A novel BRCA2 splice variant identified in a young woman

 Sharing a newly published article where a novel c.682‐2delA variant involving the AG consensus at the 3′ end of BRCA2 intron 8 was detected. The case involved a 33‐year‐old Italian breast cancer patient belonging to a HBOC family (BRCAPro score: 88%) with no other known pathogenic BRCA mutation. 

 

A novel BRCA2 splice variant identified in a young woman - Nicolussi - - Molecular Genetics & Genomic Medicine

github-based, community-maintained list of cancer clinical informatics resources

Sean Davis created a github-based, community-maintained list of cancer clinical informatics resources. 
"Contributions are welcome!" https://lnkd.in/d-uphUc

For now, it's named as

ci4cc-informatics-resources 

https://github.com/seandavi/ci4cc-informatics-resources

CIViC is an open access, open source, community-driven web resource for Clinical Interpretation of Variants in Cancer

CIViC's Role in Precision Medicine

Realizing precision medicine will require this information to be centralized, debated and interpreted for application in the clinic. CIViC is an open access, open source, community-driven web resource for Clinical Interpretation of Variants in Cancer. Our goal is to enable precision medicine by providing an educational forum for dissemination of knowledge and active discussion of the clinical significance of cancer genome alterations.

CIViC is a community-edited forum for discussion and interpretation of peer-reviewed publications pertaining to the clinical relevance of variants (or biomarker alterations) in cancer. These interpretations may include associations between molecular alterations (or lack of alteration) and one or more drugs, diagnoses, prognoses or other treatment decisions. These interpretations of clinical significance (or lack of clinical significance) are purely for research purposes. A finding of no interpretation does not necessarily indicate lack of relevance for any specific variant or biomarker alteration. Interpretations are not presented in ranked order of potential or predicted importance.These interpretations make no promise or guarantee of any clinical benefit (or lack of clinical benefit).

https://civic.genome.wustl.edu/#/home

Elephants are resistant to cancer

Whole-genome sequencing of 644 elephant tissue samples using the HiSeq 2500 System identified multiple copies of TP53. Compared to human cells, elephant cells demonstrated increased apoptotic response following DNA damage, which could account for the low incidence of cancer (4.81%) in elephant populations.

Related Links
What elephants can teach scientists about fighting cancer in humans http://www.latimes.com/science/sciencenow/la-sci-sn-elephant-cancer-story-20151007-story.html

How elephants avoid cancer http://www.nature.com/news/how-elephants-avoid-cancer-1.18534

Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans Journal of the American Medical Association, DOI: 10.1001/jama.2015.13134
http://jama.jamanetwork.com/article.aspx?articleid=2456041

Ambry to share aggregated anonymous data from 10,000+ human exomes.

• • 
    
• • Exciting times.
  Firms are starting to be more open with the data they have collected for the benefit of mankind. But do watch out for the fine print. there's a disclaimer that although the data is 'free to download and use, the company retains copyright.'
  • 
    
  • 
    
  • 
    
  By Andrew Pollack
 
• Posted March 08, 2016

GENETIC TEST FIRM TO MAKE CUSTOMERS’ DATA PUBLICLY AVAILABLE

Original post can be found here.

In an unusual move, a leading genetic testing company is making genetic information from the people it has tested publicly available, a move the company says could make a large trove of data available to researchers looking for genes linked to various diseases.

The company, Ambry Genetics, is expected to announce on Tuesday that it will put information from 10,000 of its customers into a database called AmbryShare.

“We’re going to discover a lot of new diagnostic targets and a lot of new drug targets,” Aaron Elliott, interim chief scientific officer at Ambry, which is based in Southern California, said in an interview. “With our volume, we can pull out a significant number of genes just by the sheer number we are looking at.”

The 10,000 people all have or have had breast or ovarian cancer and were tested by Ambry to see if they have genetic variants that increase the risk of those diseases. Ambry returned to the samples from those customers and, at its own expense, sequenced their exomes — the roughly 1.5 percent of a person’s genome that contains the recipes for the proteins produced by the body.

