Prostate Cancer Complexity

The Mormons' religious beliefs have proven to be quite a boon for cancer epidemiologists. Members of the Church of Jesus Christ of Latter-day Saints, following religious tenets, have meticulously recorded their family trees for centuries. Recognizing the research value of such data, Mark Skolnick, chief scientific officer at Myriad Genetics Inc. in Salt Lake City, computerized those records at the church's family history library 25 years ago. Recently, researchers had high hopes that the data wo

Apr 30, 2001
Eugene Russo
The Mormons' religious beliefs have proven to be quite a boon for cancer epidemiologists. Members of the Church of Jesus Christ of Latter-day Saints, following religious tenets, have meticulously recorded their family trees for centuries. Recognizing the research value of such data, Mark Skolnick, chief scientific officer at Myriad Genetics Inc. in Salt Lake City, computerized those records at the church's family history library 25 years ago. Recently, researchers had high hopes that the data would help them track down genes linked to prostate cancer.

Those hopes have been whittled down. So far, comprehensive family histories haven't elucidated the cancer's hereditary underpinnings--the genetic component of prostate cancer continues to confound loci researchers. And, these researchers are not the only ones scratching their heads. Those studying genes involved in prostate cancer tumorigenesis have been able to find only a few tumor suppressor genes specific to prostate cancer, which was diagnosed in 170,000 men last year. "There are a lot of ideas about how to pursue prostate cancer," says William Foulkes, an assistant professor of medicine at McGill University. "But it's not obvious that there's any new technique out there that's going to solve the problems suddenly."

Unlike colon or breast cancer research, research into prostate cancer, which killed 31,000 men in 2000, hasn't yet uncovered genes that provide real prognostic value. Studies investigating tumorigenesis, for example, speak to the biology of the cancer itself; they are potentially useful for drug targeting but may not elucidate clinical markers. And, linkage studies can't directly show the genes that would have the greatest impact on understanding and treating most prostate cancer cases because they are acquired, not familial. Researchers estimate that familial genes explain between one and 10 percent of all cases. Investigators hope, however, that confirmed susceptibility loci are also mutated in cases of acquired prostate cancer, and that loci will provide clues for the mechanism of disease onset.

Many Loci, Few Genes

University of Utah prostate cancer researchers, in collaboration with Myriad Genetics, spent years comparing the DNA of individuals and their relatives. They found that a piece of chromosome 17 segregated to affected people. Then, they gradually honed in on smaller regions of the chromosome by comparing the different-sized chromosome pieces that segregated in different pedigrees. With enough families and enough chromosome pieces, they were able eventually to narrow the region down to a single candidate gene, a suspected prostate cancer susceptibility locus.1

Yet, as with nearly all susceptibility loci identified thus far, confirmation in other families has been elusive. The locus on chromosome 17, called ELAC2, is one of five susceptibility loci identified. Analyzing everything from large pedigrees to smaller sets of sibships, researchers have identified loci on chromosomes 1, 20, and X. Only ELAC2 (also called HPC2) and HPC1 on chromosome 1 have received any substantial level of confirmation, and only ELAC2 has been cloned.

Two recent papers actually shed doubt on the validity of ELAC2 as a true prostate cancer susceptibility locus.2,3 Foulkes suggests that, taken together, the evidence is scant. "I think [it's] a big blow because people were hoping that ELAC2 was the real thing," he comments. Foulkes co-authored a review article last year provocatively titled "High risk genes predisposing to prostate cancer development--do they exist?"4

"When we started [investigating] prostate cancer, we didn't think it was going to be anything like this difficult," says Lisa Cannon-Albright, senior author of the February ELAC2 paper and a professor of genetic epidemiology at the University of Utah. "We found these big pedigrees, lovely segregation. We were very confident that it was going to be very straightforward, and similar to breast cancer. But that's not at all the case." Albright says half a dozen or so prostate cancer research groups have attempted to confirm each other's data in recent years with little success.

"I think everybody had the notion that this was going to be difficult," says Stephen Thibodeau, the chair of experimental pathology at the Mayo Clinic in Rochester, Minn. "But certainly I think a lot of people are surprised how little information has come out of the linkage studies and how difficult it's been to confirm some of these observations." Thibodeau's group and collaborators have been working on trying to refine an area of linkage on chromosome 20, an area they singled out last summer.5 Despite generating a physical map of the region, and identifying transcripts within the region, they have no gene. A March paper by Thibodeau's group and collaborators at the University of Michigan reported that after studying an additional 172 families, they could not provide statistically significant support for a locus at chromosome 20.6

Foulkes contends that finding an X chromosome gene may be more likely. A group headed by Jeff Trent, chief of the cancer genetics branch at the National Human Genome Research Institute (NHGRI), first reported an X chromosome locus in 1998.7 Foulkes cites epidemiological evidence that brothers are more likely to have prostate cancer than are fathers and sons, suggesting susceptibility could be X-linked.

