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Knome | The First Whole-Genome Sequencing Co. October 31, 2007

Posted by ramunas in personal.

I’ve read a short review in Nature summarizing personal genomics companies, like 23andme.com and navigenics.com. Surprisingly, a third – Knome – based in Cambridge, MA, came to my attention:

We are the first firm to offer individuals the opportunity to have their entire personal genome sequenced. Using the latest advances in whole-genome sequencing, we will sequence your genome and will provide you with a comprehensive and detailed analysis of the results under the direction of a leading geneticist. Further, our proprietary genome management platform will enable you to retain complete control over your private genomic information.

Well, its not genotyping (as other 2 offers), but sequencing of whole genome.

In addition to being amongst the first individuals in history to be fully sequenced (a group that, to date, includes only James Watson, co-discoverer of DNA, and Craig Venter, one of the pioneers who first sequenced the human genome), you will be able, for the first time, to use detailed knowledge of your own genetic information to make decisions that can significantly enhance your lifestyle, health and medical care. Once your entire genome has been sequenced, you can stay current on future genetic discoveries without having to take additional tests. Beyond health-related applications, your sequenced genome can provide insights into your own ancestry and genealogy.

Wanna stand near Watson and Venter? Do it at Knome 🙂

We are selecting a limited number of individuals to participate in our initial launch phase. If you are interested in purchasing a private copy of your personal genome, please contact us. Due to the significant costs associated with our services, we reserve the right to refuse access at our complete and sole discretion.

Hsien, I think that have some similarities with immaginatory SellMyDna.com services, but real. Bercy, hurry up to sign in! 🙂


SMAD7 | Colorectal Cancer October 31, 2007

Posted by ramunas in cancer genetics, colorectal cancer, genetic testing, research.

A message is simple: variants (SNP’s) in SMAD7 gene (which is involved in TGF-beta and Wnt signaling; shown in red on the left side) influence colorectal cancer (CRC) risk.

Particulary association between rs4939827 and CRC was highly statistically significant. This study was performed by UK researchers and just published in Nature Genetics.

Just another SNP for future personalized genomic screen and risk assessment.

(image source)

Gene’s Mountains and Hills | Cancer October 21, 2007

Posted by ramunas in breast cancer, cancer genetics, colon cancer, research.
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A picture of huge (and ugly) macro-anatomical sample of cancer is an often finding in some chapters of textbook about cancer genetics. It has no educational value from a present personalized medicine perspective. A picture of expression profiling or mutated genes provides more relevant and contemporary understanding.

Here is how an individual colon cancer from a patient Mx38 looks like (source):

Kind of avantgarde picture in an early 20 century? Don’t worry – it will go mainstream soon like a pop-art cartoon…

A researchers team lead by notorious Bert Vogelstein (co-author of colorectal cancer mutagenesis model) performed (second) amazing study – they sequenced several individual cancers DNA:

In a systematic search of 18,191 genes representing more than 90 percent of the protein-coding genes in the human genome — about 5,000 more than in the first screen — the Johns Hopkins scientists found that most cancer-causing gene mutations are quite diverse and can vary from person to person. They found that an average 77 genes are mutated in an individual colon cancer and 81 in breast cancer. Of these, about 15 are likely to contribute to a cancer’s key characteristics, and most of these genes may be different for each patient (via).

These data suggest a genetic landscape dominated by genes that each are mutated in relatively few cancers:

“There are gene ‘mountains’ represented by those that are frequently altered and have been the focus of cancer research for years, in part because they were the only genes known to contribute to cancer,” says Bert Vogelstein, M.D., an investigator at the Howard Hughes Medical Institute and co-director of the Ludwig Center at Johns Hopkins. “Now, we can see the whole picture, and it is clear that lower peaks or gene ‘hills’ are the predominant feature.

It looks like “few mountains surrounded by many hills.”

Surprisingly, they found that an average 77 genes are mutated in an individual colon cancer and 81 in breast cancer. Of these, about 15 are likely to contribute to a cancer’s key characteristics, and most of these genes may be different for each patient.

