Prostate Cancer | Old&New SNPs and deCODEPrCa February 15, 2008Posted 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, 2008Posted 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.
Five SNPs Array Predicts Prostate Cancer | Focus5 (TM) January 17, 2008Posted 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.
A New Tumor Markers & Targets January 3, 2008Posted by ramunas in breast cancer, liver cancer, prostate cancer, pten, research.
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.)
Happy 2008! | And Briefly About 2007 December 31, 2007Posted 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)
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.
deCODE’ing Predisposition to Cancer November 17, 2007Posted by ramunas in breast cancer, cancer genetics, colon cancer, deCODE, genetic testing, prostate cancer.
Today launched personal genomics service of Icelandic company de CODE – deCODEme – totally surprised me. That was a smash for 23andMe and Navigenics, I think. For a promotional price for the Genetic Scan for $985 (plus sales tax / VAT) users can receive a bunch of information regarding personal genome variation, or SNP’s (discovered mainly in companies own studies and replicated by others), which can predispose to as much as 17 common disease (colorectal, prostate and breast cancers included), eye color, your hair color and many other physical attributes and also discover the origin of ancestry. Wow, kind of social-genomic-network!
I’ve jumped inside deCODEme portal, and will briefly summarize oncological side of this service (disclaimer: most of the text bellow can be found inside deCODEme portal after logging).
The deCODEme genome scan test for these common genetic variants related to these onco-disease:
– 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 risk to the development of breast cancer.
Note: Strongly acting mutations (like in BRCA1/2 genes) comprise a small percentage of breast cancer cases (2-5%). Variants that are more common but carry less risk play a role in a much larger proportion of cases, perhaps in almost all breast cancer cases. Such variants may individually be quite common with each one alone having little effect on breast cancer risk. However if a person inherits many of these variants, the risks from them might combine to produce a substantial increase in the individual’s overall risk. Combinations of these common breast cancer risk variants may or may not show up as an obvious family history of breast cancer.
Note: It has been estimated that up to 30% of colorectal cancers may be due to genetic factors. A fraction (~5%) of colorectal cancer cases occur in families with multiple cases of the disease and appear to be inherited in a dominant manner. An example of such condition is multiple polyposis of the colon, where the inner surface of the colon is covered with thousands of polyps. These cases are in some instances known to be caused by specific mutations in genes that increase the risk of the disease substantially (up to 100%). Individuals belonging to such families should seek counselling about preventive measures. The deCODEme genome scan does not include the rare highly familial cancer genes such as APC, MLH1, MSH2, MSH6, and PMS2. Variants that are more common, but confer less risk, play a role in a much larger proportion of colorectal cancer cases. Such variants may individually be quite common with each one alone having little effect on the colorectal cancer risk. However if a person inherits many of these variants, the risks from them might combine to produce a substantial increase in the individual’s overall risk. To date two common genetic variants have been found that increase the risk of developing colorectal cancer. These are variants on chromosome 8, not close to any known gene, and in the SMAD7 gene on chromosome 18.
– Prostate cancer. Includes the three variants from the 8q24 region and the two from chromosome 17 and an interpretation of their associated risk of developing prostate cancer.
Note: Prostate cancer has been shown to have the strongest genetic component of all cancers. To date several genetic variants have been discovered to increase the risk of developing prostate cancer. These are three variants in the chromosome 8q24 region that lacks any know genes, and two on chromosome 17, one of which is in the TCF2 gene.
Other reviews (updated):
Novel Immune Biomarker | Prostate Cancer August 16, 2007Posted by ramunas in cancer genetics, prostate cancer, research.
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Being also involved in cancer immunology, this article from Mayo Clinic published in Cancer Research last week, is of great interest for me – researchers for the first time have identified immune molecule B7-H3 as a biomarker, that appears to play a role in prostate cancer development and in predicting cancer recurrence and progression after surgery.
This study demonstrate that nearly all normal, pre-malignant and cancerous prostate cells have B7-H3 on their surface. Unlike PSA, B7-H3 stays attached to the surface of prostate cancer cells and does not appear to migrate, thus making B7-H3 a particularly attractive target for therapy. The researchers believe that B7-H3 kills or paralyzes immune cells that are trying to attack the cancer. Their findings indicate that B7-H3 may prove useful as a diagnostic, prognostic and even therapeutic tool because it is stably or increasingly displayed by tumor cells as prostate cancers develop — even after initiation of anti-hormone therapy, which is the most common treatment for advanced prostate cancer, says EurekaAlerts.
