Originally published April 6.
By Turna Ray
Researchers from Decode Genetics and Radbound University Nijmegen Medical Center have discovered a SNP that both confers hereditary risk of urinary bladder cancer and is associated with somatic mutations linked to the growth of low-grade tumors. The discovery of this SNP "appears to bridge the divide" between germline and somatic mutations in UBC, according to the researchers.
Decode is hoping to incorporate the recently discovered SNP — a common single-letter variant on chromosome 4p16 called rs798766[T] — as well as several other variants discovered by the company and other researchers, into a multi-gene panel test for UBC, Kari Stefansson, president of research at Decode and senior author on the paper, told Pharmacogenomics Reporter this week.
"Our aspiration is to gather enough variants that confer enough risk to make it into a meaningful genetic test," Stefansson said. "We are still a little bit short of having a sufficiently large risk conferred by these variants to make it into a genetic test, but we have been pulling up more and more. And I expect that within a year we will have enough SNPs that confer sufficient risk to make it meaningful.
"But it's always a judgment call how large this risk has to be before it becomes clinically meaningful," Stefansson added.
Decode's research effort in this area, particularly the discovery of rs798766[T]'s association with UBC, is described in a paper published this week in Nature Genetics.
The SNP rs798766[T] will join a set of four gene markers that have already been linked to UBC in previous studies. These four variants are located at 8q24.21 (30 kb upstream from MYC); 3q28 (near TP63); 8q24.3 (in PSCA); and 5p15.33 (at a locus containing TERT). With the hope of discovering additional SNPs linked to UBC, researchers from Decode and numerous other institutions analyzed a genome-wide association dataset comprising 611 Icelandic UBC patients, and 37,478 controls; they also looked at datasets from nearly 1,300 Icelandic UBC patients and more than 1,800 Dutch controls.
Patient samples were genotyped on Illumina's HumanHap300 or HumanCNV370-Duo BeadChips. After discarding SNPs that did not meet quality-control requirements, the researchers tested more than 300,000 SNPs for links to UBC.
"No SNPs reached our genome-wide significance threshold (P Nature Genetics paper. "However, the most significant marker in this analysis was the previously reported marker at 8q24.21, rs9642880 (odds ratio (OR) = 1.22,P = 2.5 × 10−7)." The variant located at 3q28 was among the top 20 markers, but SNPs on 8q24.3 or 5p15.33 did not fall among the top ranking SNPs.
According to the paper, the researchers had already tried to replicate eight of the markers in the top 20. As such, they focused on genotyping the 12 markers that hadn't been analyzed previously in control samples from patients in Italy, the UK, Spain, Sweden, Belgium, Germany, Eastern Europe, and the Netherlands.
"Of these 12 follow-up markers, one, rs798766 on chromosome 4p16.3, replicated in the combined follow-up groups (P = 8.5 × 10−8) and reached genome-wide significance in the overall analysis of the discovery and follow-up groups (OR = 1.24, 95% CI 1.17–1.32, P = 9.9 × 10−12)," the researchers state in the paper.
In further analysis, looking at rs798766's association with the other top-ranking SNPs, researchers reported that "although rs798766 is strongly correlated (r2 > 0.8) with 20 other HapMap CEU SNPs in the region, none of those SNPs showed stronger association with UBC than rs798766."
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The study found that patients who carry rs798766[T] are at 25 percent greater risk of developing UBC per copy carried than are non-carriers. The 5 percent of patients in the study who are at highest risk from this combination of five markers are at approximately 60 percent greater than average risk of UBC. The average lifetime risk of UBC is about 4 percent for men in the US, Decode estimates.
The researchers noted in the paper that the rs798766 variant was located in a linkage disequilibrium block that is centromic to and 70 kb away from an LD block that contains FGFR3. "This gene has a strong link with UBC, as activating somatic mutations in FGFR3 are the most common mutations in low-grade bladder tumors that do not invade the submucosa, where they have been found in 84 percent of cases and in 74 percent of stage-Ta UBC tumors overall," the researchers pointed out in the paper.
Attempting to hone in on the prognostic value of this newly discovered SNP, the researchers then looked at whether the frequency of rs7987669[T] differed among UBC subtypes. They reported that in combined analysis on nine samples sets, the frequency of rs798766[T] was significantly higher in patients with low risk of progression than in those with high risk of progression. Furthermore, rs798766[T] was also found to be
associated significantly with a younger age at diagnosis of UBC.
Additionally, immunohistochemistry was used to assess the level of FGFR3 protein in stage-Ta UBC tumors, scoring the tumors as having low or high levels of FGFR3. Researchers found that patients with high levels of FGFR3 in their tumors had a higher frequency of rs798766[T] than the patients with low levels of FGFR3.
The researchers conclude in the paper that their findings suggest that increased expression of FGFR3, either by germline variation or by downregulation of microRNAs targeting FGFR3 RNA, may lead to the development of UBC. "First, increased production of FGFR3 protein may increase the rate of urothelial proliferation and thus facilitate the accumulation of mutations that contribute to UBC development," the researchers state in the paper. "Second, increased transcription may increase the chance of mutation in the FGFR3 gene itself.
"Further work will be needed to elucidate the link between germline variation at the TACC3-FGFR3 locus and urinary bladder carcinogenesis," the team observed.
As Decode continues to hone in on gene markers linked to UBC, Stefansson expects that the company "will have more than enough to put together a good test within a year."
Stefansson added that the discovery of rs798766[T] and its association to UBC offers a "more holistic view" of the pathogenesis of a common form of cancer and has not just diagnostic, but therapeutic implications.
"The fact that there is a link between germline and somatic mutations [in rs798766[T]] does not have a large implication when it comes to diagnostics," he explained. "But when you are putting together a drug to try to treat a tumor on the basis of discoveries like this, it becomes clear that the drugs could not only be used for intervention but also for prevention."
Although Decode is no longer in the drug development business, the company is open to partnering with pharmaceutical companies on this and other findings, Stefansson added.
If Decode succeeds in developing a test for UBC, it would join its current portfolio of genetic tests, which currently includes a test for prostate cancer, glaucoma, type 2 diabetes, atrial fibrillation, myocardial infarction, and breast cancer.
Approximately 70,000 people in the US are diagnosed with bladder cancer annually, and more than 14,000 people will die of the disease. While approximately half of all UBC cases result in low-grade tumors and treatment is initially successful, tumors often recur.
The researchers noted that while this study focused on patients of European descent, incidence of UBC varies between ethnicities. "It is our hope that the publication of these findings will contribute to the swift analysis of the impact of these variants in cohorts of other continental ancestries," the researchers said in a statement.