Complexity of Breast Cancer August 20, 2008
Posted by ramunas in breast cancer, cancer genetics, familial cancer, genetic testing, hereditary cancer, research.3 comments
This is an exciting time in the study of hereditary factors involved in breast cancer susceptibility. Breast cancer for a long time was classified according histology. Now genetics play a significant role and better knowledge ensures better management and treatment.
Hereditary breast cancer (HBC) accounts for as much as 10% of the total BC burden. Only about 30 percent of these cases will be found to be due to a germline mutations in well known BRCA1 and/or BRCA2 genes, but the rest won’t have these mutations. Less than 10 percent of remaining HBC will fall into other rare conditions – and here we can see breast cancer as heterogeneous disease (ref.):
Cowden, Li-Fraumeni syndromes, heterozygosity for Ataxia telangiectasia-mutated gene (ATM) or for CHEK2 1100delC or other rare conditions Nijmegen breakage syndrome (NBS1), familial diffuse gastric cancer (CDH1), Peutz-Jeghers syndrome (STK11), Fanconi anemia (BRIP1, PALB2), Bloom syndrome (BLM)) contribute sligthly – there is consensus for ten most important genes involved in HBC (ref.)
An estimated additional 15–20% of those affected with BC will have one or more first- and ⁄ or second-degree relatives with BC (familial or polygenic breast cancer). Therefore, when these numbers are combined, familial BC risk accounts for approximately 20–25% of the total BC burden (see figure).
Here we’re talking about so called low-penetrance susceptibility genes and variants (SNPs), like rs2981582 in FGFR2, rs889312 in MAP3K1, rs3803662 in TNRC9, rs1801270 in CASP8 and many more, most of which were hot topics in the recent years. Particular alleles (particular “letter” variants of these digitalized “rs” SNPs) only increase risk slightly (twice or so) and are intense study object now, but they sooner or later will enter clinical practice.
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.add a comment
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.
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)
A New Tumor Markers & Targets January 3, 2008
Posted by ramunas in breast cancer, liver cancer, prostate cancer, pten, research.2 comments
Yes, there are some already in 2008!
- STAT5b – a key regulator of tumorigenesis and mediator of cytokine-growth factor signaling pathway through Janus kinases and signal transducers-activators (JAK/STAT). STAT5b phosphorylation and activation is mediated by several kinases known to be overexpressed in breast cancer, such as epidermal growth factor receptor, HER2, and c-Src. Breast tumor kinase (Brk), also known as protein tyrosine kinase 6, is a nonreceptor tyrosine kinase expressed in more than 60% of breast cancers. STAT5b as well as Brk were established as potential target for breast cancer therapy [ref.] Interestingly, knock-out mouse with defect in this signaling system have dwarfism and are immunodeficient.
Also STAT5 is overexpressed in almost all recurrent prostate cancers that are resistant to hormone therapy and suggest it as a potential drug target in prostate cancer, particularly resistant to other therapies (via).
- NUMB – article in Nature describe a previously unknown function for human NUMB tumour suppressor as a regulator of tumour protein p53. NUMB prevents ubiquitination and degradation of p53 and regulate p53-dependent phenotypes. In breast cancers there is frequent loss of NUMB expression and NUMB-defective breast tumours display poor prognosis (ref.).
- The EGF (epidermal growth factor) gene 61* G allele polymorphism (SNP) G/G genotype is associated with almost threefold risk for development of hepatocellular carcinoma in liver cirrhosis through modulation of EGF levels (ref.)
- Loss of PTEN expression due to gross mutations is significantly associated with the basal-like cancer (BBC) subtype in human sporadic and BRCA1-associated hereditary breast cancers, article in Nature reports. Interestingly, hereditary mutations in PTEN are responsible for so called rare PTEN-hamartoma tumors syndromes: Cowden syndrome (macrocephaly; skin, intestine, breast and thyroid neoplasias), Bannayan-Riley-Ruvalcaba sydrome, Proteus syndrome, and Proteus-like syndrome.
- RASSF1A A133S polymorphism is associated with breast cancer pathogenesis in general and modifies breast cancer age of onset in BRCA1/2 mutations carriers – it was associated with earlier onset of breast cancer compared with those individuals with either a BRCA1/2 mutation or the A133S polymorphism alone (36.0 versus 42.0 years old, P = 0.002) (ref.)