Lot of texbooks state, that c.a. 7-8 genes are mutated in colon cancer. And they were ten-fold  wrong: mutations in 77 for colon and 81 genes for breast cancer are required to develop.

The scientists say that directing therapies at common pathways that are linked by both prevalent and rare gene mutations is a better approach than aiming treatments at specific genes. They also note that personalized cancer genomics paves the way for tailored therapies and diagnostics focusing on the alterations identified in a particular patient’s cancer. Many of the mutations identified by scientists could be important in developing individualized cancer vaccines and monitoring patients for early recurrence of their disease.

GMO and Environment | Blog Action Day October 15, 2007

Posted by ramunas in media, personal.

Today is an International Blog Action Day, when more than 15000 bloggers are blogging about single common issue – environment (and hi-tech journal Wired issued special 15.10 edition). And this blog is not an exception.

I’m an avid proponent of in-vitro biotechnology, when genetically modified organisms (GMO) are used for production of useful enzymes, drugs and materials and are grown in controlled environment. I believe, that bio-assistance, bio-mimicry, neobiological industry, nanotechnolgy will help to solve many of contemporary environmental problems and foster the shift from linear “cradle to grave” to sustainable cyclic “cradle to cradle” closed loop manufacturing principle in industry. But I remain quite skeptical when GM plants are grown in an open field, mainly because of unpredictable impact on ecosystem due to gene flow (and some effect on local economics), and try to buy as much organic/local as can afford. It is also clear now, that organic farming can yield up to three times as much food as conventional farming in developing countries, and holds its own against standard methods in rich countries (ref).

There were no direct scientificaly sound evidence for the negative GM plants effect on ecosystem which lead to criticism. However, just recently in PNAS October 8th issue published article provides the first unbiased scientific evidence that toxins from GMO Bt corn may travel long distances in streams and may harm stream insects that serve as food for fish.

These results compound concerns about the ecological impacts of Bt corn raised by previous studies showing that corn-grown toxins harm beneficial insects living in the soil (via).

Stream insects are important prey for aquatic and riparian predators, and widespread planting of Bt crops has unexpected ecosystem-scale consequences (abstract).

Bye, bye Monsanto, aren’t you? 🙂 Smart breeding seems to be far more attractive option.

Exciting Discoveries of 2007 | Breast Cancer October 13, 2007

Posted by ramunas in breast cancer, cancer genetics, familial cancer, research.

It seems that year 2007 is one of the most exciting year in breast cancer genetics. There have been at least 7 new genes strongly linked to breast cancer this year (and still there is some time left for discoveries).

As you may already know, BRCA1 and BRCA2, highly penetrant autosomal dominant breast cancer genes, were discovered in 1994 and 1995 respectively (a very informative article is written by Steven Narod, the most cited author in the world working in the breast cancer field). These known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks.

Then only in 2002, a new low-penetrance gene CHEK2 (particularly 1100delC mutation) was described with twofold increase of breast cancer risk in women and a tenfold increase of risk in men. There are data that it could be also multiorgan cancer susceptibility gene. And now starts “Golden 2007”:

  • Just recently (October 7th) a multicenter international study linked a new gene called HMMR to increased breast cancer risk and stated. It is mutated in about 10 percent of the population and mutations in HMMR gene can increase breast cancer risk by one third (ref.).

Interestingly, researchers used sophisticated computerized network-modeling tool that allows many different types of existing scientific data sources to be analyzed easily to identify genes that impact cancer development.

These in silico findings for three HMMR haplotype-tagging SNPs (htSNPs) were then verified on 2,475 women with breast cancer and 1,918 healthy women were studied in Israel and New York. Biotage Pyrosequencing genotyping platform was used. They also found, that HMMR gene, encoding a centrosome subunit, interacts with the well-known breast cancer gene BRCA1, which together with BRCA2, is mutated in about one of every 300 individuals, or less than 1 percent of the population.

The study found that women with a variation in the HMMR gene had a higher risk of breast cancer, even after accounting for mutations in the BRCA1 or BRCA2 genes. In particular, the risk of breast cancer in women under age 40 who carry the HMMR variation was 2.7 times the risk in women without this variation.

