Abstract
Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 369-378 |
| Number of pages | 10 |
| Journal | Nature medicine |
| Volume | 22 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2016 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. / Kumar, Akash; Coleman, Ilsa; Morrissey, Colm; Zhang, Xiaotun; True, Lawrence D.; Gulati, Roman; Etzioni, Ruth; Bolouri, Hamid; Montgomery, Bruce; White, Thomas; Lucas, Jared M.; Brown, Lisha G.; Dumpit, Ruth F.; DeSarkar, Navonil; Higano, Celestia; Yu, Evan Y.; Coleman, Roger; Schultz, Nikolaus; Fang, Min; Lange, Paul H.; Shendure, Jay; Vessella, Robert L.; Nelson, Peter S.
In: Nature medicine, Vol. 22, No. 4, 01.04.2016, p. 369-378.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer
AU - Kumar, Akash
AU - Coleman, Ilsa
AU - Morrissey, Colm
AU - Zhang, Xiaotun
AU - True, Lawrence D.
AU - Gulati, Roman
AU - Etzioni, Ruth
AU - Bolouri, Hamid
AU - Montgomery, Bruce
AU - White, Thomas
AU - Lucas, Jared M.
AU - Brown, Lisha G.
AU - Dumpit, Ruth F.
AU - DeSarkar, Navonil
AU - Higano, Celestia
AU - Yu, Evan Y.
AU - Coleman, Roger
AU - Schultz, Nikolaus
AU - Fang, Min
AU - Lange, Paul H.
AU - Shendure, Jay
AU - Vessella, Robert L.
AU - Nelson, Peter S.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.
AB - Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.
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U2 - 10.1038/nm.4053
DO - 10.1038/nm.4053
M3 - Article
VL - 22
SP - 369
EP - 378
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 4
ER -