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iBlog, iBack, iGene January 7, 2009

Posted by ramunas in cancer genetics, familial cancer, genetic testing, hereditary cancer, personal, research.

I am back. 2008 were quite important for me – graduated clinical genetics and virtually shifted from traditional-pediatrics based genetics and focused solely to cancer and adult onset disease, also half-sunk in molecular lab – working in best equipped lab with cool people is great. This month will try to handle pyrosequencing and Illumina genotyping, wow.

And defented my long-rolled PhD in tumor cell kinetics and T regulatory cells (enjoy the power of Open Access).

Do you know that 4154delA mutation of BRCA1 gene seems to originated in the Eastern Baltic Sea region of the Northern Europe? Read my and colleagues articles.

Research is the best way to find new health improving strategies. Such example could be  CIMBA –  “Consortium of Investigators of Modifiers of BRCA1/2″) – an international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers. The goal is to find SNPs which could be important in modifing BRCA mutation effects and thus important in clinic for correct genetic risk stratification. A newly formed Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC) currently is activelly recruiting patients from Lithuania and Latvia for the involvement in CIMBA (contact person for LT – me).

Spare time (hm, a night:) is a good for website developing – www.genetika.lt – is my new website in constant progress in lithuanian language to help translate cancer genetics in understandable manner for patients and doctors. This lovely header is creation of this weekend with the genuine help of Gimp buddy:

Von Hippel-Lindau (VHL) disease – a rare tumor predisposing disorder, where targeted surveillance and early diagnostics is crucial for the improved patients survival – is no longer an  “incognito” in my country – developed genetic testing and counseling service will help for these families to get the best from current medical practice. More about VHL.

And for 2009 several new genetic testing are scheduled to come – Familial Adenomatous Polyposis, Multiple Endocrine Neoplasia syndrome (type I and II), Neurofibromatosis type II and Li-Fraumeni syndrome – developing National Hereditary Childhood Cancer Research Platform.

Thats for now – greetings from Vilnius, European Capital of Culture 2009.


Familial Cancer Database Online | FaCD September 4, 2008

Posted by ramunas in bio-software, cancer genetics, familial cancer, hereditary cancer, Resources, technology.

Familial Cancer Database Online is a very useful online tool for experts in cancer genetics to assist in making a genetic differential diagnosis in cancer patients as well as remind tumor spectrum associated with certain hereditary disorders.

And its dynamic cyberinfrastructure already brings the most updated content in the field of clinical cancer genetics with intention to develop further.

The content was created and is edited by dr. Rolf Sijmons (on the left – during poster presentation at ESHG meeting in Barcelona this year), clinical geneticist and associate professor clinical oncogenetics at the Dept. of Genetics of the University Medical Center Groningen (UMCG), the Netherlands. However, other experts who want to contribute to particular syndrome files are invited to contact the editor; these authors will be listed in the syndrome files they contributed to.

And I’m pleased of being included in the list of contributors for the contribution to rare hereditary disorder called Mosaic Variegated Aneuploidy syndrome, where in addition to other symtomes the risk for several cancers (leukemia, rhabdomyosarcomas and embrional kidney cancers) is increased.

FaCD is intended for free of charge use by health professionals with at least basic knowledge of clinical cancer genetics.

Complexity of Breast Cancer August 20, 2008

Posted by ramunas in breast cancer, cancer genetics, familial cancer, genetic testing, hereditary cancer, research.

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.
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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).

Five SNPs Array Predicts Prostate Cancer | Focus5 (TM) January 17, 2008

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


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.

Happy 2008! | And Briefly About 2007 December 31, 2007

Posted by ramunas in breast cancer, BT Test, cancer genetics, DiaGenic, familial cancer, genetic testing, MammaPrint, Oncotype DX, PC Detect, prostate cancer, sporadic cancer, technology.

(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.
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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.
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Here is probably the most accurate breast&ovarian cancer risk/mutation probability calculation web-application released from Cambridge University Genetic Epidemiology UnitBOADICEA.

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.

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).