Microsatellite instability in prostate cancer by PCR or next-generation sequencing

Hempelmann, Jennifer A.; Lockwood, Christina M.; Konnick, Eric Q.; Schweizer, Michael T.; Antonarakis, Emmanuel S.; Lotan, Tamara L.; Montgomery, Bruce; Nelson, Peter S.; Klemfuss, Nola; Salipante, Stephen J.; Pritchard, Colin C.

doi:10.1186/s40425-018-0341-y

Cited by 97 publications

(93 citation statements)

References 38 publications

(47 reference statements)

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“…Hypermutation and MSI are rare and sporadic features of PCa [39] that are associated with hereditary cancer predisposition. In PCa, high MSI is associated with poorly differentiated stage [40,41] ranging from 1% of primary tumor cases to up to 12% metastatic cases [42]. To our knowledge, this is the only reported MSI-H case of an early metastasis retaining androgen sensitivity that has been modelled in vivo.…”

Section: Discussionmentioning

confidence: 99%

Patient-derived xenografts and organoids model therapy response in prostate cancer

Karkampouna

Manna

Filippo

et al. 2020

Preprint

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Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe a novel androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa).RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbours BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modelled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX-and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds.This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds. Conflict of interest and Disclosure Statement:The authors declare no conflict of interest.

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Section: Discussionmentioning

confidence: 99%

Patient-derived xenografts and organoids model therapy response in prostate cancer

Karkampouna

Manna

Filippo

et al. 2020

Preprint

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“…In a small case series of patients with mismatch repair‐deficient prostate cancer, more than 25% of the patients did not have a single MSI marker shifted using the traditional five‐marker NIH panel 14 . An expanded MSI panel validated specifically in prostate cancer may be more sensitive for identifying MSI‐high patients with mCRPC 15 …”

Section: Discussionmentioning

confidence: 99%

“…14 An expanded MSI panel validated specifically in prostate cancer may be more sensitive for identifying MSI-high patients with mCRPC. 15 Patients with mCRPC and an HR DNA repair gene mutation have responded favorably to the combination of nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) in a small prospective trial. 6 Patients 1 (germline BRCA2 alteration) and 2 (somatic ATM alteration) both had pathogenic HR DNA repair mutations.…”

Section: Discussionmentioning

confidence: 99%

Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with metastatic castration resistant prostate cancer

et al. 2020

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Background Immune checkpoint inhibition has been shown to have limited efficacy in patients with metastatic prostate cancer. Prostate cancers that harbor certain homologous recombination (HR) DNA repair gene mutations, inactivating CDK12 mutations or have underlying mismatch repair deficiency may be effectively treated with immunotherapy. Combination therapy may improve clinical response rates to immune checkpoint blockade. We observed profound prostate‐specific antigen (PSA) and/or objective responses to immune checkpoint blockade following prior treatment with bipolar androgen therapy (BAT) and enzalutamide. Methods We report three cases of patients with metastatic castration resistant prostate cancer (mCRPC) undergoing therapy with anti‐PD‐1 inhibitors. All patients underwent both somatic molecular testing and germline genetic testing. Results Two of the three patients with mCRPC harbored an inactivating mutation in an HR DNA repair gene (BRCA2, ATM). No patient demonstrated mismatch repair deficiency, nor were CDK12 alterations present. All three patients had been treated with BAT and enzalutamide before immune checkpoint blockade, a paradoxical approach for the treatment of mCRPC developed by our group. Conclusions These cases of mCRPC suggest that immune checkpoint blockade may have therapeutic potential in patients with prostate cancer, especially following immune activation (“priming”) using BAT and enzalutamide.