- Colony stimulating factor-1 (CSF1) circulating levels confer a 33% increased risk of postmenopausal breast cancer and is associated with an 85% reduced risk of premenopausal breast cancer (ref.)
- more?
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 
Happy 2008! | And Briefly About 2007 December 31, 2007
Posted by ramunas in BT Test, DiaGenic, MammaPrint, Oncotype DX, PC Detect, breast cancer, cancer genetics, familial cancer, genetic testing, prostate cancer, sporadic cancer, technology.6 comments
(artwork by Hollis Sigler, 1948-2001)
Happy New Year 2008! Especially to all people, who encountered and battled cancer. Also for those who work to help fight this disease. Lot of advances in our understanding about this condition were achieved this year. It is too naive think that we could completely eliminate cancer, but it is very realistic to think that we can (and will able) to better predict and control this disease.
2007 will be known in history as a breakthrough in understanding of our (Humans: Homo sapiens sapientis) genome variation and enormous success in genome wide association studies (GWAS) for complex disorders ) cancer included (e.g. see my post about breast cancer).
2008 will be definitely an exciting journey through a highway (yet in a desert) of personalized genomics:
(from a movie Electroma, 2007)
I believe that individual molecular profiles will soon help to improve the early detection of cancer : over 50 novel DNA methylation-based biomarkers of breast cancer (by Orion Genomics) can replace mamography in a near future.
(courtesy of Biotage)
Also 37 gene expression markers from peripheral blood (by DiaGenic) will be offered in UK by Opaldia from 2008 (also covered by EyeOnDna, GeneticsAndHealth and MedGadget).
A new BT Test (by Provista Life Sciences) is designed to complement other testing methods to aid doctors in more accurately diagnosing breast cancer in its early stages, when life-saving treatment is most effective (via). The BT Test utilizes a proprietary algorithm to evaluate the levels and relationship of multiple, cancer associated protein biomarkers in blood serum. This data is coupled with a patient’s personal medical profile to generate a comprehensive report designed to assist healthcare providers in making an earlier diagnosis of breast cancer (via).
Two gene-expression assays, Oncotype DX and MammaPrint, have been developed and extensivelly reviewed in 2007, to determine the risk of breast cancer recurrence in patients with stage I or II node-negative breast cancer. In the future, these tests may be useful in determining the need for systemic adjuvant therapy in such patients (ref.).
Unexpectedly, some years ago alterations in mitochondrial DNA – our reminder about The Seven Daughters of Eve – have been suspected to play an important role in the development and progression of cancer. Several mutations have been identified in a wide variety of human tumors, including breast, colorectal, ovarian, gastric, hepatic and esophageal cancers, as well as hematological malignancies [ref.]. Some studies this year points to the importance of the variants in D-loop in familial breast cancer.
Genomic alterations in a new cancer marker – nucleophosmin (NPM1) (by Ipsogen) – has an enormous impact in the biological study, diagnosis, prognostic stratification, and monitoring of minimal residual disease of various lymphomas and leukemias (especially acute myeloid leukemia (AML)). The discovery of NPM1 gene alterations also represents the rationale basis for development of molecular targeted drugs.
Panacea Pharmaceuticals (hm, what a name…) has initiated manufacturing of PC Detectsm kits, the Company’s diagnostic test for prostate cancer, under GMP condition. It based on detection of Human Aspartyl (Asparaginyl) beta-Hydroxylase (HAAH), a cancer biomarker. HAAH has been established as an excellent biomarker for many types of cancer, including prostate cancer. The protein is typically undetectable in sera from cancer-free individuals, thus, an elevated serum protein level of HAAH is highly diagnostic for cancer. PC Detectsm is recommended as an adjunct to the prostate specific antigen (PSA) test and the digital rectal examination (DRE), the currently recommended prostate cancer screening methods (ref.).
A booming field in micro-RNA and cancer field is expected to blossom in forthcoming years – microRNA-10b and breast cancer metastases is a recent example in Nature. It is truly biology’s Big Bang in our 21st century – The RNA revolution.
