In the Journals

Genomic alterations in prostate cancer could help define disease risk

Chromosomal alterations could potentially identify men with low-risk prostate cancer detected by needle biopsy who have higher-risk disease in their prostate glands, according to results of a study published in Mayo Clinic Proceedings.

“We have discovered new molecular markers that can help guide men in their decisions about the course of their prostate cancer care,” George Vasmatzis, PhD, co-director of the Center for Individualized Medicine Biomarker Discovery Program at Mayo Clinic in Rochester, Minnesota, said in a press release. “Overtreatment has been [an] issue for the group of men that our study targets. We found that the presence of genetic alterations in low-risk cancer can help men decide whether treatment or active surveillance is right for them.”

Gleason score — the sum of the two highest Gleason patterns — is the most important clinical and pathologic feature for determining risk. However, the needle biopsy procedure often only captures Gleason pattern 3, leaving uncertainty as to whether the patient has low-risk Gleason score 6 disease or if a higher Gleason pattern was missed.

Studies following prostatectomy show Gleason score upgrading using prostatectomy specimens in more than one-third of cases, suggesting limitations of the needle biopsy.

Vasmatzis and colleagues sought to identify chromosomal abnormalities that distinguished Gleason pattern 3 in insignificant tumors from Gleason pattern 3 in significant tumors, reasoning that such abnormalities would be less common Gleason score 6 disease, but would most likely be shared between adjacent Gleason pattern 3 and Gleason pattern 4/5 of significant prostate cancer.

Researchers conducted DNA sequencing on certain Gleason patterns to detect chromosomal rearrangements — including abnormal junctions and copy number variations — in 154 frozen specimens from 126 men who underwent prostate cancer surgery. The discovery set included men with clinically insignificant disease (Gleason score 6 tumors less than 0.5 cm3, n = 49), large-volume Gleason score 6 tumors (confined tumors greater than 1 cm3 in volume with negative surgical margins, n = 23), Gleason score 7 tumors (n = 29), and Gleason score 8 and higher tumors (n = 25).

Researchers identified potential chromosomal rearrangement biomarkers with a higher frequency in intermediate- and high-risk prostate cancer than in low-risk disease. For validation, they performed fluorescence in situ hybridization on 152 archived surgical specimens from 124 patients with insignificant prostate cancer (n = 41), large-volume Gleason score 6 tumors (n = 26), Gleason score 7 tumors (n = 28), and Gleason score 8 or higher tumors (n = 29).

Results showed abnormal junction count did not differentiate low-risk from intermediate- and high-risk disease. However, researchers observed that loci corresponding to genes implicated in prostate cancer were altered more frequently in disease with intermediate and high risk for progression.

Further analysis found six potential markers more frequently seen in Gleason pattern 3 of a Gleason score 7 tumor than in Gleason pattern 3 of a Gleason score 6 tumor.

Researchers cross-validated five of these potential markers and found deletions in PTEN and CHD1 had areas under the receiver operating characteristic curve (AUC) of 0.87 (95% CI, 0.77-0.97) and 0.73 (95% CI, 0.6-0.86). Researchers calculated AUCs of 0.71 (95% CI, 0.59-0.84) for gains in ASAP1, 0.82 (95% CI, 0.71-0.93) for gains in MYC, and 0.77 (95% CI, 0.66-0.89) for gains in HDAC9 (P .01 for all).

“The needle biopsy procedure samples only a small portion of the tumor. It is not uncommon that a man with Gleason pattern 3 on needle biopsy specimen harbors a higher-grade cancer next to the pattern 3 that was missed by the procedure,” John C. Cheville, MD, co-director of the Center for Individualized Medicine Biomarker Discovery Program at Mayo Clinic, said in the press release. “Therefore, if we identify these alterations in a Gleason pattern 3, there is a higher likelihood that Gleason 4 pattern is nearby.”

Difficulty finding fresh frozen biopsy material with enough tumor cells to allow for genomic testing served as a limitation to this study. Researchers overcame this limitation by conducting the discovery step in the frozen tissue and developing assays relevant to formalin-fixed paraffin-embedded specimens.

“We have developed a discovery and validation process for the identification of genomic abnormalities in low risk of progression and intermediate and high risk of progression to prostate cancer genes,” Vasmatzis and colleagues wrote. “Even though a number of previous reports have implicated these genes in prostate cancer progression, our study is the first to describe the potential of this specific panel of [chromosomal rearrangement] to address a critical need for the care of patients with prostate cancer genes.” – by John DeRosier

Disclosures: NIH funded this study. Vasmatzis and Cheville report no relevant financial disclosures. One author reports a grant and royalties from GenomeDx and a patent with Mayo Clinic.

