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Colon cancer gene expression | Genomic Health January 30, 2008

Posted by ramunas in cancer genetics, colon cancer, genetic testing, sporadic cancer.
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The producers (Genomic Health) of breast cancer recurrence 21 gene expression test Oncotype DX (launched in 2004) recently reported the results of two studies, which found genes that could help predict the likelihood of recurrence of and chemotherapy benefit for early-stage colon cancer (via).

Results of the studies were presented January 26, 2008 at ASCO GI, the American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium, in Orlando, Florida.

Both study reports used Genomic Health’s quantitative RT-PCR to analyze RNA expression for 375 cancer-related and reference genes from colon tumors of patients who were treated with surgery alone or with surgery and adjuvant 5-fluorouracil/leucovorin (5-FU/LV) chemotherapy (ref.).

In first study (765 + 270 patients) and researchers found 65 genes significantly associated with colon cancer recurrence across – the individual gene expression was associated with an up to 11-fold difference in the risk of disease recurrence (via).

The second study analyzed colon cancers from an additional 508 patients who were treated with surgery plus 5-FU/LV chemotherapy. Fifty six genes were discovered that were significantly associated with disease prognosis for stage II and III colon cancer

Fifteen of the 56 genes were also used as a preliminary model to stratify patients into recurrence-risk categories (via).

Overall, Genomic Health has completed four independent studies involving 1,851 colon cancer patients to evaluate a total of 761 genes. This data will support the selection of the final gene set (ref).

Not long is to wait for the new test (an analog to breast cancer Oncotype DX) to personalize treatment decisions for early-stage colon cancer patients.

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deCODE’ing Predisposition to Cancer November 17, 2007

Posted by ramunas in breast cancer, cancer genetics, colon cancer, deCODE, genetic testing, prostate cancer.
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Today launched personal genomics service of Icelandic company de CODEdeCODEme – 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.

– Colorectal cancer. Includes the variants on chromosome 8 and in the SMAD7 gene and interpretation of their associated risk for the development of colorectal 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):

Gene’s Mountains and Hills | Cancer October 21, 2007

Posted by ramunas in breast cancer, cancer genetics, colon cancer, research.
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A picture of huge (and ugly) macro-anatomical sample of cancer is an often finding in some chapters of textbook about cancer genetics. It has no educational value from a present personalized medicine perspective. A picture of expression profiling or mutated genes provides more relevant and contemporary understanding.

Here is how an individual colon cancer from a patient Mx38 looks like (source):

Kind of avantgarde picture in an early 20 century? Don’t worry – it will go mainstream soon like a pop-art cartoon…

A researchers team lead by notorious Bert Vogelstein (co-author of colorectal cancer mutagenesis model) performed (second) amazing study – they sequenced several individual cancers DNA:

In a systematic search of 18,191 genes representing more than 90 percent of the protein-coding genes in the human genome — about 5,000 more than in the first screen — the Johns Hopkins scientists found that most cancer-causing gene mutations are quite diverse and can vary from person to person. They found that an average 77 genes are mutated in an individual colon cancer and 81 in breast cancer. Of these, about 15 are likely to contribute to a cancer’s key characteristics, and most of these genes may be different for each patient (via).

These data suggest a genetic landscape dominated by genes that each are mutated in relatively few cancers:

“There are gene ‘mountains’ represented by those that are frequently altered and have been the focus of cancer research for years, in part because they were the only genes known to contribute to cancer,” says Bert Vogelstein, M.D., an investigator at the Howard Hughes Medical Institute and co-director of the Ludwig Center at Johns Hopkins. “Now, we can see the whole picture, and it is clear that lower peaks or gene ‘hills’ are the predominant feature.

It looks like “few mountains surrounded by many hills.”

Surprisingly, they found that an average 77 genes are mutated in an individual colon cancer and 81 in breast cancer. Of these, about 15 are likely to contribute to a cancer’s key characteristics, and most of these genes may be different for each patient.

Lot of texbooks state, that c.a. 7-8 genes are mutated in colon cancer. And they were ten-fold  wrong: mutations in 77 for colon and 81 genes for breast cancer are required to develop.

The scientists say that directing therapies at common pathways that are linked by both prevalent and rare gene mutations is a better approach than aiming treatments at specific genes. They also note that personalized cancer genomics paves the way for tailored therapies and diagnostics focusing on the alterations identified in a particular patient’s cancer. Many of the mutations identified by scientists could be important in developing individualized cancer vaccines and monitoring patients for early recurrence of their disease.

A BRAF Story | Colorectal, Thyroid CA and Melanoma September 6, 2007

Posted by ramunas in cancer genetics, colon cancer, colorectal cancer, genetic testing, hereditary cancer, HNPCC, sporadic cancer.
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For the first time I’ve read about BRAF oncogene in a poster presented during one of the European Society of Human Genetics conference, probably in Amsterdam, Holland. It appeared that a single amino acid substitution (p.V600E), a hotspot point mutation, is an useful marker to exclude HNPCC (hereditary non-polyposis colorectal cancer). Interestinlgy, this somatic mutation of BRAF gene, which belongs to the RAF family of protein kinases from the RAS/RAF/MAPK pathway, is more than 90% present in sporadic colorectal cancers with methylated hMLH1 gene. Therefore, if you have access to a tumor DNA after simple PCR test you can exclude or suspect hereditary form of this cancer. The detection of a positive BRAF-V600E mutation in a colorectal cancer suggests a sporadic origin of the disease and the absence of germline alterations of MLH1, MSH2 and also of MSH6. These findings have a potential impact in the genetic testing for HNPCC diagnostics and suggest a potential use of BRAF as exclusion criteria for HNPCC or as a molecular marker of sporadic cancer (via).

