Million Veteran Program Drives Prostate Cancer Research

About 15,000 veterans are annually diagnosed with prostate cancer. Fortunately, those veterans enrolled in the US Department of Veterans Affairs (VA) Million Veteran Program (MVP) provide researchers with a deep pool of genetic data that can help identify causes, aid diagnosis, and guide targeted treatments.

More than 1,000,000 veterans have enrolled in MVP and donated their anonymized DNA to foster research. It is also one of the most genetically diverse health-related databases: 20% of participants identify as Black, 8% as Hispanic, 2% as Asian American, and 1% as Native American. 

Ethnically and racially diverse data are particularly important for advancing the treatment of underserved groups. In a 2020 review, researchers found a number of areas where Black veterans differed from White veterans, including prostate-specific antigen (PSA) levels, incidence (almost 60% higher), clinical course, and mortality rate (2 to 3 times greater). To facilitate research, the MVP developed the “DNA chip,” a custom-designed tool that tests for > 750,000 genetic variants, including > 300,000 that are more common in minority populations.

“The whole thing about understanding genetics and diversity is like a circular feedback loop,” Director of MVP Dr. Sumitra Muralidhar said in a VA news article. “The more people you have represented from different racial and ethnic backgrounds, the more we’ll be able to discover genetic variants that contribute to their health. The more we discover, the more we can help that group. It’s a complete circular feedback loop.”

In addition to veterans’ blood samples and 600,000-plus baseline surveys on lifestyle, military service, and health, the MVP has collected upwards of 825,000 germline DNA samples, which have helped inform research into prostate cancer, the most commonly diagnosed solid tumor among veterans. By mining these data, researchers have built more evidence of how genes add to risk and disease progression.

In one study preprint that has not been peer reviewed, VA researchers investigated the significance of high polygenic hazard scores. The scores are strongly associated with age at diagnosis of any prostate cancer, as well as lifetime risk of metastatic and fatal prostate cancer. However, because they’re associated with any prostate cancer, the researchers say, there is concern that screening men with high polygenic risk could increase overdiagnosis of indolent cancers.

The researchers analyzed genetic and phenotypic data from 69,901 men in the MVP who have been diagnosed with prostate cancer (6413 metastatic). They found their hypothesis to be correct: Among men eventually diagnosed with prostate cancer, those with higher polygenic risk were more likely to develop metastatic disease. 

Genetic risk scores like PHS601, a 601-variant polygenic score, can be performed on a saliva sample at any time during a person’s life, the researchers note. Thus, the scores provide the earliest information about age-specific risk of developing aggressive prostate cancer. These scores might be useful, they suggest, to support clinical decisions not only about whom to screen but also at what age.

Another study led by Stanford University researchers and published in Nature Genetics aimed to make screening more targeted, in this case prostate specific antigen screening. Estimates about PSA heritability vary from 40% to 45%, with genome-wide evaluations putting it at 25% to 30%, suggesting that incorporating genetic factors could improve screening. 

This study involved 296,754 men (211,342 with European ancestry, 58,236 with African ancestry, 23,546 with Hispanic/Latino ancestry, and 3630 with Asian ancestry; 96.5% of participants were from MVP)—a sample size more than triple that in previous work. 

The researchers detected 448 genome-wide significant variants, including 295 that were novel (to the best of their knowledge). The variance explained by genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino ancestry, and 8.6% to 15.3% for Asian ancestry, and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels.

The researchers say their study highlights how including higher proportions of participants from underrepresented populations can improve genetic prediction of PSA levels, offering the potential to personalize prostate cancer screening. Adjusting PSA for individuals’ predispositions in the absence of prostate cancer could improve the specificity (to reduce overdiagnosis) and sensitivity (to prevent more deaths) of screening.

Their findings, the researchers suggest, also explain additional variation in PSA, especially among men of African heritage, who experience the highest prostate cancer morbidity and mortality. They note that this work “moved us closer to leveraging genetic information to personalize PSA and substantially improved our understanding of PSA across diverse ancestries.”

A third study from a team at the VA Tennessee Valley Healthcare System also investigated the risk of inheriting a predisposition to prostate cancer. These researchers explored pathogenic variants using both genome-wide single-allele and identity-by-descent analytic approaches. They then tested their candidate variants for replication across independent biobanks, including MVP.