Overall, the risk of breast cancer was 23 percent higher in women who had one copy of genetic variant (the A-C-A haplotype: rs7712023-rs299290-rs10515860), and 46 percent higher in women who had inherited two copies. In addition, those women were diagnosed an average of 12 months younger than women from the control group, suggesting that HMMR is linked to early-onset breast cancer.

Interestingly, this breast cancer susceptibility gene functionally is oncogene, i.e. its overexpression may lead to centrosome amplification and genomic instability.

  • On May, in Science a new candidate breast-cancer susceptibility gene Rap80 (has 15 exons), was described (in three articles: 1, 2, 3), which is required for the normal DNA-repair function of the well-known breast cancer gene BRCA1.

Cancer-causing mutations in the BRCA1 protein fail to bind to the Rap80 ubiquitin-binding protein. Consequently BRCA1 is unable to identify DNA damage sites in the genome. When BRCA1 fails to fix DNA damage, cancer-causing mutations accumulate, spawning the development of breast and ovarian malignancies (via).

“Thus Rap80, by interacting with a BRCA1 region that is essential for BRCA tumor suppression, now becomes a candidate to investigate as another breast cancer disease gene in families that do not have BRCA1 and BRCA2 mutations, but have a history of breast and/or ovarian cancer,” say researchers. “In collaboration with other researchers we are currently looking to see if families that have a history of breast cancer, but lack BRCA1 and BRCA2 mutations, have any gene sequence changes in Rap80 (via).”

  • Another gene, mostly confined to sporadic breast cancer (probably), is infamous FoxP3, the hottest topic in immunology and marker of T regulatory cells (and one of candidate markers for my PhD work), but also acts as X-linked tumor suppressor gene. About 80 percent of the cancer tissues studied did not express the gene at all and it is found to be a represor of HER-2, a protein that typically marks a more aggressive form of breast cancer (also target of Trastuzumab (Herceptin) monoclonal antibody).
  • Two very important genome-wide association huge collaborative studies published on May by UK (Douglas Easton et al) and USA (Hunter D. et al) researchers, unexpectedly identified FGFR2 (fibroblast growth factor receptor), TNRC9, MAP3K1 and LSP1 genes as important breast cancer susceptibility loci.

The team found that women who carry one faulty copy of FGFR2 (four mutations) appear to have a 20% elevated risk of breast cancer, while those with two altered versions – one in six women – face up to a 60% greater chance of the illness (via).

“This is probably the most important paper on breast cancer genetics since the cloning of BRCA2 in 1995”. “This finding opens up new avenues of research into the causes and prevention of breast cancer by identifying a new biological pathway (rj: cell growth and signaling) relevant to risk of the disease” (ref.)

Researchers hesitate to advocate testing women for the FGFR2 gene. Hunter believes that “it is premature to recommend screening women for these variants” until scientists know more about other genetic risk factors (via).

If I’ve missed something, please remind it in the comments field.

Personalized Oncogenetics/Oncology October 8, 2007

Posted by ramunas in cancer genetics, genetic testing, research.

In one recent article I’ve found a good summary of research approaches in cancer that lead individualized cancer management (research field –> clinical target):

  • Germline mutation analysis –> Personalized risk assessment and guided prevention
  • Gene expression profiling (multigene assays, gene signatures) –> Prognosis optimization, predictive response to specific therapies
  • Tissue single-gene mutation analysis –> Improvement of predictive precision
  • Circulating tumor cells –> Individual prognosis, fine-tuning
  • Single-nucleotide polymorphism analysis –> Host tailored therapy
  • Cancer stem cells –> Cancer eradication therapy

I could add advances in tumor immunology, especially a better understanding of immune editing and immunosuppressive networks (T regs etc) as well as monoclonal therapy (see a picture which I’ve added to Wikipedia a couple years ago) and cancer vaccines.

(Update: e.g., VentureBeat presents innovative Bellicum prostate cancer dendritic cells vaccine based on modified CD40 activation.)

