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Virtual Cancer Information And Services | Second Life July 31, 2007

Posted by ramunas in bio-software, cancer genetics, media, technology.
1 comment so far

Cyberspace now become more and more widespread phenomena. A Virtual world Second Life, created by Linden Research, Inc , ScienceRoll sees as a new creative education environment. Personally, I have to do a lot in my first (real) life, before I can join a Second Life, but anyway, this environment reminds me a lot of SF’s ideas, I’d read before – William Gibson’s cyberspace, Matrix and S. Lukjanenko’s DeepTown. Interestingly, lot of corporations and real-world institutions are opening their offices in this virtual world, and American Cancer Society’s (ACS) is not an exception. Forbes announces, that on July 27 and 28, almost 2,500 people gathered online in the world of Second Life and run a virtual relay race to raise money for cancer research.

The third annual virtual “Relay for Life” marks the grand opening of the American Cancer Society’s (ACS) virtual headquarters in the Second Life community, which is a co-sponsor of the relay.

Well, I would better join a bicycle ride to raise a funds, but anyway:

The new virtual building, which opened June 1, is designed to provide the same cancer information and services to people in the virtual world as the organization provides in the real world. The building includes presentation and meeting rooms for cancer education sessions and fund-raising meetings, and will soon feature a staffed link to the group’s National Cancer Information Center. The headquarters also features green space and gardens to showcase user-created art that expresses the personal fight against cancer.

“Already, we have existing peer-to-peer Second Life cancer support groups coming to us to use the facility and our resources. We are certain that, going forward, the community will find untold uses for our office space in terms of education, advocacy, fund raising and community support,” said Moss.

It is interestingly whether they have genetic counseling room there? I think that kind of service would be great, especially if you’d implement a portable hyper-DNA-collection-USB device 🙂

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New Gene Expression Profiling Tests| Colon Cancer July 26, 2007

Posted by ramunas in cancer genetics, colon cancer, ColoPrint, genetic testing, sporadic cancer.
3 comments

Here is fresh news: during the 9th World Congress on Gastrointestinal Cancer in Barcelona Dr. Laura van ‘t Veer, co-founder and Chief Research Officer of Dutch genomic profiling company Agendia (which already offers MammaPrint and CupPrint gene expression profiling (GEP) tests), presented unpublished study data about developed robust gene expression signature that can predict the risk of colon cancer relapse and recurrence. The prognostic profile outperforms traditional clinicopathological risk assessment factors currently used by physicians to make treatment decisions [via].

“Our results show that the microarray gene expression profile we are now developing for colon cancer is able to identify stage II colon cancer patients who have a high risk of experiencing a recurrence of their disease within the next years. This may facilitate the identification of patients who would benefit most from adjuvant chemotherapy. The gene expression profile is currently being tested on further validation samples for translation into a high-throughput diagnostic test readily available for clinical practice.”

This new commercial ColoPrint test will be out early 2008 and is principally based on the same technology as recently FDA approved MammaPrint test and will be its follower. Meanwhile, California based GenomicHealth company has announced that it will move one of its research projects, a test to predict the likelihood of colon cancer recurrence, into full-scale clinical development and intends to follow a similar clinical development path as it did for its Oncotype DX breast cancer assay.

Note: The published literature on GEP tests primarily consists of validation studies to identify the optimal set of cancer-related genes. Also prospective clinical trials testing the utility of these techniques have yet to be reported, but there is no doubt that the use of gene microarrays or RT-PCR analysis of RNA will play an important role in providing information regarding prognostic and predictive characteristics of subsets of cancer patients [ref.].

Breast Cancer Information Core | Significant Updates July 26, 2007

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.
5 comments

As you may already noticed, in the beginning of this year the most comprehensive open-access online BRCA1/2 mutation database Breast Cancer Information Core (BIC) – an international collaborative effort hosted by NHGRI – added significant improvements and more are on the way:

Changes to the BIC include redesigned search tools, a field classifying the “clinical importance” of each mutation and inclusion of additional information on a subset of mutations. Expect to see additional cosmetic and content changes in the coming months.

A field of “clinical importance” is worth further in deepth analysis. There are three categories:

1. Clinically important (“Yes”):

Clinical

  • Based on available data, it is the opinion of the BIC steering committee that sequence change of this type interferes with gene function and results in an increased risk of cancer.
  • All clinically important alleles may not confer the same degree of risk and the precise degree of risk associated with this mutation cannot be estimated.

Basic Science

    • This sequence change may abolish some or all of the normal functions of this gene. Some alleles may produce a stable mutant mRNA or protein.
    • However, many mutant alleles of this type do not produce mRNA or the encoded protein is unstable.

