Resistance to chemotherapy and role of BRCA2 February 22, 2008
Posted by ramunas in BRCA, cancer genetics, hereditary cancer, ovarian cancer, research.3 comments
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.
BRCA1 mutations in cancer stem cells February 1, 2008
Posted by ramunas in BRCA, breast cancer, cancer genetics, hereditary cancer, research.1 comment so far
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)
When Having BRCA Mutation Is Not So Bad or Even Better January 3, 2008
Posted by ramunas in BRCA, breast cancer, genetic testing, hereditary cancer, ovarian cancer.4 comments
There are data accumulating, that having BRCA1/2 mutation from a clinical point of view is not worse that not having it and being affected by breast or ovarian cancer.
There was a study published in 2oo7 summer and discussed, which showed that women mortality from breast cancer is similar for carriers of a BRCA founder mutations and noncarriers (at least in Israeli).
And now, a new 2008 study found, that BRCA1/2 mutation even increases survival in ovarian cancer patients (Ashkenazi)- after 5-years, 46% of the carriers were still alive, compared with 34.4% of the noncarriers. This may be due to distinct clinical behavior and/or to a better response to chemotherapy. (ref.)
I think this is another pros for genetic testing with relaxed criteria (and definitely good news for a BRCA patients), since the main drawback of being BRCA mutation carrier is increased risk for an early breast/ovarian cancer compared with general population, and identifying of high risk patients before the disease strikes could prevent disease and improve survival.
However, I personaly think that present mutations detection fees are overpriced – and I believe that in a very near future there will be a dramatic decrease for all molecular genetic testing prices. A two approaches could be possible, IMHO, (i) a complex (sequencing of all coding regions/whole genome) and (ii) a simple – exploiting already existing technology more effectively and creatively in a cost effective way. I vote for a Simple Genetics 
Guidelines on Risk Assessment for Hereditary GynCa November 4, 2007
Posted by ramunas in BRCA, HNPCC, breast cancer, cancer genetics, colorectal cancer, genetic testing, hereditary cancer, ovarian cancer.3 comments
Recently guidelines on risk assessment for inherited gynecologic cancer (Hereditary Breast/Ovarian Cancer (HBOC) and the Lynch/Hereditary Non-Polyposis Colorectal (HNPCC)) predispositions were published by The Society of Gynecologic Oncologists (SGO).
Hereditary cancer risk assessment is a process that includes assessment of risk, education and counseling conducted by a provider with expertise in cancer genetics, and may include genetic testing after appropriate consent is obtained (ref).
Genetic risk assessment enables physicians to provide individualized evaluation of the likelihood of having one of these gynecologic cancer predisposition syndromes, as well the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes (ref).
Up to 10% of breast cancer and 10-15% of ovarian cancer cases are related to BRCA 1/2 genes mutations (“faulty genes”), so called HBOC syndrome.
Mutations in BRCA1 genes confers a 39% to 46% chance of a woman developing ovarian cancer and a 65% to 85% risk of a woman developing breast cancer by age 70 years. The BRCA2 gene is associated with an ovarian cancer risk for 10% to 27% and a breast cancer risk for 45% to 85% by age 70 years (ref., subscription needed).
For comparison, overall life time breast cancer risk in the western population is 10-12%, and ovarian 1,5-2%.
The SGO guidelines recommend genetic risk assessment for women with a 20% to 25% likelihood of having BRCA1 or BRCA2 mutations. For patients whose probability of predisposition is greater than 5% to 10%, the guidelines suggest that genetic risk assessment “may be helpful.”(ref.)
It is a new thing (“20-25%”) for me, because to my knowledge, a guidelines in USA set by the American Society of Clinical Oncology (ASCO) suggested a 10% likelihood of finding BRCA1/2 mutations to undertake genetic testing. A stringent 20% likelihood threshold of having BCRA mutations is already applied in UK.
Lynch/HNPCC syndrome is caused by germline mutations in genes that oversee DNA mismatch repair. The family predisposition conferred by mutations in genes MLH1, MSH2, or MSH6 includes not only colorectal cancer and cancers of the endometrium but also cancers of the ovary, stomach, small intestine, and other organs. Women with one of these mutations have a 42% to 60% likelihood of developing endometrial cancer and a 9% to 12% chance of developing ovarian cancer by the age of 70 years. Their lifetime risk for colorectal cancer is 40% to 60 (via).