Since proteins perform most of the functions in the body, sequencing just that part of the genome provides considerable information, and is less expensive than sequencing the entire genome.

AmbryShare will not contain the actual exome of each person, because that would pose a risk to patient privacy. Rather it will contain aggregated data on the genetic variants.

For example, a researcher could look up how frequently a particular mutation occurs among the 10,000 people. Ones that occur frequently in these 10,000 patients, but not among healthy people, could raise the risk of developing those cancers.

Specialists welcomed Ambry’s move, but some said it was unclear how useful the information will be. The Exome Aggregation Consortium, an academic collaboration based at the Broad Institute of M.I.T. and Harvard, already has a similar publicly available database containing information from more than 60,000 exomes.

“It is not clear to me that 10,000 exomes changes the game much,” said David B. Goldstein, professor of genetics at Columbia University.

Ambry said its data would be from people with the diseases it tests for, like epilepsy and intellectual development problems, while the Broad database covers a more general population. Ambry said it hoped to add data from as many as 200,000 customers a year to the database.

The Ambry customers whose data is being used were not told specifically about this project. But in ordering tests they consent to having their samples used for research.

Various labs, including Ambry, have been pooling information on which mutations in certain known breast cancer risk genes are harmful or not. AmbryShare is different — aimed more at novel discoveries of genes linked to diseases.

Data can be valuable to drug companies. The consumer genetics company 23andMe sells access to data from its testing to drug makers and uses that data to develop drugs itself.

Charles Dunlop, founder and chief executive of Ambry, said he was approached by drug companies, but decided to make the company’s data freely available to expedite research.

“I’ve got Stage 4 cancer myself,” he said, referring to advanced prostate cancer that is in remission. “I don’t want to wait an extra day.”

He said Ambry had spent $20 million on the project. Ambry is privately held and majority-owned by Mr. Dunlop and his family, insulating it somewhat from shareholder pressure.

---

Correction: March 10, 2016 

An earlier version of this article described incorrectly the step that Ambry is taking with its customers’ data. It is making the data publicly available; it is not putting the data in the public domain. While the data is free to download and use, the company retains copyright.

Baylor releases Exome and WGS data of 7 cancer patients with Open Access

An open access pilot freely sharing cancer genomic data from participants in Texas

• Scientific Data 3, Article number: 160010 (2016) 
• ​doi:10.1038/sdata.2016.10
•  In a pilot Open Access (OA) project from the CPRIT-funded Texas Cancer Research Biobank, many Texas cancer patients were willing to openly share genomic data from tumor and normal matched pair specimens. For the first time, genetic data from 7 human cancer cases with matched normal are freely available without requirement for data use agreements nor any major restriction except that end users cannot attempt to re-identify the participants (http://txcrb.org/open.html).

There's whole exome seq data and 2 whole genome sequencing data where the sample quality is good enough for WGS.

A copy of the open-access TCRB data, conditions of use, and the HGSC’s Mercury informatics pipeline is available now for DNAnexus Platform users.

The full paper is here http://www.nature.com/articles/sdata201610

A copy of the data is also available for DNAnexus Platform users here https://dnanexus.github.io/tcrb-data/

C. Jimmy Lin talks about crowdsourced funded Genomics research

Have you heard of http://raregenomics.org/ ? They are a 'non-profit organization that gives families afflicted by rare genetic disorders access to genome sequencing and expert analysis. One can't help but notice the similarity to BGI-Shenzhen which is the 'first citizen-managed , non-profit research institute in China'. Perhaps this is the start of a trend for research that benefits citizens directly. Instead of getting/waiting for government funding / which complicates and slows down the research (see grant cycle) you can get funding directly from the ones that benefit. The tip of the iceberg is when publicly funded research is unavailable for public access without paying subscription fees.