2. Not clinically important (“No”):

Clinical

  • Based on available data, it is the opinion of the BIC steering committee that this sequence change is neutral or of little clinical importance.
  • Some sequence changes of this type may be associated with modest increases in cancer risk.
  • Some individuals carrying this sequence change also could carry a clinically significant mutation.

Basic Science

    • It is likely that the mRNA and protein produced by this allele generally functions similar to wild type.
    • However, this protein contains multiple functional domains and some biological functions of this allele may be compromised.

3.”Unknown”:

    • Insufficient data exist at this time to allow assessment of the clinical or functional implications of this sequence change.
    • Although we attempt to update the BIC database on a regular basis, we also suggest searching the medical literature (PubMedGoogle) to determine if new information is available on this sequence change.

BIC is very useful database. And those new improvements will shed some light on polymorphisms. But variants of unknown significance (VUS), which are polymorphisms of uncertain clinical importance and account for up to 50% of all identified BRCA1 and BRCA2 sequence alterations, still could be not easy thing to interpret without functional expression studies, phylogenetic analysis and other approaches.

More than 600 mtations in BRCA1 genes and more than 450 in BRCA2 genes are reported to date. Only about 2-3 of all breast cancer cases can be attributed to inherited mutations in BRCA1/2 genes, and up till 15% of all ovarian cancer cases (10% – BRCA1, 5% – BRCA2), unselected for ethnicity [ref.]. The overall frequency of of BRCA1 gene mutation is 0,0007 – i.e. about one woman in 700 is a heterozygous carrier [ref.] and somewhat less for BRCA2. Interestingly, that irrespective of family history between 20-25% of women diagnosed with ovarian cancer between the ages of 41 and 50 will carry a BRCA1/2 mutation [ref.].

Gene-expression Profiling in Cancer | A Brief Review July 24, 2007

Posted by ramunas in breast cancer, cancer genetics, GeneSearch, MammaPrint, Oncotype DX, sporadic cancer, technology.
10 comments

It seems I’m getting more and more interested in gene-expression profiling (GEP) oncotests. In the Internet the information about this topic is quite messy and dispersed, so here I will try to draw some focus on this emerging technology (what will be added to a Genetic testing section later).

So, if we want to make gene-expression profiling, or in the other words, to answer an important question – what genes are expressed in a particular cell type of an organism, at a particular time, under particular conditions? [ref.]- first we need to have a sample of a tumor tissue to analyze its RNA pattern (or more precisely, messenger RNA (mRNA)). Here, unlike in mutations search, we’re not interested in DNA. RNA is quite instable molecule, so you need be quite cute and smart to manage preserve and analyse it.

A breast cancer is currently a holy grail for gene-expression profiling research to identify genes associated with breast cancer and to measure their activity in tumor cells, i.e. obtain its gene expression profiles.

Several techniques for measuring gene expression are available: a) a microarray based analysis and b) reverse transcriptase-polymerase chain reaction (RT-PCR). To measure gene expressions with a microarray you need to have a “fresh” (or “unpreserved”) tumor tissue samples. Tumor samples are frequently preserved in this way in Europe. Whereas in the United States tumor samples are more commonly preserved in formalin and embedded in paraffin blocks. Microarray analysis cannot be done on tissue that has been preserved in this way [ref.]. Since our pathologists are accredited by College of American Pathologists, they’re using paraffin blocks as well. Instead, for formalin-fixed and paraffin embedded (FFPE) tumor tissue blocks RT-PCR can be used to measure gene expression.

Therefore its important to know, that because of this difference in common methods of tissue processing has led to the development of tests in Europe and the United States that are quite different from one another, and that are based on measurements of the activity of different sets of genes.

In Europe, using microarray analysis, researchers are studying the usefulness of at least two different groups, or “panels”, of genes in studies on early stage tumors from node negative patients. One is a 70-gene panel, and another is a 76-gene panel. 1,2 Only three genes are common to both panels, while all the others are unique to one test or the otherB. In spite of this difference, both panels have yielded results that appear to be promising,3 and a commercial test based on the 70-gene panel is already available in the United States under the name MammaPrint®. (via)

Based on 76-gene panel Johnson&Jonson’s companies Veridex research, a two genes expression The GeneSearch™ Breast Lymph Node (BLN) Assay test was recently approved dy FDA, and is based on RT-PCR (i.e. for analysis in FFPE).