The physician-research team examined tissue from 338 consecutive patients who had cancers confined to the prostate and were treated exclusively with a radical prostatectomy (surgery to remove the prostate) between 1995 and 1998. All tumors and precancerous tissues displayed B7-H3, but patients with the highest levels of B7-H3 within their prostate tumors (19.8 percent) were four times more likely to experience cancer progression compared to those with weak levels of B7-H3 within their tumors. Moderate levels of B7-H3 also correlated with a slightly higher risk of recurrence (35 percent) (via).
B7-H3, a member of the B7 family of the Ig superfamily proteins, is expressed on the surface of the antigen-presenting cells and down-regulates T cell functions by engaging an unknown counterreceptor on T cells [ref.]. Mayo Clinic Cancer Center was the first to discover the B7-H family of immune molecules in 2001. They showed that B7-H3 and other members of the B7-H family, such as B7-H1, can have an inhibitory function and actually protect cancers as they develop [via].
To understand how B7-H3 affects the immune system, and whether a mutation of B7-H3 is involved in the anti-immune activity, more research is necessary. Mayo is planning clinical trials for a number of cancers in late 2008, and researchers are currently developing the necessary therapeutic antibodies to be used in these studies. Investigators expect that clinical laboratory tests for the B7-H proteins may become available at Mayo to assist with the assessment of patients with kidney cancer by late 2007 or early 2008, and then for prostate cancer patients shortly thereafter [ref.] .
Well, B7-H3 molecule is already patented (what a shame!) not only by Mayo, who already holds patents to B7-H1, B7-B4 (check it here) and has licensed the patent rights to Medarex, Inc., but also by pharmaceutical company Wyeth for use as immunoregulatory agent (here it is). In addition, Mayo Clinic has filed a patent application related to B7-H3. Drs. E. Kwon, T. Roth and Y. Sheinin and Mses. C. Lohse and S. Kuntz are inventors of this technology. Track it further on PatentLens or Google Patent Search.
(photo source: B7-H3 immunohistochemistry)
Association With Prostate and Colon Cancer | 8q24 August 7, 2007Posted by ramunas in cancer genetics, colon cancer, familial cancer, genetic testing, prostate cancer.
Recent two years were (and continues to be) very prolific in the research of common genetic variants, implicated in cancer, notably breast, prostate and colon. In this post I’ll summarize advances surrounding 8q24 region and its importance in prostate and colon cancer. All data of conducted association studies were published in high impact factor journals and repeatedly confirmed by independent researchers in different populations what means there is really something in the region 8q24.
In 2006 two variants of chromosome 8q24 were reported to be associated with increased risk of prostate cancer (PrCA):
- Dr. Kari Stefansson groupreported region 8q24, identified through a genome-wide linkage scan study of Icelandic prostate cancer (PrCA) families . Common variant allele -8 (microsatellite DG8S737 ) was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US – odds ratio (OR) 1.79 for Icelandic patients. The frequencies of the DG8S737 -8 allele and the rs1447295 A allele were significantly greater in the men with prostate cancer. In the Icelandic samples, allele -8 of DG8S737 and allele A of rs1447295 were substantially correlated. The combined results for the European groups yielded an estimated OR of 1.62 for DG8S737 -8 and an OR of 1.51 for rs1447295 A. Genotyping of African American men with prostate cancer with controls resulted in the odds ratio 1.60. The estimated population attributable risk for the – 8 allele (DG8S737) was 16% among African-Americans versus 5% to 11% among men of European ancestry. The “relatively high” population frequency of the – 8 allele in African Americans, “which confers an estimated population attributable risk of about 16% and could alone produce more than a 10% greater incidence of prostate cancer in African Americans than in European Americans,” the authors suggest [via].
In all four case-control groups, the frequency of cancers with DG8S737 -8 was significantly greater in men with PrCA with higher Gleason scores than among those with lower scores and might have a stronger association with the more aggressive forms.There is no immediate clinical impact of the finding, researchers said, because it applies to the population at large rather than individuals.
- On March 2007 Australian population-based case-control study concluded that the A allele of rs1447295 is associated with a higher risk of PrCA regardless of tumor aggressiveness, suggesting that such a variant, or a variant in linkage disequilibrium with it, plays a role early in prostate carcinogenesis .
- On April 2007 a study from US further confirms the importance of these two polymorphic variants (rs1447295 and DG8S737) as risk factors for PrCA .