Obviously, the confirmation should be done by testing for germline mutations mismatch repair (MMR) genes (mostly MLH1, MSH2, MSH6). Also, immunohistochemistry may point you which protein is missing. The Bethesda guidelines , original (1997) and revised (2003), are designed to select cases for analysis of microsatelite instability (MSI) features of tumor, but testing for BRAF mutation can yield additional and faster information.

Conventional strategy for genetic testing of affected individuals from families with suspected hereditary non-polyposis colorectal cancer (source):

However,

Screening of mismatch repair (MMR) genes can be avoided in cases positive for V600E if no other significant evidence, such as fulfilment of the strict Amsterdam criteria, suggests MMR associated HNPCC. In this context, mutation analysis of the BRAF hotspot is a reliable, fast, and low cost strategy which simplifies genetic testing for HNPCC, one article states.

That is a story about colorectal cancer, but it was interesting for me to find out, that the same mutation of BRAF oncogene can be present in thyroid cancer. That may be useful in predicting the level of aggression of thyroid cancer and help guide treatment options and follow-up care, says the new research paper published in the September issue of the “Annals of Surgery”.

Researchers concluded, that BRAF V600E mutation is primarily present in conventional papillary thyroid cancer. It is associated with an aggressive tumor phenotype and higher risk of recurrent and persistent disease in patients with conventional papillary thyroid cancer. Testing for this mutation may be useful for selecting initial therapy and for follow-up monitoring.

Study author, Kebebew E, explained that identification of the mutation in patients with thyroid cancer could be very useful in a variety of ways. For example, patients with the mutation may be candidates for a more aggressive approach to surgery, such as removing the central lymph node along with the diseased thyroid, to avoid the possibility of metastasis following surgery. BRAF V600E testing could also be useful for deciding between low- or high-dose radioiodine ablation therapy.

Other BRAF mutations are found in melanoma and BRAF possitive tumors may be more sensitive to a new class of drugs – protein MEK inhibitors (such as PD0325901, developed by Pfizer Research and Development).

Association With Prostate and Colon Cancer | 8q24 August 7, 2007

Posted by ramunas in cancer genetics, colon cancer, familial cancer, genetic testing, prostate cancer.
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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 group (from infamous deCODE Genetics, Iceland) reported region 8q24, identified through a genome-wide linkage scan study of Icelandic prostate cancer (PrCA) families [1]. 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 [2].
  • On April 2007 a study from US further confirms the importance of these two polymorphic variants (rs1447295 and DG8S737) as risk factors for PrCA [3].

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 [10].

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]

References:

  1. Laufey Amundadottir et al. A common variant associated with prostate cancer in European and African populations, Nat Genet 38 (6), 652-8 (Jun 2006)
  2. 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
  3. 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)
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  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.
  9. 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.
  10. 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]

New Gene Expression Profiling Tests| Colon Cancer July 26, 2007

Posted by ramunas in cancer genetics, colon cancer, ColoPrint, genetic testing, sporadic cancer.
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Here is fresh news: during the 9th World Congress on Gastrointestinal Cancer in Barcelona Dr. Laura van ‘t Veer, co-founder and Chief Research Officer of Dutch genomic profiling company Agendia (which already offers MammaPrint and CupPrint gene expression profiling (GEP) tests), presented unpublished study data about developed robust gene expression signature that can predict the risk of colon cancer relapse and recurrence. The prognostic profile outperforms traditional clinicopathological risk assessment factors currently used by physicians to make treatment decisions [via].

“Our results show that the microarray gene expression profile we are now developing for colon cancer is able to identify stage II colon cancer patients who have a high risk of experiencing a recurrence of their disease within the next years. This may facilitate the identification of patients who would benefit most from adjuvant chemotherapy. The gene expression profile is currently being tested on further validation samples for translation into a high-throughput diagnostic test readily available for clinical practice.”

This new commercial ColoPrint test will be out early 2008 and is principally based on the same technology as recently FDA approved MammaPrint test and will be its follower. Meanwhile, California based GenomicHealth company has announced that it will move one of its research projects, a test to predict the likelihood of colon cancer recurrence, into full-scale clinical development and intends to follow a similar clinical development path as it did for its Oncotype DX breast cancer assay.

Note: The published literature on GEP tests primarily consists of validation studies to identify the optimal set of cancer-related genes. Also prospective clinical trials testing the utility of these techniques have yet to be reported, but there is no doubt that the use of gene microarrays or RT-PCR analysis of RNA will play an important role in providing information regarding prognostic and predictive characteristics of subsets of cancer patients [ref.].