Right now, the greatest hope may lie with HPC1. Albright hopes to start collaborating with HPC1 investigators Trent and William Isaacs, a urologist at Johns Hopkins University, to find the gene itself. "I have this feeling that if we put our heads together, we could find [the gene]," says Albright. Lawyers from Myriad Genetics and NHGRI collaborator Genzyme Corp. are trying to hammer out an agreement. Thibodeau says that about half of the studies on HPC1 show evidence for linkage, and half do not. HPC1 is the only site that has been the subject of an extensive meta-analysis by the International Consortium on Prostate Cancer Genetics. An analysis of some 700 families backed up initial observations.

Started by the NCI in 1995 and currently chaired by Isaacs, the consortium has facilitated the sort of large-scale, international collaboration that figures to be essential for boosting linkage confirmation power. Albright notes that such collaboration is in sharp contrast to the cutthroat competition characteristic of the field of breast cancer genetics. Members of the consortium, which meets once or twice a year, recently submitted a grant request to the National Institutes of Health that would pay for the creation of a joint dataset to be stored indefinitely and accessed and analyzed by multiple groups.

Turning to Tumors

Studying family histories is only one way to try to decipher prostate cancer genetics. Investigators also study prostate cancer tumors, in hopes of discovering which genes are critical for staving off cancerous cells; in contrast with linkage specialists, they pay less attention to the origins of those mutations. Thibodeau, however, says that the two areas are complementary. For example, a tumor suppressor gene mapped to a chromosome may suggest a candidate susceptibility locus.

Although recent findings have been encouraging, evidence remains minimal here too. "We know very little, and the little we know is obvious," says Pier Paolo Pandolfi, head of molecular and developmental biology at Memorial Sloan-Kettering Cancer Center in New York. Two of the known prostate cancer tumor suppressors, p53 and Rb, are commonly mutated in many cancers, so, not surprisingly, are mutated in prostate as well. Because they're so commonly mutated, their causal role for prostate cancer remains unclear. Pandolfi's group recently demonstrated that knocking out the tumor suppressors p27 and Pten leads to prostate cancer in a mouse model, findings that could lead to drug targets.8 The putative tumor suppressor Nkx3.1, first shown to have a functional role in prostate cancer in mice by researchers at the Center for Advanced Biotechnology and Medicine in Piscataway, N.J., appears to be the only prostate cancer tumor suppressor that's tissue-specific, according to the group's ongoing research.9

Earlier this month, an international collaboration of investigators, using tissue arrays to scan hundreds of tumors, identified a candidate tumor suppressor called ANX7.10 Senior author Harvey B. Pollard, the chair of anatomy and cell biology at the Uniformed Services University School of Medicine, says that the ANX7 could have prognostic value based on its apparent mechanistic role; it promotes apoptosis by affecting intracellular calcium stores, signals critical to coaxing cell death or division.

Also critical in the case of prostate cancer: discovering the genetic origins of tumor metastasis. As with many cancers, prostate cancer does not pose its greatest threat in situ, but when it spreads and metastasizes. Prostate cancer cells have an unexplained affinity for bone. If caught early before metastasis, prostate cancer is effectively treated with surgery and radiation.

Trying to explain and predict metastasis is yet one more piece of an exceedingly complicated puzzle that has thus far baffled researchers. Albright concedes that environmental or other gene interactors might be more important in the case of prostate cancer than genetically well-described cancers such as breast or colon. But her intuition, based on tracking lineages, is that it's as familial or more familial than breast cancer. "The picture is actually way more complex than breast cancer," she comments. "But that's what we're all going to say while we're not successful--'It's because it's so complex.'"

Eugene Russo can be contacted at
1. S.V. Tavtigian et al., "A candidate prostate cancer susceptibility gene at chromosome 17p," Nature Genetics, 27:172-80, February 2001.

2. J. Xu et al., "Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer," American Journal of Human Genetics, 68:901-11, April 2001.

3. D. Vesprini, "HPC2 variants and screen-detected prostate cancer," American Journal of Human Genetics, 68:912-7, April 2001.

4. Singh et al., "High risk genes predisposing to prostate cancer development - do they exist?" Prostate Cancer Prostatic Diseases, 3:241-7, 2000.

5. R. Berry et al., "Evidence for a prostate cancer-susceptibility locus on chromosome 20," American Journal of Human Genetics, 67:82-91, July 2000.

6. C.H. Bock et al., "Analysis of the prostate cancer-susceptibility locus HPC20 in 172 families affected by prostate cancer," American Journal of Human Genetics, 68:795-801, March 2001.

7. J.F. Xu et al., "Evidence for a prostate cancer susceptibility locus on the X chromosome," Nature Genetics, 20:175-9, October 1998.

8. A. Di Cristofano et al., "Pten and p27(KIP1) cooperate in prostate cancer tumor suppression in the mouse," Nature Genetics, 27:222-4, February 2001.

9. R. Bhatia-Gaur et al., "Roles for Nkx3.1 in prostate development and cancer," Genes and Development, 13:966-77, April 15, 1999.

10. M. Srivastava et al., "ANX7, a candidate tumor suppressor gene for prostate cancer," Proceedings of the National Academy of Sciences," 98:4575-80, April 10, 2001.