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

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]