The researchers discovered the gene WNT9B E152K more than doubled the risk of familial prostate cancer. Meta-analysis, collectively encompassing 500,000 patients, confirmed the genome-wide significance. The researchers say WNT9B shares an “unexpected commonality” with the previously established prostate cancer risk genes HOXB13 and HNF1B: Each are required for embryonic prostate development. Based on that finding, the researchers also evaluated 2 additional genes, KMT2D and DHCR7, which are known to cause Mendelian genitourinary developmental defects. They, too, were nominally associated with prostate cancer under meta-analyses.

Tens of thousands of participants in MVP have had prostate cancer. The genetic research they participate in advances detection, prediction, and treatment for themselves and others, and science in general. The research is not only about finding causes, but what to do if the cancer develops. An “acting on MVP prostate cancer findings” study at VA Puget Sound Health Care System is testing how communicating with veterans about MVP prostate cancer results will affect their care. Those with prostate cancer will be screened to determine genetic contributions to their cancers. Those found to have a gene-based cancer diagnosis will be offered genetic counseling. Their immediate family will also be offered screening to test for inherited prostate cancer risk.

In 2016, the VA partnered with the Prostate Cancer Foundation to establish the Precision Oncology Program for Cancer of the Prostate (POPCaP). In collaboration with MVP and the Genomic Medicine Service, the program uses genetic information to individualize treatments for veterans with advanced prostate cancer. 

US Army Veteran James Perry is one of the beneficiaries of the program. First diagnosed with prostate cancer in 2001, he was initially treated with radiation therapy, but the cancer recurred and spread to his lung. The John J. Cochran Veterans Hospital in St. Louis sent a sample of Perry's lung tumor to the laboratory for genetic testing, where they discovered he had a BRCA1 gene mutation.

His oncologist, Dr. Martin Schoen, recommended Perry enroll in AMPLITUDE, a clinical trial testing the effectiveness of poly-ADP ribose polymerase inhibitors, a new class of drugs to treat hormone-sensitive prostate cancer. One year later, Perry’s lung tumor could barely be seen on computed tomography, and his PSA levels were undetectable.

"I would highly recommend enrolling in a trial," Perry told VA Research Currents. “If a veteran has that opportunity, I would encourage it—anything that is going to give you a few more days is worth it.” In the interview, Perry said he enjoyed being part of the trial because he knows he is getting the most advanced care possible and is proud to help others like himself.

"We are honored to support VA's work to improve the lives of veterans who are living with advanced prostate cancer," Vice President and National Director of the PCF Veterans Health Initiative Rebecca Levine said. "Clinical trials play a vital role in bringing new treatments to patients who need them most. Mr. Perry's experience illustrates VA's commitment to provide state-of-the-art cancer care to all veterans who need it."

About 15,000 veterans are annually diagnosed with prostate cancer. Fortunately, those veterans enrolled in the US Department of Veterans Affairs (VA) Million Veteran Program (MVP) provide researchers with a deep pool of genetic data that can help identify causes, aid diagnosis, and guide targeted treatments.

More than 1,000,000 veterans have enrolled in MVP and donated their anonymized DNA to foster research. It is also one of the most genetically diverse health-related databases: 20% of participants identify as Black, 8% as Hispanic, 2% as Asian American, and 1% as Native American. 

Ethnically and racially diverse data are particularly important for advancing the treatment of underserved groups. In a 2020 review, researchers found a number of areas where Black veterans differed from White veterans, including prostate-specific antigen (PSA) levels, incidence (almost 60% higher), clinical course, and mortality rate (2 to 3 times greater). To facilitate research, the MVP developed the “DNA chip,” a custom-designed tool that tests for > 750,000 genetic variants, including > 300,000 that are more common in minority populations.

“The whole thing about understanding genetics and diversity is like a circular feedback loop,” Director of MVP Dr. Sumitra Muralidhar said in a VA news article. “The more people you have represented from different racial and ethnic backgrounds, the more we’ll be able to discover genetic variants that contribute to their health. The more we discover, the more we can help that group. It’s a complete circular feedback loop.”