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“…A total of 60 cancer-related genes and 17 microsatellite foci [23], which were selected from QIAseq Targeted DNA Custom Panel (Qiagen), including 2,615 primers for the regions of interest and an average exon coverage of 99.87%, were used for the construction of the custom panel (Table 1).…”

Section: Design Of the Custom Gene Panelmentioning

confidence: 99%

“…In 10 cases (case nos. 9,12,14,16,18,19,[21][22][23][24], the FFPE tissues from biopsy and/or resection along with endometrial LBC, were subjected to gene panel analysis. For cases no.…”

Section: Correlation Of the Genetic Diagnosis From Lbc And Ffpe Specimentioning

confidence: 99%

Analysis by Next-Generation Sequencing Panel Covered 60 Genes and 17 Microsatellite Foci in Endometrial Screening Liquid-Based Cytology Specimens A Comparative Study to Tissue Specimens

Akahane¹,

Kitazono²,

Yanazume³

et al. 2020

Preprint

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BackgroundLiquid-based cytology (LBC) is now a widely used method for cytologic screening and diagnosis of cancers. Since the cells are fixed with alcohol-based fixatives and the specimens are stored in a liquid condition, LBC specimens are also conducive for genetic analysis. MethodsHere, we established a small cancer gene panel including 60 genes and 17 microsatellite markers for next-generation sequencing and applied to residual LBC specimens obtained by endometrial cancer screening to compare with corresponding formalin-fixed paraffin-embedded (FFPE) tissues. ResultsA total of 53 FFPE and LBC specimens (n=24) were analyzed, revealing characteristic mutations for endometrial cancer including those of PTEN, CTNNB1, PIK3CA, and PIK3R1 . Eight cases had higher scores for both tumor mutation burden (TMB) and microsatellite instability (MSI), which agree with defective mismatch repair (MMR) protein expression. Paired endometrial LBC, and biopsied and/or resected FFPE tissues from 7 cases, demonstrated almost the same mutations, TMB, and MSI profiles in all cases. ConclusionThese findings demonstrate that the small cancer gene panel proved to be able to detect therapeutically actionable gene mutations in endometrial LBC and FFPE specimens and that LBC specimens obtained by endometrial cancer screening is an alternative and useful source of molecular testing. BackgroundEndometrial cancer is the most common gynecologic cancer worldwide, affecting over 500,000women every year [1]. Since lifestyle changes can affect the risk of developing endometrial cancer, an epidemiological approach is essential to manage the disease [2]. Moreover, genome-wide association studies have identified new susceptibility loci for endometrial cancer in the human genome, providing candidate genes for further studies that aim to unravel the mechanisms driving 4 carcinogenesis, which could offer new opportunities for early screening and detection or identification of therapeutic targets [3]. Unlike squamous cell carcinoma of the uterine cervix with pathogenesis closely related to that of human papilloma virus infection [4], endometrial carcinogenesis is linked to common cancer gene mutations and genome instability [5,6].Cytology specimens including conventional smear, cytospin, liquid-based cytology (LBC), and cell block are valuable sources of routine molecular diagnostics [7]. In fact, extensive studies have been reported that variety of cytology materials, containing LBC specimens, are available for molecular testing by next-generation sequencing (NSG), especially in non-small cell lung cancer [7][8][9][10][11][12].Meanwhile, the endometrial cytology is not only safe and easy clinical procedure but also comparable to suction endometrial biopsy for detecting atypical endometrial hyperplasia and cancers [13][14][15][16].Since 1987 in Japan, a cytologic examination for endometrial cancer screening is established by a national health insurance low. Thereafter, endometrial cytology using a specific device is introduced as a less invasive and less...

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Microsatellite instability in prostate cancer by PCR or next-generation sequencing

Cited by 97 publications

References 38 publications

Patient-derived xenografts and organoids model therapy response in prostate cancer

Patient-derived xenografts and organoids model therapy response in prostate cancer

Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with metastatic castration resistant prostate cancer

Analysis by Next-Generation Sequencing Panel Covered 60 Genes and 17 Microsatellite Foci in Endometrial Screening Liquid-Based Cytology Specimens A Comparative Study to Tissue Specimens

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