Integrative Genomic Analysis of Coincident Cancer Foci Implicates CTNNB1 and PTEN Alterations in Ductal Prostate Cancer

Gillard, Marc; Lack, Justin; Pontier, Andrea; Gandla, Divya; Hatcher, David; Sowalsky, Adam G.; Rodriguez-Nieves, Jose Antonio; Griend, Donald Vander; Paner, Gladell P.; VanderWeele, David J.

doi:10.1016/j.euf.2017.12.003

Cited by 32 publications

(46 citation statements)

References 44 publications

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“…Although we did not intentionally sequence the acinar carcinoma component in patients with mixed ductal-acinar tumors, the fact that concurrent ductal and acinar carcinomas share common ERG rearrangements and other alterations suggests that the DDR alterations are likely shared between these components as well. 4,9 This study adds to the literature suggesting that aggressive histologic subtypes of localized prostate cancer (eg, primary Gleason pattern 5 acinar carcinomas, small cell carcinomas, and now dPCs) may be enriched for MMR defects. 25…”

Section: Discussionmentioning

confidence: 73%

“…Similar to a prior report, we found that PTEN alterations were generally mutually exclusive of mutations in genes associated with WNT-signaling activation (eg, APC and CTNNB1 mutations), although there was one patient with a pathogenic MSH2 mutation that had secondary alterations in APC , PTEN , and PIK3R1 . 9 There were three additional patients in whom WNT-pathway alterations co-occurred with PI3K-pathway alterations, including one patient with an APC and PIK3CA mutation, and two patients with CTNNB1 and PIK3CA mutations. Compared with patients with CRPC, there were fewer PTEN alterations and more PIK3CA mutations in our dPC cohort, with an overall similar incidence of PI3K-pathway alterations (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…5–8 Limited gene expression profiling studies have found similarities between dPC and patients with acinar tumors, and there is molecular evidence that concurrent ductal and acinar tumors are clonally related. 4,9,10 More recent immunohistochemical profiling studies have demonstrated that positive phospho–mammalian target of rapamycin staining correlated with risk of biochemical recurrence in patients with ductal carcinoma. 11 In a separate study, it was found that loss of PTEN protein expression occurred more frequently in dPC compared with acinar adenocarcinoma, again, potentially implicating mammalian target of rapamycin signaling pathway in the pathobiology of dPC.…”

Section: Introductionmentioning

confidence: 99%

“…6 More recently, a study evaluating genomic and transcriptomic differences between foci of ductal and acinar prostatic carcinoma from the same individual found enrichment for mutations in CTNNB1 and PTEN within the ductal foci, with associated WNT- or PI3K- pathway activation. 9…”

Section: Introductionmentioning

confidence: 99%

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Genomic Characterization of Prostatic Ductal Adenocarcinoma Identifies a High Prevalence of DNA Repair Gene Mutations

Schweizer

Antonarakis

Bismar

et al. 2019

JCO Precision Oncology

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PURPOSE Ductal prostate cancer (dPC) is a rare variant of prostatic adenocarcinoma associated with poor outcomes. Although its histopathologic features are well characterized, the underlying molecular hallmarks of this aggressive subtype are not well described. We sought to provide a comprehensive overview of the spectrum of mutations associated with dPC. METHODS Three case series across multiple institutions were assembled. All patients had a diagnosis of dPC, and histopathologic classification was confirmed by an expert genitourinary pathologist. Case series 1 included men who were prospectively enrolled in a tumor sequencing study at the University of Washington (n = 22). Case series 2 and 3 included archival samples from men treated at Johns Hopkins Hospital (n = 21) and University of Calgary (n = 8), respectively. Tumor tissue was sequenced on a targeted next-generation sequencing assay, UW-OncoPlex, according to previously published methods. The frequency of pathogenic/likely pathogenic mutations are reported. RESULTS Overall, 25 patients (49%) had at least one DNA damage repair gene alteration, including seven (14%) with a mismatch repair gene mutation and 16 (31%) with a homologous repair mutation. Germline autosomal dominant mutations were confirmed or suspected in 10 patients (20%). Activating mutations in the PI3K pathway (n = 19; 37%), WNT pathway (n = 16; 31%), and MAPK pathway (n = 8; 16%) were common. CONCLUSION This study strongly suggests that dPCs are enriched for actionable mutations, with approximately 50% of patients demonstrating DNA damage repair pathway alteration(s). Patients with dPC should be offered next-generation sequencing to guide standard-of-care treatment (eg, immune checkpoint inhibitors) or triaged toward an appropriate clinical trial (eg, poly [ADP-ribose] polymerase inhibitors).

