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Resistance to chemotherapy and role of BRCA2 February 22, 2008

Posted by ramunas in BRCA, cancer genetics, hereditary cancer, ovarian cancer, research.

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.


Looking to the cancer genetics future | ICG-FBOC meeting February 20, 2008

Posted by ramunas in breast cancer, cancer genetics, familial cancer, genetic testing, hereditary cancer, media, ovarian cancer, personal.
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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.

Prostate Cancer | Old&New SNPs and deCODEPrCa February 15, 2008

Posted by ramunas in cancer genetics, familial cancer, genetic testing, hereditary cancer, prostate cancer, research, sporadic cancer.
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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).

Pathways in Human Cancer February 2, 2008

Posted by ramunas in cancer genetics, media, prostate cancer.

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 in cancer stem cells February 1, 2008

Posted by ramunas in BRCA, breast cancer, cancer genetics, hereditary cancer, research.
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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)