The SGO statement divides the Lynch/HNPCC guidelines into those for patients with a 20% to 25% chance of having the inherited predisposition and those with a greater than 5% to 10% chance. The guidelines reflect both personal and family profiles, with the “revised Amsterdam criteria” included for the higher-risk group.
“revised Amsterdam criteria” for HNPCC are as follows (ref.):
- Patients have at least 3 relatives with a Lynch/HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis) in 1 lineage,
- One affected individual should be a first-degree relative of the other 2,
- At least 2 successive generations should be affected, and
- At least 1 HNPCC-associated cancer should be diagnosed before age 50 years.
Performing the genetic testing and finding out that a patient does or does not have a genetic mutation can allow us to reduce risks for other related cancers, and can have tremendous impact for the patient’s family members if a mutation is found.
When assessments identify women at high risk for these cancers, they could receive magnetic resonance imaging breast screening, colorectal screening with colonoscopy, and preventive surgery, but the medical community must become aware of the importance of these strategies in improving individual outcomes. (ref.)
Update on Research | CIMBA & BRCA Trial September 5, 2007
Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, research.1 comment so far
Just let you know about some updates in Research section (all in UK):
- CIMBA (from Cambridge Genetic Epidemiology Unit and stands for “Consortium of Investigators of Modifiers of BRCA1/2″) is an international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers. The aim of CIMBA is to provide sufficient sample sizes to allow large scale studies in order to evaluate reliably the effects of genetic modifiers. It is sure, that identification of genetic modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers will lead to an improved understanding of breast cancer. This knowledge may prove useful for the determination of individualized risk of cancer amongst carriers, who have significantly increased, but variable, risk for breast, ovarian and some other cancers.
Any group can contribute to research if can provide at least 92 BRCA1 and BRCA2 mutation carriers genotype and risk factors data. Currently there is a list of 27 international groups contributing to research.
Recently there was the first report published in Cancer Epidemiology Biomarkers & Prevention , where the F31I polymorphism in AURKA oncogene, which previously has been associated with breast cancer risk in the homozygous state, was not found to be associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations were genotyped for F31I.
A review of CIMBA is available at Breast Cancer Research.
- The BRCA Trial (an international trial supported by Breakthrough & Cancer Research UK), which is interested in developing and improving individualized treatments for a specific type of hereditary breast cancer (again for BRCA1 and BRCA2 carriers).
The cancer research is an important field to gain a new knowledge not only in cancer genetics. And if somebody would like to support it, should consider buying pinky Nokia’s phone or Belkin’s Apple iPod
Genetic Test Disclosure | BRCA Study August 17, 2007
Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer.2 comments
Generally, principles of predictive testing for cancer predisposition are the same as for the adult-onset diseases. Therefore it is not allowed to test children till the age of 18 in most countries because of the lack of effective preventative interventions at a young age. Such an early knowledge could result in unnecessary anxiety and worries. Notable exceptions are MEN 2 (A and B) syndrome, Von-Hippel-Lindau syndrome and familial adenomatous polyposis (FAP), also other rare early tumor predisposition syndromes, when there is high risk of cancer in an early ages and preventative measures are effective even at early childhood (e.g. for MEN2A thyroidectomy is advised till the age of 5 years and as young as 2 years for MEN2B, because metastases has been reported. (source))
However, a new study in the forthcoming Aug. 20 Journal of Clinical Oncology about parental communication of BRCA results to children under the age of 25 years old, reveals that more than half of the parents told their children about their genetic test results.
“Some parents reported that their children didn’t seem to understand the significance of the information shared, and that some had initial negative reactions. Further research is needed to understand the impact of this communication on these children in order to provide optimal counseling for families with a genetic risk of cancer” said the study’s author, Angela Bradbury, M.D., director of Fox Chase Cancer Center’s Family Risk Assessment Program.
This study probably rely on published data from previous presentations.
More about patients attitudes towards positive BRCA genetic test result read in EyeOnDNA recent post, where around half women in a BRCA+ group had taken no preventive action.
Breast Cancer Information Core | Significant Updates July 26, 2007
Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.2 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 (PubMed – Google) 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.].
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.1 comment so far
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.
New mutation nomenclature | HGVC July 19, 2007
Posted by ramunas in BRCA, cancer genetics, genetic testing.add a comment
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?