Common use of FFPE and a need for gene expression profiling using RT-PCR has led researchers in the United States to investigate several other panels of genes that produce too much or too little protein in early stage, node-negative, and estrogen receptor-positive breast cancer cells. A 21-gene panel commercial Oncotype DX test is one of example, which recently was approved by TEC to inform decision making about adjuvant chemotherapy only for a women with estrogen receptor-positive, node-negative, tamoxifen-treated breast cancer.

Let’s have a closer look at these genes [ref.]:

Measurements of five of those 21 genes (Beta-actin, GAPDH, RPLPO, GUS, and TFRC ) are used as “controls” – that is, to verify that the test has not been contaminated or run improperly.

The other 16 genes, which produce their proteins at varying levels in different tumors, include:

  • genes associated with cell proliferation (Ki-67, STK15, Survivin, Cyclin B1, and MYBL2);
  • genes associated with cellular invasion (Stromolysin 3, and CathepsinL2);
  • genes associated with HER2 activity (GRB7 and HER2);
  • genes associated with estrogen activity (ER, PR, Bc12, and SCUBE2); and
  • three other genes with distinctly different activity in cancer cells (GSTM1, BAG1, and CD68).

This Oncotype DX panel has only a single gene overlap with the 70-gene MammaPrint® panel. The reason for such diversity between gene panels under investigation are because of differences in tissue preparation, differences in laboratory methodologies, and differences in measurement techniques. At present, these gene-expression profile tests have only been validated on stored sample tissue.

Whether one of the existing panels will prove to be significantly superior to others, or whether newer panels will emerge that have better predictive power remains to be seen. It is clear that additional validation studies and more clinical experience are needed to establish the reliability of gene expression profiling for predicting tumor recurrence and response to specific treatments (ref.)

TBC

Management of an Inherited Predisposition to Breast Cancer | NEJM July 23, 2007

Posted by ramunas in BRCA, breast cancer, cancer genetics, familial cancer, genetic testing, hereditary cancer.
3 comments

There have been recently a nice review about management of inherited predisposition to breast cancer published in NEJM. It is also possible to listen to this article via audio podcast stream, a new service offered by NEJM as a beta version (and don’t forget to vote).

There are several quotes which seems to be important for me (from a point of good summary):

Recent estimates of breast-cancer risk by the age of 80 years are 90% for carriers of the BRCA1 mutation and 40% for carriers of the BRCA2 mutation, with corresponding risks of ovarian cancer of 24% and 8%, respectively; annual risks vary according to age:

(My note:  to analyze properly the graph above, you should remember, that lifetime risk for a female breast cancer in a western population is about 10-12% and for ovarian – about 2,5%. [Ref.])

Although imperfect, annual mammography is recommended for women with BRCA mutations beginning between the ages of 25 and 30 years, when breast-cancer risk begins to increase.10,37 For women without documented BRCA mutations who have a substantial familial risk of breast cancer, screening is suggested to begin at an age that is 5 to 10 years earlier than the youngest age at diagnosis in the family. The recent Digital Mammographic Imaging Screening Trial (DMIST) reported that digital mammography may be more accurate than mammography without computer-aided detection in younger women or in those with dense breasts.

(my comment: mammography before the age 30 is not recommended according UK NICE guidelines and I support this view, because a breast tissue is too dense.)

MRI should be considered as a complement to mammography, rather than as a replacement…The positive predictive value is expected to be lower in lower-risk populations, and MRI screening is likely to be most cost-effective for mutation carriers (as opposed to women at lower risk),43 particularly for BRCA1 carriers and for the subgroup of BRCA2 carriers with dense breasts.44

Ultrasonography did identify a significant number of mammographically occult tumors. Of the 83 cancers in these series, only 32 (39%) would have been identified by mammography alone, whereas 45 (54%) would have been detected by a combination of mammography and ultrasonography. This finding suggests that ultrasonography may add benefit beyond mammography alone in women with a hereditary risk but provides little incremental benefit in women undergoing screening with MRI.

Screening for other BRCA-associated cancers (e.g., ovarian, prostate, male breast, and pancreatic cancers) is often recommended even though there is no clear proof of benefit.

Risk-reducing salpingo-oophorectomy (RRSO) is an important preventive intervention in BRCA mutation carriers. Although this surgery has not been evaluated in randomized trials, retrospective and prospective cohort studies indicate a reduction in the risk of BRCA-associated gynecologic cancer of 80 to 96%57,58,59 and a reduction in the risk of breast cancer of approximately 50%, most likely through the induction of premature menopause.58,59,60

Risk-reducing mastectomy (RRM) reduces the risk of breast cancer by at least 90% in mutation carriers… RRSO and RRM do not entirely prevent the risk of subsequent breast or ovarian cancer. The residual risk of primary peritoneal cancer after RRSO has been reported to be 0.2% annually.57 The absolute risk after RRM has not been clearly defined.