(photo from Economist)
Tumor immunology, with cancer immunoediting concept in ahead, T regulatory cells and advances in therapeutic cancer vaccines is an important future promise. Individualized cancer immunotherapy with RNA loaded dendritic cells (DC) vaccines (by Argos Therapeutics) is one of the opportunities and new generation of choices.
Who will catch the COBRA? December 17, 2007
Posted by ramunas in breast cancer, cancer genetics, familial cancer, research.1 comment so far
I expect very exciting news about recently discovered cofactor of BRCA1 (COBRA1) – a member of the negative elongation factor (NELF) complex, a BRCA1-interacting protein. Cofactor of BRCA1 (COBRA1) was first identified as a protein that binds to the breast cancer susceptibility gene product BRCA1. It modulates estrogen-dependent and independent transcription and suppresses the growth of breast cancer cells. Its expression is significantly reduced in metastatic and recurrent breast cancer, pointing to a tumor suppressor function in breast cancer development [ref.].
Furthermore, a lack of COBRA1 expression in breast carcinoma may serve as a useful indicator for poor prognosis (ref).
Interestingly, COBRA1 is overexpressed in the majority of primary upper gastrointestinal adenocarcinoma, what suggests COBRA1 as a novel oncogene in UGCs that regulate AP-1 binding and the expression of TFF1 in upper gastric epithelia [ref.].
One genome-wide study identified a total of 134 genes that were either activated or repressed upon small hairpin RNA-mediated reduction of COBRA1. Interestingly, many COBRA1-regulated genes reside as clusters on the chromosomes and have been previously implicated in cancer development.
It’s not too big gene – just 13 small exons, Venter and Watson have several SNPs in intronic regions. I am eager to know its involvement in cancer predisposition.
There is a great “streaming” from the North – Finnish studies of TopBP1 (topoisomerase IIbeta binding protein 1 which displays sequence homology as well as functional similarities with BRCA1) points to a novel breast cancer susceptibility gene, where CLSPN (involved in monitoring of replication and sensoring of DNA damage and cooperates with CHK1 and BRCA1) does not appear to be associated with susceptibility.
So, who will catch the COBRA? Maybe TRANSFOG.
BOADICEA Final Version Released December 15, 2007
Posted by ramunas in bio-software, breast cancer, cancer genetics, familial cancer, genetic testing, hereditary cancer, ovarian cancer, technology.1 comment so far
Here is probably the most accurate breast&ovarian cancer risk/mutation probability calculation web-application released from Cambridge University Genetic Epidemiology Unit – BOADICEA.
BOADICEA is a computer program that enables the user to estimate BRCA1/BRCA2 mutation carrier probabilities and breast/ovarian cancer risks based on polygenic model. The BOADICEA Web Application (BWA) has been designed in collaboration with clinical geneticists and researchers, in order to make BOADICEA risk estimations much quicker and easier.
It differs from available (BRCAPRO, Gail, Couch, Frank, Manchester model etc.), since it assumes not only high penetrance genes (eg. BRCA) for risk calculation, but also contribution of other low penetrance genes, most not yet identified (thus polygenic).
For more than a year lot of users tested beta phase (I am grateful to Alex Cunningham, the main developer and programmer, for letting to participate during this phase) and the final version was released. Excellent work, I would say!
The approach was first described by Antoniou AC et al. in 2004 and it was shown that overall familial risks of breast cancer predicted by this model were close to those observed in epidemiological studies.
Anyone can register to use the program including researchers, healthcare professionals and the public. However, if you are a member of the public and you are concerned about your family history, it is strongly advised that you seek guidance first from your general practitioner (see Advice for members of the public).
N.B. Be aware, however, that current model is based on genetic epidemiology of UK population. For other populations it may give not correct risk estimation.
P.S. I would like to apologize my readers for not posting long – I’m completely drowned in the final year of my residency and end of a year…
Complexities of BRCA genes December 4, 2007
Posted by ramunas in breast cancer, cancer genetics, familial cancer, genetic testing, hereditary cancer, ovarian cancer, sporadic cancer.3 comments
There are some exciting news in cancer genetics. An extremely informative article about BRCA 1/2 genes mutations in different populations was published recently in Nature Reviews Cancer, which highlighted the complexity of BRCA mutation data and interpretation problems.
