Abstract
Extensive intratumoral genetic heterogeneity exists among prostate tumors with similar pathology.
Major finding: Extensive intratumoral genetic heterogeneity exists among prostate tumors with similar pathology.
Approach: A low-input library protocol allowed whole-genome sequencing of routine biopsies.
Impact: Intratumoral heterogeneity should be considered in the clinical management of localized prostate cancer.
Most patients with prostate cancer are diagnosed with localized disease, but significant clinical heterogeneity exists among patients who are assigned the same prognostic risk category and whose tumors share similar pathologic features. Boutros and colleagues performed genomic profiling of 74 prostate cancer samples from untreated patients with localized, intermediate-risk, Gleason score 7 disease. Significant intrapatient heterogeneity was observed, with genomic instability and copy-number abnormalities varying widely between patients. In addition to several genomic abnormalities previously associated with aggressive disease, several recurrent alterations not previously linked to prostate cancer were identified, such as focal amplification of MYCL. MYCL-amplified tumors were genomically distinct from MYC-amplified tumors and were associated with younger age at treatment, suggesting that MYCL-amplified tumors may represent a separate disease subtype. MYCL amplification was heterogeneous among glands within an individual prostate; consistent with these findings, whole-genome sequencing of 23 spatially distinct tumor regions within formalin-fixed, paraffin-embedded routine biopsy specimens from 5 patients revealed extensive intraprostatic heterogeneity at the level of copy-number abnormalities, genomic rearrangements, and single-nucleotide variants. Evidence of clonal evolution could be observed in each tumor, and one tumor appeared to be multiclonal in nature. Nonsynonymous mutations, including those deemed to be potentially actionable or have prognostic value, were rarely observed in every sampled region of an individual tumor. The high degree of intraprostatic heterogeneity observed even in localized disease suggests a potential reason for the heterogeneous clinical outcomes observed among patients with similar disease pathology and should be considered in stratification and treatment of patients with potentially curable prostate cancer.
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