brca1-methylation-associated-with-risk-for-high-grade-ovarian-cancer/

A new computational method developed by researchers at the New York Genome Center (NYGC) allows scientists to identify rare gene mutations in cancer cells with greater accuracy and sensitivity than currently available approaches.
The technique is called Lancet and represents a major advance in the identification of tumour cell mutations, a process known as somatic variant calling.
"With its unique ability to jointly analyse the whole genome of tumour and matched normal cells, Lancet provides a useful tool for researchers to conduct more accurate genome-wide somatic variant calling," notes first author Giuseppe Narzisi, PhD, Senior Bioinformatics Scientist, NYGC.
To identify gene mutations in cancer cells, researchers sequence the genomes of tumour cells and normal cells. Current computational methods then involve comparing both tumour and normal to a reference genome and looking for differences unique to the tumour. Lancet instead uses an approach called micro-assembly to reconstruct the complete sequences of small regions of the genome without relying on a reference. Because the approach does not rely on a reference to identify variants, it also works well in regions of the genome where comparing reads to a reference is challenging for technical reasons. By using a data structure called a coloured de Bruijn graph, Lancet jointly analyses the tumour and normal DNA, providing greater sensitivity to find rare variants unique to the tumour while also providing greater accuracy of differentiating tumour variants from those present in healthy tissue in that individual. Using Lancet to combine the sequencing data from the normal and tumour cells represents a more powerful way of identifying mutations, Dr. Narzisi said, since users are no longer dependent on analysing sequence data from tumour and normal cells separately.
In the study, through extensive experimental comparison on synthetic and real whole-genome sequencing datasets, the researchers demonstrated that Lancet performed better and had higher accuracy and better sensitivity to detect somatic variants compared to the most widely-used somatic variant callers.
"In our study, we show that existing tools are not that precise in scoring mutations, so that some candidate variants which were highly scored by some tools ended up being false positives," Dr. Narzisi said. "That becomes a problem when you want to prioritize which variants to validate using other technologies or you want to move forward with a clinical study. You may end up focusing on variants that do not exist."
EurekAlertwww.eurekalert.org/pub_releases/2018-03/nygc-ngt032218.php

University of Colorado Cancer Center researchers recently completed the largest-ever study of thyroid cancer genetics, mining the data of 583 patient samples of advanced differentiated thyroid cancer and 196 anaplastic thyroid cancers. In addition to identification of specific genes that may drive these cancers and thus provide attractive targets for treatment, the researchers found that in several samples of advanced differentiated and anaplastic thyroid cancer (the most aggressive and dangerous forms of the disease), mechanisms meant to repair faulty DNA had been broken. These broken repair mechanisms led to a subset of thyroid cancers accumulating a high number of genetic alterations – and this “high mutation burden” is a marker recognized by the FDA to recommend treatment with anti-cancer immunotherapies.
“Anaplastic thyroid cancer is a particularly terrible cancer – people wonder what makes it so bad, and advanced thyroid cancer causes significant morbidity. I’ve had a very productive relationship with Foundation Medicine, primarily to study rare salivary gland cancers and I’m pleased that we’ve been able to extend our collaboration to the study of thyroid cancers to hopefully answer some of these questions,” says Daniel Bowles, MD, clinical and translational investigator at CU Cancer Center and Head of Cancer Research at the Denver Veterans Administration Medical Center.
Bowles worked with first author Nikita Pozdeyev, MD, PhD, to analyse tumour samples submitted by oncologists from around the United States to Foundation Medicine for genetic analysis that could inform treatment strategies. Interestingly, the fact that clinicians who submitted these samples were specifically seeking possible treatment strategies meant that the majority of samples were from advanced cancers.
“Genetic analysis of early-stage thyroid cancers is most often not necessary – we successfully treat these tumours with surgery and radioactive iodine,” Pozdeyev says. “But with distant metastases, genetic information becomes important for treatment. Because oncologists had sought this genetic information, our study is enriched for advanced cases.”
The researchers point out that even large treatment centres are likely to only a few of these most dangerous, anaplastic thyroid cancers every year. Due to the current study’s industry-academia collaboration, the researchers were able to explore 196 of these anaplastic thyroid cancers, “giving us sufficient analytical power to use machine learning and statistical analysis to make sense of the data,” Pozdeyev says.
In addition to finding that some anaplastic thyroid cancers carried a high overall mutation burden that could make immunotherapy an attractive treatment option, the group found specific genetic changes driving anaplastic cancers, including amplifications of the genes KDR, KIT and PDGFRA. These genes encode a kind of on-off switch called “receptor tyrosine kinases” that many cancer cells use to speed their growth and proliferation. In this case, these receptor tyrosine kinases happen to be targeted by the drug lenvatinib, which earned FDA approval for use in kidney cancer.  In collaboration with Drs. Bryan Haugen and Rebecca Schweppe, the researchers treated a cohort of thyroid cancer cell lines with lenvatinib, finding that it was the cell line with amplification of KDR, KIT and PDGFRA that was especially sensitive to the drug, hinting that treatment with lenvatinib may be an attractive strategy against a subset of anaplastic thyroid cancers.