Inherited mutations in the BRCA1 and BRCA2 tumour-suppressor genes are the strongest indicators of breast and/or ovarian cancer risk. Prevalence of BRCA1 and BRCA2 mutations among high-risk cancer patients may vary by ethnicity, study inclusion criteria and mutation detection techniques.
In general, germline mutations in known breast cancer risk genes account for ~20% of breast cancers associated with family history. Aproximately 1-29% of such families will have mutations in BRCA1 gene and 1,5-25% in BRCA2 gene (ref.). As you’ve already noticed, there is wide variance, which is dependent on selection criteria, studied populations and technology used.
Moreover, there is a huge variation in penetrance (i.e. a proportion of persons who carry mutation and will develop disease). Studies show that the penetrance of deleterious BRCA1 and BRCA2 mutations is lower overall in a general population than in high-risk families, but the variability is broad and the confidence intervals are wide. One of the reason of such variability may be family-specific genetics and/or environment modifiers (the evidence for that is RAD51 polymorphism, which modify penetrance of BRCA2 (revied by GeneSherpa).
The most consistent and clearly written range I’ve found (and now use in practice) in a new edition of I.D.Young “Risk Calculation in Genetic Couseling“:
Cumulative risks for breast and ovarian cancer to age 70 years for BRCA1 mutation carriers average around 70-85% and 45-60%, respectively, for multiple-case (i.e. high risk) families, whereas average risks of 65% and 40% have been obtained for unselected (i.e. sporadic) cases. Comparable risks for BRCA2 carriers are 60-85% (breast) and 27%-31% (ovarian) for mulitple-case families and 45% (breast) and 11% (ovarian) for unselected cases.
As we approach the goal of personalized medicine, it is important to recognize the contribution of an individual patient’ s genotype to her (or his) breast cancer ovarian cancer syndromes include early age of cancer risk, as well as the gene–gene and gene–environment relationships that may modify mutation penetrance in each individual.
The results of sporadic breast/ovarian cancer studies suggest BRCA1 mutation frequencies ranging from 4 to 29% and BRCA2 mutation frequencies from 0.6 to 16% (ref.)
The important conclusion for clinicians is that it is likely most BRCA1 and BRCA2 mutations occurring in a clinical setting will be present in individuals with no family history of breast cancer.
Some BRCA1 and BRCA2 mutation carriers without family history of disease may have comparatively low (but still clinically significant) mutation-associated penetrance, whereas others may have uninformative family structures that do not reveal family history regardless of mutation penetrance, such as small size, few female relatives or patrilineal inheritance of the mutation (ref.).
One of the most useful ways to approach penetrance estimates is to examine founder mutations, or high frequency individual alleles that are particular to a specific population.
I’ve found very useful definition of founder mutation:
A recurrent mutation that occurs on a single haplotype in a population may be considered a founder mutation, while a mutation that occurs on more than one haplotype is considered to have occurred multiple times in the population history and is not a founder mutation (a haplotype is a set of nearby genetic markers that segregate together as a unit through generations) (ref.).
There is a schematic representation of most important known founder mutations:
And an excerpt from a table:
There are two common mutations of BRCA1 gene in Lithuania (the same as in Latvia and more or less in Poland, what reflect long coexistence of populations, although the origin is different – there are data of X and Y chromosome analysis in Baltic countries performed by my previous colleague), although I’ve found one protein truncating deletion not previously described anywhere (already submitted inquiry to BIC mutation database).
Mammaprint TIME’s November 30, 2007
Posted by ramunas in MammaPrint, breast cancer, cancer genetics, genetic testing.add a comment
Amsterdam based Agendia’s 70 gene expression test MammaPrint® was awarded by TIME Magazine as one of five best innovations of the year 2007 in the health category.
“With MammaPrint, a genetic test of a tumor’s DNA, patients and doctors can get a better handle on how likely it is that the cancer will spread”
It’s also the first microarray test approved by the FDA.
As you may noticed, there are several guys (aka doctors) on the corporate page design. Accidentally, when I was browsing our local website about COPD, I was surprised to find the same “template-doctors” there
