www.cancer-genetics.com

Happy DNA day! This year in Europe we celebrate it for the first time officially. What a coincidence - yeasterday I’ve received gene T-shirt with mapped 1st chromosome from the magazine Science - wearing it all this day

On this occasion I would like to introduce you to SimpleGenetics(TM) genetic test reviews - it could be an independent wiki-based resource dedicated to the provision of reviews and unbiased information about commonly available genetic tests, its clinical validity and utility.

The project aims to improve the quality and accessibility of information regarding genetic tests and help to make informed choice decision for physicians and/or patients.

The information would be reviewed and edited by registered clinicians or scientists working in clinical genetic settings.

There is a preference for objective, scientific evidence-based, comprehensive reviews of clinical evidence and appreciate contribution of both genetic testing companies, clinicians and users to satisfy these goals.

I made this draft in February, and there is some information about Mammaprint available already. Let me know what you think about it and future involvement/contribution/etc. possibility.

Check out at SimpleGenetics.com

I beg a big pardon for not writing so long - it could lasts till the middle of June, till my final residency (at last) exams - now I’m deep in Emerys&Rimoins Medical Genetics, LDDB, Possum databases etc. Afterwards I hope to concentrate (and work) on my favourite topic - cancer genetics - again.

Before that, I’ll go to Spain - and be in Barcelona during Conference of European Society of Human Genetics (May 31-June 3) and then move to Madrid - to attend biannual Familial Cancer conference (June 5-6, a very good event - thanks organizers for fellowships). If somebody happened to be there - that would be really nice to meet you indeed! (will present my posters in Cancer Genetics section). Also, good ideas where to stay in Barcelona or Madrid are more than welcome

Happy Earth Day, BTW! And be aware about links of chemical cocktails to cancer.

p.s. recently there was a techy conference about blog’s in my city, and was pleased to have an opportunity to have short talk. Not about genetics or medicine, but green blogs - like Worldchanging, Treehugger and Ekoblogas - a bunch of blogs which I also like to read:

Tumor resistance to chemotherapy is an often failure of successive treatment (together with adverse effects).

As you know, BRCA2 mutations are associated with an increase in breast and ovarian cancer risk, as the gene’s normal function is to repair damaged DNA. But these cancer-causing faults are bad news for the tumour itself, as they also render it sensitive to DNA-damaging chemotherapy drugs like cisplatin. Unfortunately, many BRCA2 tumours develop resistance to cisplatin (ref.).

(BRCA2 repairs a stretch of DNA; source)

Interestingly, the researchers found that, when exposed to cisplatin, some ovarian cancer cells develop secondary mutations on their BRCA2 gene that restore the gene’s ability to repair DNA (via). This is called positive mutation in general genetics - a mutation which improves adaptive properties of a cell (if we look from a cancer cell perspective).

The discovery raises the possibility that blocking BRCA2 function in such patients might allow doctors to overcome drug resistance and continue with cisplatin treatment. And maybe this mechanism will be true to other DNA-repair genes such as BRCA1, which may help explain drug resistance to a variety of cancers (via).

Another study finds the similar mechanism involved in resistance to PARP (Poly(ADP-Ribose) polymerase) inhibitors, a new class of drugs which are known to be more effective in BRCA1/2 mutation cases, because they work by selectively killing cells which have no functioning BRCA gene.

These observations have implications for understanding drug resistance in BRCA mutation carriers as well as in defining functionally important domains within BRCA2 (ref.). Sure, therefore it is featured by Nature.

Next week I’m going to International Collaborative Group on Familial Breast and Ovarian Cancer (ICG-FBOC) meeting (9th symposium) named “Looking to the future cancer diagnostics & treatment: the impact of genetics“ in Cyprus (Κύπρος), Larnaka (Λάρνακα). There is going to be an extensive programme with the presentations of well known researchers from UK (Manchester, London), Norway and Greece. I look really forward to meeting these people and listen to their presentations.

If anyone of my readers are going to be there - please drop me a note - that will be nice to meet you there.

This week was undoubtfully very important in elucidation of genetic predisposition to prostate cancer. Three teams (two public and one private) reported their SNP studies in Nature Genetics.

A two-stage genome-wide association study (GWAS), lead by well known Cancer Research UK researchers dr. Rosalind Eeles and Douglas F Easton, was performed on Australian and UK men and confirmed previously associated genetic variants (SNP’s) to prostate cancer at 8q24, occurring in three distinct blocs, which were best “tagged” by SNPs rs6983267, rs1016343 and rs4242384 (as you know, our genome is fragmented and genetic information passes through generations by distinct “blocks” of DNA, called haplotypes, and which can be “marked/tagged” by representative spots, called “tag SNP” - a kind of genetic folksonomy marks) and 17q (a strongest association with rs7501939 (at 17q12) and rs1859962 (at 17q24) . Also several genetic variants on seven new loci on chromosomes 3 (rs2660753), 6 (rs9364554), 7 (rs6465657), 10 (rs10993994), 11 (rs7931342), 19 (rs2735839) and X (rs5945619) were identified, which could explain ~6% of the genetic risk for prostate cancer (a highly significant SNP rs10993994 in MSMB (beta-microseminoprotein) gene proximal promoter constitutes ~2% of risk).

Constantly innovative deCODE based on own results issued predisposition to prostate cancer test deCODE PrCa of 8 SNPs for $500, which is the second commercially available genetic test for prostate cancer after Focus5 test offered by Proactive Genomics. Two new SNP’s single-letter variations (rs721048 on chromosome 2 and rs5945572 on the X chromosome are also included in deCODEme genotyping service, and subscribers can check it out now.