No randomized, controlled trials of screening methods or prophylactic interventions have been conducted specifically in mutation carriers; guidelines are based largely on expert opinion and on observational studies and trials involving women at high risk for cancer… Randomized, controlled trials of surgical interventions to prove mortality benefits are not likely to be feasible.

Data are also needed regarding the optimal duration and time to initiate hormonal chemoprevention in young women identified as having a hereditary risk for breast cancer. Finally, the potential role of preimplantation genetic diagnosis in women who carry BRCA mutations warrants consideration; data are needed regarding the safety of hormonal treatments that are used to induce ovulation in these women.

Ultrasonography and breast examination may increase detection rates slightly but at a cost of more false positive results and additional evaluations. Preventive mastectomy and salpingo-oophorectomy for BRCA mutation carriers are options that should be discussed with women who are at increased risk. Oophorectomy is performed after childbearing, since the greatest increase in the risk of ovarian cancer occurs later than that of breast cancer in BRCA mutation carriers.

Personalized DNA Analyzer | Precautions July 20, 2007

Posted by ramunas in media, technology.
1 comment so far

Those GreenFluorescentProtein (GFP) Bunny lovers should welcome a first personalized PCR device – Spartan DX!

When Steve Wozniak assembled a first personal computer prototype Apple-I in 1976 nobody thought that will be so widespread as is today.

I think the fiction world, desribed in William Gibson, Bruce Sterling and Paul Di Filippo novels, has already came into reality.

For “only” $14,995 U.S. dollars, you can take a Spartan DX Personal DNA Analyzer to your next family reunion and start checking for those “non-paternity events.” (via)

Or even perform a cancer predisposition test. I am convinced that predictive DNA testing can not be regarded as solely laboratory practice – it must be appropriately interpreted (before and after genetic testing) by a specialist (i.e. clinical geneticist). Otherwise you can misinterpret the data and have all the worst consequences behind that.

This research-only device is just begging for application in some sort of futuristic lab or organization. Like maybe in a Gattaca-style research center.(via)

Can you foresee an impact of these “DNA results on demand”?

Improved DNA Electrophoresis | Better Than TBE or TAE Buffer July 20, 2007

Posted by ramunas in research, technology.
2 comments

When I run my electrophoresis gel I have a plenty time to update this blog :). But it seems that a significant time lag needed to run EF will shrink soon – ScienceDaily reports, that a better DNA separation electrophoresis from Johns Hopkins University allows to do it five times faster and less expensive. Buffer solutions ingredients involved in the EF process have been unchanged for 30 years, and its seems they are not the best ones: the evidence shows that the compound lithium boric acid in DNA electrophoresis is the optimal solution for this process.

“A process that normally takes around one and a half, two hours to do can be done in 10 minutes – in some instances it can be 10-fold faster,”

inventor claims. Well, I do it usually for 30-40 minutes, but anyway…

According to Dr. Brody, the finding is “not just a useful discovery for cancer research, but also for the neurosciences, developmental biology – increasingly, many fields involve DNA analysis.” The process has already been gaining acceptance and use internationally (via) .

Evidence-based Genetic Testing | Breast Cancer July 20, 2007

Posted by ramunas in breast cancer, cancer genetics, genetic testing, MammaPrint, Oncotype DX, sporadic cancer.
6 comments

On 18th of July, Blue Cross and Blue Shield Association, the Technology Evaluation Center (TEC), which is assessing medical technologies through objective, scientific evidence-based, comprehensive reviews of clinical evidence, has announced final decision on several genetic oncological tests.

The Medical Advisory Panel (MAP) concluded that:

The use of Oncotype DX™ to inform decision making about adjuvant chemotherapy meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria for women with estrogen receptor-positive, node-negative, tamoxifen-treated breast cancer;

  • all other uses of Oncotype DX™ do not meet TEC criteria;
  • use of MammaPrint® gene expression profiling does not meet the TEC criteria;
  • use of the Breast Cancer Gene Expression Ratio gene expression profiling does not meet the TEC criteria.
  • use of epidermal growth factor receptor (EGFR) mutation analysis to predict therapeutic sensitivity to erlotinib (Tarceva®) therapy (for non-small cell lung and pancreatic cancer) does not meet the TEC criteria. (via)

TEC five criteria are used to assess whether a technology improves health outcomes such as length of life, quality of life and functional ability.