First area is quite well established.:

Among these syndromes, HBOC (Hereditary breast ovarian cancer syndrome) and HNPCC /FAP are of the highest clinical significance because a large body of evidence supports the implementation of genetic analysis in clinical intervention strategies in these clinical situations. Indeed, although HBOC accounts for 5–10% of all breast‑-ovarian cancers and HNPCC for 2–4% of colorectal cancers, the high incidence of these tumor types reflect a substantial number of inherited cancers. It is estimated that in the US among 300,000 new annual breast and ovarian cancer cases, approximately 15,000 to 30,000 are attributed to germline BRCA mutations. Similarly among 150,000 colorectal cancer cases approximately 3300 to 6000 are considered to be familial. It is clear that a sensible number of cancer patients could be offered a life-saving early diagnosis, or optimally tumor prevention if genetic screening programs were applied. The development of such strategies could help prevent cancer onset in mutation carriers (via).

Gene expression profiling have already entered marked as commercial tests but gene expression studies have widely been criticized for methodology, diversity of genes used and the reproducibility outside highly specialized laboratories. However, despite criticism expressed on the validity of gene sets, a recently published study produced encouraging results by confirming that most gene signature models had high rates of concordance in their outcome predictions for the individual samples [ref].

The possible superiority of these tests over standard predictors is assessed in two large randomized prospective trials the TAILORx( designed by the NCI in the USA) and the MINDACT in the European Union, that are currently recruiting patients with the aim to test the validity of the 21-gene recurrence score (as for Oncotype DX) and the 70-gene profile (as for Mammaprint) respectively.

In general it is foreseen by file experts that genomic research will soon be in the position to provide easily applicable versions of gene sets that will give clinicians the opportunity to provide cancer patients a truly personalized treatment (via).

Or just simply state – the future is now! I am convinced, that oncology with cancer genetics in front, will be (or already is) the first truly acknowledged personalized medicine practice.

Caspase 8 Story | Breast Cancer October 5, 2007

Posted by ramunas in breast cancer, cancer genetics, familial cancer, research.
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An important example, how we need to interprete association studies with caution between different populations. One recent study published in Nature Genetics and performed on an Asian population (Chinese) reported a six-nucleotide insertion-deletion polymorphism (-652 6N del) in the CASP8 promoter region to be strongly associated with a decreased risk of multiple types of cancer (including lung, esophageal, gastric, colorectal, cervical and breast cancers).

Caspases are important in the life and death of immune cells and therefore influence immune surveillance of malignancies (via) and genetic variants influencing immune status could modify cancer susceptibility. Indeed, the deletion destroys a stimulatory protein 1 binding site and decreases CASP8 transcription and T lymphocytes (could be those my beloved T regs?) with the deletion variant have lower caspase-8 activity and activation-induced cell death upon stimulation with cancer cell antigens.

However, a large study investigating the effect of this deletion in four independent large European BC case-control studies, including data from a total of 7,753 cases and 7,921 controls found, that the CASP8 -652 6N del variant has no significant effect on BC risk in Europeans – the combined per allele odds ratio (OR) was 0.97.

Interestingly, the other variant (D302H (rs1045485)) of caspase 8 gene (CASP8 ) slightly decreases the risk of breast cancer (with odds ratios (OR) of 0.89 for heterozygotes and 0.74 for rare homozygotes, compared with common homozygotes (via)).

“More breast cancer genes will be identified over the next year or so, and this may help define pathways that might be good treatment targets,” Dr. Angela Cox from Sheffield University Medical School, UK told Reuters Health. “It may be also possible to identify combinations of genes which together account for a higher percentage of the familial risk.” (via)

The protein produced by the CASP8 gene participates in programmed cell death, or apoptosis, a defense mechanism that allows cells to commit suicide rather than develop into a tumor. DNA damage can trigger apoptosis, and one hypothesis is that the CASP8 SNP may enhance the body’s ability to clear cancerous cells from the body and thereby lower the risk of breast cancer (via)).

BlogActionDay | October 15 October 4, 2007

Posted by ramunas in media.
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Genes/Genetics are closely related with Environment, and I think every (human) geneticist should be concerned and informed about environmental issues as well. To raise awareness about this topic, on BlogActionDay – October 15 th – thousands of bloggers will join to write about single topic – environment. CancerGenetics won’t be an exception.