These two SNPs confer relatively modest increases in risk – of approximately 20% and 15% per copy carried, respectively - but because they are also quite common they are each believed to contribute to about 5% of prostate cancer cases (via).

“The genetic testing market is highly competitive. No sooner does one company launch a first-of-its-kind test than another launches a similar one”, Hsien at EyeOnDNA notes about this new test.

Other study also confirms previously reported loci on 8q24 and 17q chromosomes and identifies new SNPs on 7 (rs10486567), 10 (rs10993994; strongest association) and 11 (rs10896449) chromosomes (overal 7 SNPs). Individual population attributable risk (PAR) for prostate cancer for each of the seven independent loci ranged from 8% to 20%.

These findings help clarify genetic structure of prostate cancer, shed light on plausible candidates gene regions and have implications for risk counseling, which can be of clinical importance when cumulative risk is appreciated.

Interestingly, all studies were performed using Illumina bead-chips platform.

Note: to associate any SNP with some condition a strict statistics must be applied: the results must meet or at least approach the “standart of genome-wide significance” with P value <10 minus 7 (0.00000001).

Monoclonal antibodies company Cell Signaling offers superb free at request-poster of cancer genes/proteins universe landscape, which I recently received. It also accompanies excellent book The Biology of Cancer by RA Weinberg. It is amazing when realize, that genetic variations (SNP’s or mutations) in all of these (and yet unknown) genes can predispose to developing or help to resist cancer as well as other conditions.

BRCA1 mutations are the most common cause of hereditary breast cancer and germline mutations carriers have a greatly increased lifetime incidence of breast and ovarian cancer. However, the molecular mechanisms responsible for this tissue-specific malignancy are still unknown.

A new study published in PNAS may explain why women with a mutation in the BRCA1 gene face up to an 85 percent lifetime risk of breast cancer.

The study, in mice and in human breast cancer cells, found that BRCA1 is involved in the stem cells differentiating into other breast tissue cells. When BRCA1 is missing, the stem cells tend to accumulate unregulated and develop into cancer. Researchers detected clusters of expanded stem cells in breast tissue isolated from women carrying BRCA1 mutations, and found that women with these expanded stem cells had a particularly high chance of developing breast cancer (via).

“If larger studies confirm these findings, it could potentially lead to a test to identify BRCA1 carriers at particularly high risk of developing breast cancer. This might help them and their physicians make a more informed decision about preventative measures such as prophylactic mastectomy,” says senior study author.

(image source: BRCA1 protein)

The producers (Genomic Health) of breast cancer recurrence 21 gene expression test Oncotype DX (launched in 2004) recently reported the results of two studies, which found genes that could help predict the likelihood of recurrence of and chemotherapy benefit for early-stage colon cancer (via).

Results of the studies were presented January 26, 2008 at ASCO GI, the American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium, in Orlando, Florida.

Both study reports used Genomic Health’s quantitative RT-PCR to analyze RNA expression for 375 cancer-related and reference genes from colon tumors of patients who were treated with surgery alone or with surgery and adjuvant 5-fluorouracil/leucovorin (5-FU/LV) chemotherapy (ref.).

In first study (765 + 270 patients) and researchers found 65 genes significantly associated with colon cancer recurrence across - the individual gene expression was associated with an up to 11-fold difference in the risk of disease recurrence (via).

The second study analyzed colon cancers from an additional 508 patients who were treated with surgery plus 5-FU/LV chemotherapy. Fifty six genes were discovered that were significantly associated with disease prognosis for stage II and III colon cancer

Fifteen of the 56 genes were also used as a preliminary model to stratify patients into recurrence-risk categories (via).

Overall, Genomic Health has completed four independent studies involving 1,851 colon cancer patients to evaluate a total of 761 genes. This data will support the selection of the final gene set (ref).

Not long is to wait for the new test (an analog to breast cancer Oncotype DX) to personalize treatment decisions for early-stage colon cancer patients.

Yes, it is official. 2007 already was announced as a year of human genome variation. Not surprisingly, the technology of a year 2007 was elected the next generation-sequencing (by Nature Methods).

It is truly remarkable advance not only from a technological perspective, but also it marks the end of ABI monopoly in sequencing.

Congratulations to 454 (Roche), Solexa (Illumina), Solid (ABI) and some more in the frontline (for advances and reviews visit SEQanswers.com).

(source)

Joint Swedish (Karolinska Institute) and US study published in NEJM reveals cummulative association of five (out of 16) previously known genetics variants (SNPs) with prostate cancer - three at 8q24 and one each at 17q12 and 17q24.3 (detailed table and excellent summary from SNPedia).

The idea was simple - it was known that each SNP has only a moderate association and effect wasn’t considered significant enough to justify testing individuals, but when SNPs are combined, the association may be stronger.

The study was carried out in Swedish men (2,893 prostate cancer cases and 1,781 control) and men who had any five or more of these factors associated with prostate cancer plus a family history of prostate cancer (i.e. hereditary/familial cancer), the odds ratio for prostate cancer was 9.46.

In other words, men with five or six of six risk factors, each SNP plus a family history of prostate cancer, were nearly 9.5 times more likely to have the disease.

Also, cumulative effect of these SNPs and family history was independent of PSA results.

Together, the five SNPs and family history were estimated to account for 46% of the cases of prostate cancer in the Swedish men studied. It is estimated that almost 90% of the Swedish population carries one or more of the five SNP, and the results should be tested in other populations.

Interestingly, the mechanism by which the analyzed SNPs could affect the risk of prostate cancer is still unknown.

Well, there is already commercial name for this test: Focus5™ Prostate Cancer Risk Test (by fresh Proactive Genomics). [update]

Recently, one of the collaborators group have also identified a variant rs1571801 in DAB2IP gene associated with aggressive prostate cancer.