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Exciting Discoveries of 2007 | Breast Cancer October 13, 2007

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

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Comments»

1. Walter - October 27, 2007

That’s interesting Ramunas – I wasn’t familiar with the HMMR data. HMMR is a hyaluronan-mediated motility receptor. CD44, an adhesion receptor and the major cell-surface receptor for hyaluronic acid (HA), is frequently over-expressed in cancer. Low molecular weight HA species have proinflammatory functions and accumulate at sites of inflammation and tissue injury. It’s thought that CD44 plays an important role in the clearance of HA. Is there any data demonstrating an association between inflammation and breast cancer?

2. ramunas - October 27, 2007

thank you for your comment, Walter.
inflamation and cancer progression are often taking place together, so I think to distinguish these processes would be quite difficult. I would refer to excellent reviews by Dunn PG on cancer immunoediting. In the first phase of immunoediting – elimination – cellular transformation provides sufficient proinflammatory signals for immune system about presence of tumor, what in turn try to clear it away. If we assume, that some variants (SNPs) interfere with this complex process, cancer predisposition could increase, imho.

3. deCODE’ing Predisposition to Cancer « www.cancer-genetics.com - November 17, 2007

[…] Breast cancer. It includes the variants on chromosomes 2 and 8, as well as those in the FGFR2, the TNRC9/TOX3, the LSP1, the MAP3K1 and the CASP8 genes and interpretation of their associated […]

4. Happy 2008! | And Briefly About 2007 « www.cancer-genetics.com - December 31, 2007

[…] 2007 will be known in history as a breakthrough in understanding of our (Humans: Homo sapiens sapientis) genome variation and enourmous success in genome wide association studies (GWAS) for complex disorders ) cancer included (e.g. see my post about breast cancer). […]

5. Petra - April 2, 2008

Quote: 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.

These were odds ratios. If you calculate them into risks (assuming “basic” risk is 10% lifetime in women) then you get to 12 – 16% chance of breast cancer in these women. So they have “only” 2 to 6 % more chance to develop breast cancer than a women with two normal copies of FGFR2.

6. ramunas - April 2, 2008

Bedankt, Petra! it’s really easy to misinterpret this. Will have to look more carefully for the media announcements.

7. walter - April 10, 2008

I had no idea that discovery had been made.
slightly unrelated, you may like the ubiquitin webinar that science magazine is putting on: The Ubiquitin-Proteasome Pathway

8. randy - November 8, 2008

hey

9. Stan - December 8, 2008

The finding of HMMR gene as a new common breast cancer susceptability gene was not confirmed by a much bigger study published this month by a team from the Cambridge University (Kalmyrzaev et al, CEBP Dec 2008): http://cebp.aacrjournals.org/cgi/content/full/17/12/3618

10. annapurna.k - January 26, 2009

i want to be part of reasearch in cancer treatment

11. Deb - September 5, 2009

I have already had chemo,radiation and a lumpectomy for breast cancer and now my sister has had to have a bi-lateral mastectomy because of a variance in genetics now I am facing it also I was wandering does chemo or radiation alter your genetics so they can not be properly read.?

12. Bigger Breasts Naturally - March 12, 2010

Using natural way for health must become our lifestyle now before too late

13. en.search.wordpress.com: Exciting Discoveries of 2007 | Breast Cancer « Genotyping Daily - August 1, 2010

[…] breast cancer genetics. There have been at least 7 new genes strongly linked to breast […] en.search.wordpress.com: Exciting Discoveries of 2007 | Breast Cancer AKPC_IDS += "222,";Popularity: unranked […]


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