A recent three new reports [4-6] have independently found multiple neighboring regions (rs1447295, rs16901979 and rs6983267) within a 600-kb segment of chromosome 8q24 that harbor variants associated with disease which are summarized in this scheme from review by John Witte in Nature Genetics:
The rs1447295 location could be responsible for about 7 % of PrCA cases in white men of north European descent. Thus, taken together with rs6983267, these two genetic changes could account for as much as one quarter of prostate cancer cases in white men. The increased risk conferred by these loci was observed for all age groups studied [via].
Around seven SNP’s in 8q24 play a significant role in prostate cancer [via, also Ref. 4, 6].
So, it was known that variants on chromosome 8q24 contribute risk for prostate cancer, but Haiman CA et al. decided to test whether they also modulate risk for colorectal cancer (ColCA). Interestingly, SNP rs6983267 was also significantly associated with ColCA (odds ratio = 1.22; P = 4.4 x 10(-6)).
In July 8 online edition of Nature Genetics there are even three independent replication studies published for rs6983267 and ColCA from US, UK and Canada [7-9].
The number of people who carry the variant on region 8q24 includes about half of the populations studied, researchers say. “In other words, it is very common in the general population,” said Dr. Malcolm Dunlop, of Cancer Research UK and the University of Edinburgh, Scotland. [via]
Overall, carriers of this variant have about a 20 percent higher risk of developing a colorectal malignancy compared to non-carriers, Dunlop team reports. Between 4 to 9 percent of all bowel cancers” may be traced to this particular (8q24) chromosomal locus [via].
Similar results were found in a U.S. study that was led by Christopher Haiman of the University of Southern California, Los Angeles: the rs6983267 variant conferred about a 22 percent increase in colorectal cancer risk [via].
“This is the first common genetic risk factor that has been reproducibly associated with risks in multiple cancers,” Haiman told reporters. “The association observed with this variant in both prostate and colorectal cancer provides very strong support for the hypothesis that there may be a common biological mechanism underlying cancer risk in this region of the genome.”
However, rs6983267 was found more frequently in some ethnicities than in others. “The frequency of this specific genetic variation varies widely in the population — from about 85 percent of African-Americans to as low as 30 percent of Japanese,” Haiman said.
“Although individually these markers may only contribute small amounts of risk, collectively, in certain individuals, they may actually have composite risks which are comparable to that of known, high-risk [mutations],” explained Dr. Richard Houlston, of the Institute of Cancer Research in Sutton, U.K. [via]
A consortium from Israel, Spain and the United States – uncovered a similar connection between genetic variations on 8q24 and a rise in colon cancer risk .
Chromosome 8q24 harbors oncogenes known to be involved in pathogenesis of colorectal cancer as well as uncharacterized genetic variants that have recently been shown to influence inherited risk of prostate cancer.
“These are encouraging findings, but obviously we need a lot more information about the genetic implications,” said Dr. Durado Brooks, the society’s director of prostate and colorectal cancer. “Genetic tests that might assess people’s risk or help in cancer diagnosis are still years away, and, for now, the new finding will not in any way significantly alter clinical practice. Ideally tests might someday be developed to spot genes like rs6983267, such that you could tailor interventions such as more intensive [patient] surveillance and even prevention. This is big step forward, but there is more to come.”he said. [via]
- Laufey Amundadottir et al. A common variant associated with prostate cancer in European and African populations, Nat Genet 38 (6), 652-8 (Jun 2006)
- Gianluca Severi et al. The common variant rs1447295 on chromosome 8q24 and prostate cancer risk: results from an Australian population-based case-control study, Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):610-2
- Liang Wang et al. Two Common Chromosome 8q24 Variants Are Associated with Increased Risk for Prostate Cancer Cancer Research 67 (7), 2944-50 (01 Apr 2007)
- Gudmundsson J et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet. 2007 May;39(5):631-7. Epub 2007 Apr 1.
- Haiman CA et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007 May;39(5):638-44. Epub 2007 Apr 1.
- Yeager M et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet. 2007 May;39(5):645-9. Epub 2007 Apr 1.
- Haiman CA et al. A common genetic risk factor for colorectal and prostate cancer. Nat Genet. 2007 Aug;39(8):954-6. Epub 2007 Jul 8.
- Tomlinson I et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet. 2007 Aug;39(8):984-988. Epub 2007 Jul 8.
- Zanke BW et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet. 2007 Aug;39(8):989-994. Epub 2007 Jul 8.
- Gruber SB et al. Genetic Variation in 8q24 Associated with Risk of Colorectal Cancer. Cancer Biol Ther. 2007 Jul 2;6(7) [Epub ahead of print]