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Section: Discussionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genomic Characterization of Prostatic Ductal Adenocarcinoma Identifies a High Prevalence of DNA Repair Gene Mutations

Schweizer

Antonarakis

Bismar

et al. 2019

JCO Precision Oncology

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“…The oncogenic ß-catenin activation cooperates with Pten loss to decrease the latency of prostate cancer progression. Almost half of the prostate cancer cases with the CTNNB1 mutation have associated PTEN haploinsufficiency (34). Interestingly, ß-catenin-mutant prostate tumors with Pten haploinsufficiency exhibit further loss of Pten, mimicking Pten-null ß-catenin-mutant tumors.…”

Section: Discussionmentioning

confidence: 99%

Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer

et al. 2020

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Inhibition of the androgen receptor (AR) is the main strategy to treat advanced prostate cancers. AR-independent treatmentresistant prostate cancer is a major unresolved clinical problem. Patients with prostate cancer with alterations in canonical WNT pathway genes, which lead to b-catenin activation, are refractory to AR-targeted therapies. Here, using clinically relevant murine prostate cancer models, we investigated the significance of b-catenin activation in prostate cancer progression and treatment resistance. b-Catenin activation, independent of the cell of origin, cooperated with Pten loss to drive AR-independent castrationresistant prostate cancer. Prostate tumors with b-catenin activation relied on the noncanonical WNT ligand WNT5a for sustained growth. WNT5a repressed AR expression and maintained the expression of c-Myc, an oncogenic effector of b-catenin activation, by mediating nuclear localization of NFkBp65 and b-catenin. Overall, WNT/b-catenin and AR signaling are reciprocally inhibited. Therefore, inhibiting WNT/b-catenin signaling by limiting WNT secretion in concert with AR inhibition may be useful for treating prostate cancers with alterations in WNT pathway genes. Significance: Targeting of both AR and WNT/b-catenin signaling may be required to treat prostate cancers that exhibit alterations of the WNT pathway.

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Neoplasms of the Prostate

Aparicio¹,

Pilié²,

Surasi³

et al. 2022

Holland‐Frei Cancer Medicine

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Overview Cancer of the prostate is the most commonly diagnosed nonskin neoplasm and the second leading cause of cancer‐related mortality in men in the United States. Considerable advances have been made in screening, diagnosis, and therapy options, particularly in advanced disease, but controversies about the diagnosis and management of prostate cancer, especially in the areas of screening and choice of therapy, continue to evolve. Research initiatives in advanced disease have shifted from prognostication to prediction, and current treatment considerations are focused on optimization of therapy sequence, development of rational combinations, biomarker‐driven patient selection, determining the role of local disease control in patients with metastases, and bone targeting therapies. Despite progress, prostate cancer survival has not improved at the same pace as other cancer subtypes. It is anticipated that addressing knowledge gaps will lead to the development of novel agents with unique mechanisms of action and optimization of integrated strategies (surgical, radiation, and medical) to improve overall survival. Prostate cancer awareness, clinical application of improved biopsy schemes, and advances in imaging combined with the widespread use of prostate‐specific antigen (PSA) have resulted in increased detection of early prostate cancer. The question of whether PSA screening would reduce mortality from prostate cancer has now been tested in the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial first published in 2009. Though many of the apparent discrepancies between these trials can be accounted for by trial design and patient cross‐contamination, they brought to the forefront the dilemma of overdiagnosis and overtreatment, as well as the heterogeneous nature of prostate cancer and the urgent need to improve the accuracy of identifying clinically significant early disease with lethal potential. It is hoped that enhancing the current morphologic and anatomic classification of prostate cancer with a better understanding of the molecular underpinnings of diverse disease states will lead to a more refined taxonomy of prostate cancer and ultimately improve outcomes while minimizing treatment‐related morbidity. Salient features that distinguish prostate cancer from other malignancies and frame the dilemmas surrounding it are its striking age‐dependent incidence, with progressively increasing frequency with increasing age, a strong familial and hereditary component, the variable lethality of morphologically identical cancers, the central role of androgen signaling, the preponderance of bone‐forming metastases, and metabolic derangements contributing to lethal progression. Important advances made in each of these areas will modify the approaches currently used to prevent, prognosticate, predict, and treat prostate cancer.

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Integrative Genomic Analysis of Coincident Cancer Foci Implicates CTNNB1 and PTEN Alterations in Ductal Prostate Cancer

Abstract: The aggressive subtype ductal adenocarcinoma is closely related to conventional acinar prostate cancer. Ductal foci contain additional alterations, however, leading to frequent activation of two targetable pathways.

Cited by 32 publications

References 44 publications

Genomic Characterization of Prostatic Ductal Adenocarcinoma Identifies a High Prevalence of DNA Repair Gene Mutations

Genomic Characterization of Prostatic Ductal Adenocarcinoma Identifies a High Prevalence of DNA Repair Gene Mutations

Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer

Neoplasms of the Prostate

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