University of Colorado Cancer Centerwww.coloradocancerblogs.org/largest-ever-study-of-thyroid-cancer-genetics-finds-new-mutations-suggests-immunotherapy/

People who inherit genetic changes which alter the function of their immune system are at increased risk of developing Hodgkin lymphoma, a major new study reports.
Scientists at The Institute of Cancer Research, London, identified six new genetic changes that increase the risk of developing Hodgkin lymphoma – one of the most common cancers in young adults.
Many of the DNA changes seemed to affect the function of the immune system, and three had previously been associated with autoimmune diseases such as multiple sclerosis, rheumatoid arthritis or lupus.
The researchers stressed that the link did not mean people with autoimmune diseases are at increased risk of lymphoma, but did offer important genetic clues for understanding both lymphoma and autoimmune diseases better.
One of the genetic changes discovered increases the risk of Hodgkin lymphoma by more than a third and others by at least 15% each – information that could point to new targeted drugs for the disease.
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Scientists at the ICR analysed genetic data from 5,314 cases of Hodgkin lymphoma and 16,749 controls, from four different European studies.
The study is the largest of its kind for Hodgkin lymphoma.
For most people, Hodgkin lymphoma can be successfully treated with first-line therapies – but there is a need for new treatments for those for whom first line treatment has failed.
The researchers identified six new single-letter changes in DNA that were linked to the development of Hodgkin lymphoma – and five of these affect the way a type of white blood cell, called B cells, develop.
Hodgkin lymphoma is a cancer of the B cells – which are responsible for producing antibodies as a critical component of the immune system.
The study also picked out clear differences in genetic risk between two different subtypes of Hodgkin Lymphoma – nodular sclerosis Hodgkin Lymphoma (NSHL) and mixed cellularity Hodgkin Lymphoma (MCHL).
For example, a single-letter change located in DNA near the gene LPP increased the risk of NSHL by 37%, but had little effect on the risk of developing MCHL.
Professor Richard Houlston, Professor of Molecular and Population Genetics at the ICR, said: “Hodgkin lymphoma is a cancer of immune cells called B cells, and our study links the risk of the disease to changes in the genes that control how B cells develop. Interestingly, we found that some of the genetic changes we have linked to Hodgkin lymphoma have previously been associated with the risk of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
“It doesn’t mean that if you develop an autoimmune disease you are at increased risk of lymphoma, but it does offer fascinating genetic clues to these diseases. The new information could point towards new ways of diagnosing, treating, or even helping to prevent Hodgkin lymphoma.”
Institute of Cancer Research
www.icr.ac.uk/news-archive/genetic-link-found-between-the-immune-system-and-lymphoma

New research coordinated from Karolinska Institutet links certain DNA variants to increased risk of irritable bowel syndrome (IBS) in women. The findings might help explain why IBS is more common in women than in men.
Irritable bowel syndrome is the most common gastrointestinal disorder. More than 10 per cent of the population, women more than men, suffer from recurrent symptoms including abdominal pain, gas, diarrhoea and constipation. What causes IBS is largely unknown, which hampers the development of effective treatment for many patients. Genetic predisposition to IBS is recognised, although poorly investigated.
Now an international research team led by scientists from Karolinska Institutet in Sweden have identified DNA variants that are associated with increased risk of IBS, but only in women.
“Exploiting the large UK Biobank resource, as well as several patient cohorts from European and US expert centres, we have been able to study genetic predisposition to IBS with increased statistical power, better than ever before,” says corresponding author Mauro D’Amato, visiting professor at Karolinska Institutet’s Department of Medicine in Solna and coordinator of the bellygenes initiative that led to the discovery.
The researchers used genotype data from more than 300,000 UK Biobank participants in a genome-wide association study (GWAS). They found DNA variants that associate with increased risk of a doctor’s diagnosis of IBS in women but not in men, specifically from a region on chromosome 9 previously reported to also influence puberty timing in women (age at first menstruation).
By following up this result in 2,045 patients from IBS expert centres in Sweden, Belgium, the Netherlands, Italy and the US, the researchers observed further associations with constipation-predominant IBS as well as harder stools, again only in women.
“Although we cannot point to individual genes at this early stage, we believe these results are exciting, as they converge with existing data on female preponderance and a role of sex-hormones in IBS,” says Mauro D’Amato.
Karolinska Instituteki.se/en/news/genetic-link-to-ibs-identified-in-women