In addition to veterans’ blood samples and 600,000-plus baseline surveys on lifestyle, military service, and health, the MVP has collected upwards of 825,000 germline DNA samples, which have helped inform research into prostate cancer, the most commonly diagnosed solid tumor among veterans. By mining these data, researchers have built more evidence of how genes add to risk and disease progression.

In one study preprint that has not been peer reviewed, VA researchers investigated the significance of high polygenic hazard scores. The scores are strongly associated with age at diagnosis of any prostate cancer, as well as lifetime risk of metastatic and fatal prostate cancer. However, because they’re associated with any prostate cancer, the researchers say, there is concern that screening men with high polygenic risk could increase overdiagnosis of indolent cancers.

The researchers analyzed genetic and phenotypic data from 69,901 men in the MVP who have been diagnosed with prostate cancer (6413 metastatic). They found their hypothesis to be correct: Among men eventually diagnosed with prostate cancer, those with higher polygenic risk were more likely to develop metastatic disease. 

Genetic risk scores like PHS601, a 601-variant polygenic score, can be performed on a saliva sample at any time during a person’s life, the researchers note. Thus, the scores provide the earliest information about age-specific risk of developing aggressive prostate cancer. These scores might be useful, they suggest, to support clinical decisions not only about whom to screen but also at what age.

Another study led by Stanford University researchers and published in Nature Genetics aimed to make screening more targeted, in this case prostate specific antigen screening. Estimates about PSA heritability vary from 40% to 45%, with genome-wide evaluations putting it at 25% to 30%, suggesting that incorporating genetic factors could improve screening. 

This study involved 296,754 men (211,342 with European ancestry, 58,236 with African ancestry, 23,546 with Hispanic/Latino ancestry, and 3630 with Asian ancestry; 96.5% of participants were from MVP)—a sample size more than triple that in previous work. 

The researchers detected 448 genome-wide significant variants, including 295 that were novel (to the best of their knowledge). The variance explained by genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino ancestry, and 8.6% to 15.3% for Asian ancestry, and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels.

The researchers say their study highlights how including higher proportions of participants from underrepresented populations can improve genetic prediction of PSA levels, offering the potential to personalize prostate cancer screening. Adjusting PSA for individuals’ predispositions in the absence of prostate cancer could improve the specificity (to reduce overdiagnosis) and sensitivity (to prevent more deaths) of screening.

Their findings, the researchers suggest, also explain additional variation in PSA, especially among men of African heritage, who experience the highest prostate cancer morbidity and mortality. They note that this work “moved us closer to leveraging genetic information to personalize PSA and substantially improved our understanding of PSA across diverse ancestries.”

A third study from a team at the VA Tennessee Valley Healthcare System also investigated the risk of inheriting a predisposition to prostate cancer. These researchers explored pathogenic variants using both genome-wide single-allele and identity-by-descent analytic approaches. They then tested their candidate variants for replication across independent biobanks, including MVP.

The researchers discovered the gene WNT9B E152K more than doubled the risk of familial prostate cancer. Meta-analysis, collectively encompassing 500,000 patients, confirmed the genome-wide significance. The researchers say WNT9B shares an “unexpected commonality” with the previously established prostate cancer risk genes HOXB13 and HNF1B: Each are required for embryonic prostate development. Based on that finding, the researchers also evaluated 2 additional genes, KMT2D and DHCR7, which are known to cause Mendelian genitourinary developmental defects. They, too, were nominally associated with prostate cancer under meta-analyses.

Tens of thousands of participants in MVP have had prostate cancer. The genetic research they participate in advances detection, prediction, and treatment for themselves and others, and science in general. The research is not only about finding causes, but what to do if the cancer develops. An “acting on MVP prostate cancer findings” study at VA Puget Sound Health Care System is testing how communicating with veterans about MVP prostate cancer results will affect their care. Those with prostate cancer will be screened to determine genetic contributions to their cancers. Those found to have a gene-based cancer diagnosis will be offered genetic counseling. Their immediate family will also be offered screening to test for inherited prostate cancer risk.

In 2016, the VA partnered with the Prostate Cancer Foundation to establish the Precision Oncology Program for Cancer of the Prostate (POPCaP). In collaboration with MVP and the Genomic Medicine Service, the program uses genetic information to individualize treatments for veterans with advanced prostate cancer. 