Direct to consumer treatments and research for rare genetic disorders makes sense if you think about it. Getting funding for diabetes is likely easier and makes more economical sense since the dollars benefit a larger populace.
If you have a rare genetic disorder that might be limited to your family or a few families, you are kinda out of luck.
Your options are

1. doing the research yourself
2. convince your physician to take it up as a research project
3. offer your patient sample for others to research (not the best example but TED Fellow Salvatore Iaconese open sourced his brain cancer for a cure or art)
4. well now you can go to raregenomics

Citizen science is the latest trending topic/tag. From ecology projects like http://iseahorse.org/ and http://www.birds.cornell.edu/citsci/ to sequencing projects like uBiome to 'Bioinformatics as a game' like Phylo website it will be interesting to see how this plays out for research and science education as a trend. IMHO, you can only get rare genetics disorder research started as a non-profit now since the cost of sequencing isn't cheap enough yet (see 'A $1000 genome by 2013?' )



Related Links
'la cura, the cure' http://artisopensource.net/cure/

'Interview with C. Jimmy Lin'
http://blog.ted.com/2013/01/18/rare-gifts-fellows-friday-with-c-jimmy-lin/
http://tedfellows.posterous.com/rare-gifts-fellows-friday-with-c-jimmy-lin

Translational Genomics Research Institute, personalised genomics to improve chemotherapy, cloud computing for pediatric cancer

I think it's fantastic that this is happening right now. Given that the cost of sequencing and computing is still relatively high, I can see how the first wave of personalized medicine will be lead by non-profit organizations. I am personally curious how this might pan out and would this be cost-effective for the patients ultimately? Would they be able to quantify it? 

Kudos for Dell for being a part of this exercise, though I wondered if they could have donated more to the data center or alternatively setup a mega cloud center and donate compute resources instead. Since i think the infrastructure and knowledge gleaned will be useful for their marketing and sales. 

http://www.hpcinthecloud.com/hpccloud/2012-02-29/cloud_computing_helps_fight_pediatric_cancer.html

Cloud technology is being used to speed computation, as well as manage and store the resulting data. Cloud also enables the high degree of collaboration that is necessary for science research at this level. The scientists have video-conferences where they work off of "tumor boards" to make clinical decisions for the patients in real-time. Before they'd have to ship hard drives to each other to have that degree of collaboration and now the data is always accessible through the cloud platform.


"We expect to change the way that the clinical medicine is delivered to pediatric cancer patients, and none of this could be done without the cloud," Coffin says emphatically. "With 12 cancer centers collaborating, you have to have the cloud to exchange the data."


Dell relied on donations to build the initial 8.2 teraflop high-performance machine. A second round of donations has meant a doubling in resources for this important work, up to an estimated 13 teraflops of sustained performance.


"Expanding on the size of the footprint means we can treat more and more patients in the clinic trial so this is an exciting time for us. This is the first pediatric clinic trial using genomic data ever done. And Dell is at the leading edge driving this work from an HPC standpoint and from a science standpoint."


The donated platform is comprised of Dell PowerEdge Blade Servers, PowerVault Storage Arrays, Dell Compellent Storage Center arrays and Dell Force10 Network infrastructure. It features 148 CPUs, 1,192 cores, 7.1 TB of RAM, and 265 TB Disk (Data Storage). Dell Precision Workstations are available for data analysis and review. TGen's computation and collaboration capacity has increased by 1,200 percent compared to the site's previous clinical cluster. In addition, the new system has reduced tumor mapping and analysis time from a matter of months to days.

Evolution of Homo sapiens ... via cancer

OICR's Genomics Pathway-Sequencing Project Highlights Genomic Data's Steady March Into Clinics

OICR's Genomics Pathway-Sequencing Project Highlights Genomic Data's Steady March Into Clinics

The Ontario Institute for Cancer Research has kicked off a project that promises to address some key informatics challenges related to clinical sequencing.

Lincoln Stein, platform leader of informatics and biocomputing at the OICR, described the project in a presentation at the fourth Summit on Translational Bioinformatics in San Francisco this week.

Stein said that the project, conducted in partnership with Canada's Princess Margaret Hospital and dubbed the Genomics Pathway Sequencing project, or GPS, will sequence genes in normal and tumor samples excised from patients.