On February a Dutch company Agendia’s DNA micro array-based in vitro diagnostic laboratory service MammaPrint® was approved by FDA for marketing in the U.S.. It determines the likelihood of breast cancer returning and metastasis within five to 10 years after a woman’s initial cancer. That was the first cleared molecular genetic expression test, already used in Europe from 2005. MammaPrint measures the expression (activity) of 70 genes that predict the chances of a relapse. Customized microarrays, manufactured by Agilent, are used. There is a nice open-access article on BMC Genomics describing its development and several covering articles on PubMed. Acctually, MammaPrint is commercialized version of a very known and depicted in most cancer genetics textbooks gene expression study by van’t Veer et al (2002).

However MammaPrint did not fit into TEC criteria. Could that because of a small sample size (clinical data from 302 patients)? We need to wait more for evidence data to accumulate and be sure for the relevance of this test.

Breast Cancer Gene Expression Ratio gene expression profiling, an approach developed by Massachusetts General Hospital (MGH) Cancer Center and Arcturus Bioscience, Inc., which is based on the ratio between the expression levels of two genes – HOXB13 and IL17BR, predicts the likelihood for a tumor to recur. The higher the expression level of HOXB13 and the lower the expression of IL17BR, the greater the chance of tumor recurrence (via). Unfortunately, this methodology also did not meet TEC criteria.

The same failure is for (EGFR) mutation analysis to predict response to tyrosine kinase inhibitors (TKI), like erlotinib, cause there are some data, that non-small cell lung and pancreatic cancer patients with a 15 bp exon 19 deletion could have a swift response on erlotinib (via).

Only Oncotype DX, a diagnostic multi-gene expression test from California based GenomicHealth company, that provides the likelihood of distant breast cancer recurrence in women with newly diagnosed, early stage invasive breast cancer and assesses the benefit from chemotherapy, has met quite strict TEC criteria. The assay is performed using formalin-fixed, paraffin-embedded (FFPE) tumor tissue and analyzes the expression of a panel of 21 genes using quantitative TaqMan® RT-PCR reactions in 384-well plates and the results are provided as a Recurrence Score™ (0-100) (via). They have done quite a lot of work on optimization and selection from 250 canditates genes (via).

New mutation nomenclature | HGVC July 19, 2007

Posted by ramunas in BRCA, cancer genetics, genetic testing.
2 comments

Those working with BRCA1/2 genes probably already know that new mutation nomenclature was proposed by Human Genome Variation Society (HGVC): the nucleotide numbering is from nucleotide 1 of the full gene sequence (Genbank: U14680/ BRCA1; U43746/ BRCA2) not the ATG initiator codon, as is used in biggest repository for BRCA mutations Breast Cancer Information Core (BIC). It creates a lot of confusion, since the old approach prevailed in research articles and clinical application. A new classification includes the true position of nucleotides in deletions or insertions, cause if you have, for example deleted C in a sequence ACC[C]C, the old classification truly do not show which C is deleted (you simply can not discriminate it looking at a sequence – it could be any of these four). Therefore, for example famous Ashkenazi mutations now should be described as follows:

  • BRCA1: 185delA –> c.68_69del (2 exon)
  • BRCA1: 5382insC–> c.5266dup (20 exon)
  • BRCA2: 6147delT –> c.5946del (11 exon)

Now some articles list old nomenclature in parentheses or uses only new or old classification. To define what accession number you’re useing is important, cause there are slight differences – just compare NM_000059 and U43746 of BRCA2. Its still difficult for me to switch to a new variant. I am used to rely on BIC approach. Can you remember, e.g. this masterpiece – c.533-36_5407+400del ? It looks like a free telephone number, doesn’t it? 🙂

A Newcomer BloggieGeneBaby | My Astonishment July 18, 2007

Posted by ramunas in media.
5 comments

To be frank, as a newcomer into genetics blogosphere, I didn’t expect several things that happened recently during the first few days of blogging:

  • received an invitation to join The DNA Network
  • was mentioned on genetic testing and education company DNA Direct blog
  • suggested by Bertalan to host blog carnival (fiesta?) GeneGenie on September
  • was accredited to comply with HOC code standarts (that’s very important event for me, since I feel responsibility for the accuracy of information provided here on this sensitive topic.)

A big thank for ALL of you! Will try not to disappoint you.

Before a year or so I was for the first time impressed with Web 2.0 concept in Medicine – and the ClinGenBlog was launched then (now the best forefront of that is probably ScienceRoll). The main idea was to make some kind of Open Access WBDD/OMIM/Smith’s collection on the web with tagging approach on deli.cio.us. Too much time consuming, though. I don’t update it anymore. If you feel you can develop this idea further – let’s discuss.