PTEN Deficiency in Endometrioid Endometrial Adenocarcinomas Predicts Sensitivity to PARP Inhibitors

Dedes, Konstantin J.; Wetterskog, Daniel; Mendes-Pereira, Ana M.; Natrajan, Rachael; Lambros, Maryou B.; Geyer, Felipe C.; Vatcheva, Radost; Savage, Kay; Mackay, Alan; Lord, Christopher J.; Ashworth, Alan; Reis‐Filho, Jorge S.

doi:10.1126/scitranslmed.3001538

Cited by 236 publications

(207 citation statements)

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“…PTEN is increasingly undergoing evaluation as a biomarker for identifying poor prognosis patients and selecting patients for targeted therapies, including the plethora of new agents targeting the PI3K AKT pathway 23 and DNA repair proteins. 24,25 Moreover, the identification of gross chromosomal rearrangements could also give important insights to tumour biology with reports increasingly suggesting that a subset of advanced solid cancer types are characterised by a propensity to acquire chromosomal rearrangements during their development.…”

Section: Discussionmentioning

confidence: 99%

Novel, gross chromosomal alterations involving PTEN cooperate with allelic loss in prostate cancer

et al. 2012

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There is increasing evidence that multiple chromosomal rearrangements occur in prostate cancer. PTEN loss is considered to be a key event in prostate carcinogenesis but the mechanisms of loss remain to be fully elucidated. We hypothesised that gross rearrangements may exist that cause disruption of the PTEN gene in the absence of genomic deletion. We therefore designed a novel fluorescence in situ hybridisation (FISH) assay with probes overlying regions 3 0 and 5 0 of PTEN and a third probe overlying the gene. We aimed to identify both genomic deletions and gross rearrangements of PTEN that would be overlooked by previously reported singleprobe FISH assays. We proceeded to evaluate a tissue microarray with radical prostatectomy and trans-urethral resection of the prostate specimens from 187 patients. We identified PTEN genomic loss in 45/150 (30%) radical prostatectomy patients and 16/37 (43%) trans-urethral resection of the prostate patients. Importantly, our assay detected novel chromosomal alterations in the PTEN gene (characterised by splitting of FISH signals) in 13 tumours (6.9% of all prostate cancers; 21% of PTEN-lost cancers). All PTEN-rearranged tumours had genomic loss at the other allele and had no expression of PTEN by immunohistochemistry. PTEN-rearranged tumours were significantly more likely to have an underlying ERG rearrangement. Our assay differentiated loss of the probe overlying PTEN in isolation or in combination with either one of or both the probes overlying the 3 0 and 5 0 regions. This gave an indication of the size of genomic loss and we observed considerable inter-tumoural heterogeneity in the extent of genomic loss in PTEN-lost tumours. In summary, gross rearrangements of the PTEN locus occur in prostate cancer and can be detected by a 'break-apart' FISH assay. This observation could explain the absence of PTEN protein expression in a subgroup of tumours previously classified as having heterozygous genomic loss using single-probe traditional FISH assays. Modern Pathology (2012) 25, 902-910;

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Section: Discussionmentioning

confidence: 99%

Novel, gross chromosomal alterations involving PTEN cooperate with allelic loss in prostate cancer

et al. 2012

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“…Finally, because PTEN appears to also play a role in homologous recombination, mutation, or loss of expression of PTEN may provide a "contextual" synthetic lethality in the tumor microenvironment, and thus enhance PARP inhibitor-mediated cytotoxicity (82,83). Currently, a trial combining the PARP inhibitor olaparib with NVP-BKM120 is initiating accrual.…”

Section: Combining Pi3k/akt/mtor Inhibition With Other Therapiesmentioning

confidence: 99%

The PI3K/AKT/mTOR Pathway as a Therapeutic Target in Endometrial Cancer

Slomovitz

Coleman

2012

Clinical Cancer Research

340

261

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“…On the other hand, 90% of BRCA-dependent tumors are triple negative. Moreover, similarly to the BRCA-1 mutation, the PTEN mutation, detected in 30-80% of EC cases, sensitizes cancer cells to the therapy with PARP-1 inhibitors [19][20][21]. High activity of PARP-1 is observed at the time of genome instability [22].…”

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confidence: 99%