.....

“The biggest challenge,” Stein said, “is trying to keep the amount of information in this report to a minimum without keeping potentially important information back [from physicians].”

....

For each individual, OICR researchers will sequence about 1,000 cancer-related genes in control and tumor samples and attempt to identify mutations that are of immediate relevance to the patient’s cancer care, or that are targeted by drugs that are currently being tested in trials.

...

The genes in the study — which include the usual suspects such as KRAS, p53, and B-Raf — were selected based on suggestions from oncologists in the Toronto area as well as data stored in knowledgebases at the Memorial Sloan Kettering Cancer Center, the Wellcome Trust Sanger Institute, and the National Cancer Institute.

To sequence patient samples, OICR will use Pacific Biosystems' single-molecule sequencing as a first step to discover novel mutations. It will then sequence known mutations on Sequenom's MassArray platform. The sequence variants will be confirmed using a Sanger sequencer housed at the clinical sequencing lab at Princess Margaret hospital.

Stein explained that the OICR selected the PacBio system because “it allows us to do very long reads at high coverage … currently 1,000-base-pair reads in a circular consensus, which gives high accuracy for targeted genes.”

In addition, he said, the platform has a rapid turnaround time, taking only “15 minutes per run to completely analyze … a single typical gene.”

Kevin: fascinating! Would their's become the de facto standard for clinical sequencing?

A comparison of single molecule and amplification based sequencing of cancer transcriptomes.

1. PLoS One. 2011 Mar 1;6(3):e17305.

A comparison of single molecule and amplification based sequencing of cancer transcriptomes.
Sam LT, Lipson D, Raz T, Cao X, Thompson J, Milos PM, Robinson D, Chinnaiyan AM, 
Kumar-Sinha C, Maher CA.

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor,
Michigan, United States of America.

The second wave of next generation sequencing technologies, referred to as
single-molecule sequencing (SMS), carries the promise of profiling samples
directly without employing polymerase chain reaction steps used by
amplification-based sequencing (AS) methods. To examine the merits of both
technologies, we examine mRNA sequencing results from single-molecule and
amplification-based sequencing in a set of human cancer cell lines and tissues.
We observe a characteristic coverage bias towards high abundance transcripts in
amplification-based sequencing. A larger fraction of AS reads cover highly
expressed genes, such as those associated with translational processes and
housekeeping genes, resulting in relatively lower coverage of genes at low and
mid-level abundance. In contrast, the coverage of high abundance transcripts
plateaus off using SMS. Consequently, SMS is able to sequence lower- abundance
transcripts more thoroughly, including some that are undetected by AS methods;
however, these include many more mapping artifacts. A better understanding of the
technical and analytical factors introducing platform specific biases in high
throughput transcriptome sequencing applications will be critical in cross
platform meta-analytic studies.


PMID: 21390249 [PubMed - in process]

Cell. 2011 Jan 7;144(1):27-40.

Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development.

Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, Jia M, Menzies A, Butler AP,Teague JW, Quail MA, Burton J, Swerdlow H, Carter NP, Morsberger LA, Iacobuzio-Donahue C, Follows GA, Green AR, Flanagan AM, Stratton MR, Futreal PA, Campbell PJ.

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

Abstract

Cancer is driven by somatically acquired point mutations and chromosomal rearrangements, conventionally thought to accumulate gradually over time. Using next-generation sequencing, we characterize a phenomenon, which we term chromothripsis, whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. Rearrangements involving one or a few chromosomes crisscross back and forth across involved regions, generating frequent oscillations between two copy number states. These genomic hallmarks are highly improbable if rearrangements accumulate over time and instead imply that nearly all occur during a single cellular catastrophe. The stamp of chromothripsis can be seen in at least 2%-3% of all cancers, across many subtypes, and is present in ∼25% of bone cancers. We find that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis. This phenomenon has important implications for the origins of genomic remodeling and temporal emergence of cancer. PAPERCLIP:

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID: 21215367 [PubMed - in process]