Chromosomal alterations could potentially identify men with low-risk prostate cancer detected by needle biopsy who have higher-risk disease in their prostate glands, according to results of a study published in Mayo Clinic Proceedings.

“We have discovered new molecular markers that can help guide men in their decisions about the course of their prostate cancer care,” George Vasmatzis, PhD, co-director of the Center for Individualized Medicine Biomarker Discovery Program at Mayo Clinic in Rochester, Minnesota, said in a press release. “Overtreatment has been [an] issue for the group of men that our study targets. We found that the presence of genetic alterations in low-risk cancer can help men decide whether treatment or active surveillance is right for them.”

Gleason score — the sum of the two highest Gleason patterns — is the most important clinical and pathologic feature for determining risk. However, the needle biopsy procedure often only captures Gleason pattern 3, leaving uncertainty as to whether the patient has low-risk Gleason score 6 disease or if a higher Gleason pattern was missed.

Studies following prostatectomy show Gleason score upgrading using prostatectomy specimens in more than one-third of cases, suggesting limitations of the needle biopsy.

Vasmatzis and colleagues sought to identify chromosomal abnormalities that distinguished Gleason pattern 3 in insignificant tumors from Gleason pattern 3 in significant tumors, reasoning that such abnormalities would be less common Gleason score 6 disease, but would most likely be shared between adjacent Gleason pattern 3 and Gleason pattern 4/5 of significant prostate cancer.

Researchers conducted DNA sequencing on certain Gleason patterns to detect chromosomal rearrangements — including abnormal junctions and copy number variations — in 154 frozen specimens from 126 men who underwent prostate cancer surgery. The discovery set included men with clinically insignificant disease (Gleason score 6 tumors less than 0.5 cm3, n = 49), large-volume Gleason score 6 tumors (confined tumors greater than 1 cm3 in volume with negative surgical margins, n = 23), Gleason score 7 tumors (n = 29), and Gleason score 8 and higher tumors (n = 25).

Researchers identified potential chromosomal rearrangement biomarkers with a higher frequency in intermediate- and high-risk prostate cancer than in low-risk disease. For validation, they performed fluorescence in situ hybridization on 152 archived surgical specimens from 124 patients with insignificant prostate cancer (n = 41), large-volume Gleason score 6 tumors (n = 26), Gleason score 7 tumors (n = 28), and Gleason score 8 or higher tumors (n = 29).

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Results showed abnormal junction count did not differentiate low-risk from intermediate- and high-risk disease. However, researchers observed that loci corresponding to genes implicated in prostate cancer were altered more frequently in disease with intermediate and high risk for progression.

Further analysis found six potential markers more frequently seen in Gleason pattern 3 of a Gleason score 7 tumor than in Gleason pattern 3 of a Gleason score 6 tumor.

Researchers cross-validated five of these potential markers and found deletions in PTEN and CHD1 had areas under the receiver operating characteristic curve (AUC) of 0.87 (95% CI, 0.77-0.97) and 0.73 (95% CI, 0.6-0.86). Researchers calculated AUCs of 0.71 (95% CI, 0.59-0.84) for gains in ASAP1, 0.82 (95% CI, 0.71-0.93) for gains in MYC, and 0.77 (95% CI, 0.66-0.89) for gains in HDAC9 (P .01 for all).

“The needle biopsy procedure samples only a small portion of the tumor. It is not uncommon that a man with Gleason pattern 3 on needle biopsy specimen harbors a higher-grade cancer next to the pattern 3 that was missed by the procedure,” John C. Cheville, MD, co-director of the Center for Individualized Medicine Biomarker Discovery Program at Mayo Clinic, said in the press release. “Therefore, if we identify these alterations in a Gleason pattern 3, there is a higher likelihood that Gleason 4 pattern is nearby.”

Difficulty finding fresh frozen biopsy material with enough tumor cells to allow for genomic testing served as a limitation to this study. Researchers overcame this limitation by conducting the discovery step in the frozen tissue and developing assays relevant to formalin-fixed paraffin-embedded specimens.

“We have developed a discovery and validation process for the identification of genomic abnormalities in low risk of progression and intermediate and high risk of progression to prostate cancer genes,” Vasmatzis and colleagues wrote. “Even though a number of previous reports have implicated these genes in prostate cancer progression, our study is the first to describe the potential of this specific panel of [chromosomal rearrangement] to address a critical need for the care of patients with prostate cancer genes.” – by John DeRosier

Disclosures: NIH funded this study. Vasmatzis and Cheville report no relevant financial disclosures. One author reports a grant and royalties from GenomeDx and a patent with Mayo Clinic.