US Army Veteran James Perry is one of the beneficiaries of the program. First diagnosed with prostate cancer in 2001, he was initially treated with radiation therapy, but the cancer recurred and spread to his lung. The John J. Cochran Veterans Hospital in St. Louis sent a sample of Perry's lung tumor to the laboratory for genetic testing, where they discovered he had a BRCA1 gene mutation.

His oncologist, Dr. Martin Schoen, recommended Perry enroll in AMPLITUDE, a clinical trial testing the effectiveness of poly-ADP ribose polymerase inhibitors, a new class of drugs to treat hormone-sensitive prostate cancer. One year later, Perry’s lung tumor could barely be seen on computed tomography, and his PSA levels were undetectable.

"I would highly recommend enrolling in a trial," Perry told VA Research Currents. “If a veteran has that opportunity, I would encourage it—anything that is going to give you a few more days is worth it.” In the interview, Perry said he enjoyed being part of the trial because he knows he is getting the most advanced care possible and is proud to help others like himself.

"We are honored to support VA's work to improve the lives of veterans who are living with advanced prostate cancer," Vice President and National Director of the PCF Veterans Health Initiative Rebecca Levine said. "Clinical trials play a vital role in bringing new treatments to patients who need them most. Mr. Perry's experience illustrates VA's commitment to provide state-of-the-art cancer care to all veterans who need it."

About 15,000 veterans are annually diagnosed with prostate cancer. Fortunately, those veterans enrolled in the US Department of Veterans Affairs (VA) Million Veteran Program (MVP) provide researchers with a deep pool of genetic data that can help identify causes, aid diagnosis, and guide targeted treatments.

More than 1,000,000 veterans have enrolled in MVP and donated their anonymized DNA to foster research. It is also one of the most genetically diverse health-related databases: 20% of participants identify as Black, 8% as Hispanic, 2% as Asian American, and 1% as Native American. 

Ethnically and racially diverse data are particularly important for advancing the treatment of underserved groups. In a 2020 review, researchers found a number of areas where Black veterans differed from White veterans, including prostate-specific antigen (PSA) levels, incidence (almost 60% higher), clinical course, and mortality rate (2 to 3 times greater). To facilitate research, the MVP developed the “DNA chip,” a custom-designed tool that tests for > 750,000 genetic variants, including > 300,000 that are more common in minority populations.

“The whole thing about understanding genetics and diversity is like a circular feedback loop,” Director of MVP Dr. Sumitra Muralidhar said in a VA news article. “The more people you have represented from different racial and ethnic backgrounds, the more we’ll be able to discover genetic variants that contribute to their health. The more we discover, the more we can help that group. It’s a complete circular feedback loop.”

In addition to veterans’ blood samples and 600,000-plus baseline surveys on lifestyle, military service, and health, the MVP has collected upwards of 825,000 germline DNA samples, which have helped inform research into prostate cancer, the most commonly diagnosed solid tumor among veterans. By mining these data, researchers have built more evidence of how genes add to risk and disease progression.

In one study preprint that has not been peer reviewed, VA researchers investigated the significance of high polygenic hazard scores. The scores are strongly associated with age at diagnosis of any prostate cancer, as well as lifetime risk of metastatic and fatal prostate cancer. However, because they’re associated with any prostate cancer, the researchers say, there is concern that screening men with high polygenic risk could increase overdiagnosis of indolent cancers.

The researchers analyzed genetic and phenotypic data from 69,901 men in the MVP who have been diagnosed with prostate cancer (6413 metastatic). They found their hypothesis to be correct: Among men eventually diagnosed with prostate cancer, those with higher polygenic risk were more likely to develop metastatic disease. 

Genetic risk scores like PHS601, a 601-variant polygenic score, can be performed on a saliva sample at any time during a person’s life, the researchers note. Thus, the scores provide the earliest information about age-specific risk of developing aggressive prostate cancer. These scores might be useful, they suggest, to support clinical decisions not only about whom to screen but also at what age.

Another study led by Stanford University researchers and published in Nature Genetics aimed to make screening more targeted, in this case prostate specific antigen screening. Estimates about PSA heritability vary from 40% to 45%, with genome-wide evaluations putting it at 25% to 30%, suggesting that incorporating genetic factors could improve screening. 

This study involved 296,754 men (211,342 with European ancestry, 58,236 with African ancestry, 23,546 with Hispanic/Latino ancestry, and 3630 with Asian ancestry; 96.5% of participants were from MVP)—a sample size more than triple that in previous work. 

The researchers detected 448 genome-wide significant variants, including 295 that were novel (to the best of their knowledge). The variance explained by genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino ancestry, and 8.6% to 15.3% for Asian ancestry, and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels.

The researchers say their study highlights how including higher proportions of participants from underrepresented populations can improve genetic prediction of PSA levels, offering the potential to personalize prostate cancer screening. Adjusting PSA for individuals’ predispositions in the absence of prostate cancer could improve the specificity (to reduce overdiagnosis) and sensitivity (to prevent more deaths) of screening.

Their findings, the researchers suggest, also explain additional variation in PSA, especially among men of African heritage, who experience the highest prostate cancer morbidity and mortality. They note that this work “moved us closer to leveraging genetic information to personalize PSA and substantially improved our understanding of PSA across diverse ancestries.”

A third study from a team at the VA Tennessee Valley Healthcare System also investigated the risk of inheriting a predisposition to prostate cancer. These researchers explored pathogenic variants using both genome-wide single-allele and identity-by-descent analytic approaches. They then tested their candidate variants for replication across independent biobanks, including MVP.

The researchers discovered the gene WNT9B E152K more than doubled the risk of familial prostate cancer. Meta-analysis, collectively encompassing 500,000 patients, confirmed the genome-wide significance. The researchers say WNT9B shares an “unexpected commonality” with the previously established prostate cancer risk genes HOXB13 and HNF1B: Each are required for embryonic prostate development. Based on that finding, the researchers also evaluated 2 additional genes, KMT2D and DHCR7, which are known to cause Mendelian genitourinary developmental defects. They, too, were nominally associated with prostate cancer under meta-analyses.

Tens of thousands of participants in MVP have had prostate cancer. The genetic research they participate in advances detection, prediction, and treatment for themselves and others, and science in general. The research is not only about finding causes, but what to do if the cancer develops. An “acting on MVP prostate cancer findings” study at VA Puget Sound Health Care System is testing how communicating with veterans about MVP prostate cancer results will affect their care. Those with prostate cancer will be screened to determine genetic contributions to their cancers. Those found to have a gene-based cancer diagnosis will be offered genetic counseling. Their immediate family will also be offered screening to test for inherited prostate cancer risk.

In 2016, the VA partnered with the Prostate Cancer Foundation to establish the Precision Oncology Program for Cancer of the Prostate (POPCaP). In collaboration with MVP and the Genomic Medicine Service, the program uses genetic information to individualize treatments for veterans with advanced prostate cancer. 

US Army Veteran James Perry is one of the beneficiaries of the program. First diagnosed with prostate cancer in 2001, he was initially treated with radiation therapy, but the cancer recurred and spread to his lung. The John J. Cochran Veterans Hospital in St. Louis sent a sample of Perry's lung tumor to the laboratory for genetic testing, where they discovered he had a BRCA1 gene mutation.

His oncologist, Dr. Martin Schoen, recommended Perry enroll in AMPLITUDE, a clinical trial testing the effectiveness of poly-ADP ribose polymerase inhibitors, a new class of drugs to treat hormone-sensitive prostate cancer. One year later, Perry’s lung tumor could barely be seen on computed tomography, and his PSA levels were undetectable.

"I would highly recommend enrolling in a trial," Perry told VA Research Currents. “If a veteran has that opportunity, I would encourage it—anything that is going to give you a few more days is worth it.” In the interview, Perry said he enjoyed being part of the trial because he knows he is getting the most advanced care possible and is proud to help others like himself.

"We are honored to support VA's work to improve the lives of veterans who are living with advanced prostate cancer," Vice President and National Director of the PCF Veterans Health Initiative Rebecca Levine said. "Clinical trials play a vital role in bringing new treatments to patients who need them most. Mr. Perry's experience illustrates VA's commitment to provide state-of-the-art cancer care to all veterans who need it."