Publication in Journal of Cancer Research and Clinical Oncology

J Cancer Res Clin Oncol. 2020 Jul;146(7):1701-1709.  doi: 10.1007/s00432-020-03221-x. Epub 2020 Apr 30.

Molecular Characterization of Prostate Cancer in Middle Eastern Population Highlights Differences With Western Populations With Prognostic Implication

Ramy A Abdelsalam, Ibrahim Khalifeh, Alan Box, Maria Kalantarian, Sunita Ghosh, Hatem Abou-Ouf, Tamara Lotfi, Mohammed Shahait, Nallasivam Palanisamy, Tarek A Bismar.

PMID: 32350606  DOI: 10.1007/s00432-020-03221-x

Abstract

Background: To investigate the incidence and prognostication of ERG, PTEN and SPINK1 protein expressions in prostate cancer cohort of Middle Eastern descent in comparison to published data from Western population.

Methods: Immunohistochemistry for ERG, PTEN and SPINK1 was performed in a cohort of localized PCA (n = 340). The data were correlated to pathological and clinical outcomes and compared to Western populations.

Results: ERG expression and PTEN loss were noted in 123/288 (42.7%) and 91/297 (30.6%) of patients, respectively. SPINK1 expression was assessed in a subset of cases, noted in 6/150 (4%) of patients. Only ERG expression was associated with grade groups, being more common in the lower grade groups (1-3 vs 4-5; p = 0.04). In contrast to the Western population, PTEN loss foci were more likely to be ERG negative, observed in 81% of tumor foci and patients with PTEN neg/ERG pos were more likely to exhibit biochemical recurrence (OR 2.831; 95% CI 1.10-726, p = 0.03). This association remained significant in multivariate analysis (OR 2.68; 95% CI 0.98-7.33, p = 0.05), after adjusting for GG, path stage and surgical margin.

Conclusion: This study documents significant differences in key molecular events in PCA in Middle Eastern population compared to Western populations that could explain differences in PCA incidence, progression and prognostication. ERG, PTEN and SPINK1 genomic alteration occur less frequently and the enrichment of ERG for PTEN loss is not observed. Additionally, patients with combined PTEN loss/ERG positive are at highest risk for BCR vs North American Caucasian population where PTEN loss alone seems to be associated with the worst clinical outcome. The data presented here further support differences in clonal evolution between Middle Eastern and Western population in relation to PCA and add further insight to understanding PCA molecular pathways.

Keywords: Biochemical recurrence; ERG protein expression; Gleason score; Middle eastern; PTEN; SPINK1; immunohistochemistry.

Elucidating tumor heterogeneity in prostate cancer by combined IHC & nov...

NP_RAF KINASE GENE FUSION IN PROSTATE CANCER

NP_INTRODUCTION

Genome-wide Study Reveals a Pseudogene-Associated Recurrent Gene Fusion ...

Publication in Modern Pathology

Mod Pathol. 2020 Apr 1. doi: 10.1038/s41379-020-0525-0. [Epub ahead of print]

Clonal evaluation of prostate cancer molecular heterogeneity in biopsy samples by dual immunohistochemistry and dual RNA in situ hybridization.

Dedigama-Arachchige P1, Carskadon S1, Li J2, Loveless I2, Alhamar M3, Peabody JO1, Stricker H1, Chitale DA3, Rogers CG1, Menon M1, Gupta NS3, Bismar TA4, Williamson SR3, Palanisamy N5.

Author information

1

Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA.

2

Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA.

3

Department of Pathology, Henry Ford Health System, Detroit, MI, USA.

4

Department of Pathology and Laboratory Medicine, University of Calgary Cumming School of Medicine and Calgary Laboratory Services, Calgary, Alberta, Canada.

5

Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA. npalani1@hfhs.org.

Abstract

Prostate cancer is frequently multifocal. Although there may be morphological variation, the genetic underpinnings of each tumor are not clearly understood. To assess the inter and intra tumor molecular heterogeneity in prostate biopsy samples, we developed a combined immunohistochemistry and RNA in situ hybridization method for the simultaneous evaluation of ERG, SPINK1, ETV1, and ETV4. Screening of 601 biopsy cores from 120 consecutive patients revealed multiple alterations in a mutually exclusive manner in 37% of patients, suggesting multifocal tumors with considerable genetic differences. Furthermore, the incidence of molecular heterogeneity was higher in African Americans patients compared with Caucasian American patients. About 47% of the biopsy cores with discontinuous tumor foci showed clonal differences with distinct molecular aberrations. ERG positivity occurred in low-grade cancer, whereas ETV4 expression was observed mostly in high-grade cancer. Further studies revealed correlation between the incidence of molecular markers and clinical and pathologic findings, suggesting potential implications for diagnostic pathology practice, such as defining dominant tumor nodules and discriminating juxtaposed but molecularly different tumors of different grade patterns.

PMID:

 

32238875

 

DOI:

 

10.1038/s41379-020-0525-0

Publication in Oncogene

Oncogene. 2020 Mar 30. doi: 10.1038/s41388-020-1275-7. [Epub ahead of print]

Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression.

Chandrashekar DS1, Chakravarthi BVSK1, Robinson AD1, Anderson JC2, Agarwal S1, Balasubramanya SAH1, Eich ML1, Bajpai AK3, Davuluri S3, Guru MS4, Guru AS4, Naik G5,6, Della Manna DL2, Acharya KK3,7, Carskadon S8, Manne U1,6, Crossman DK9, Ferguson JE10, Grizzle WE1,10, Palanisamy N8, Willey CD2,10, Crowley MR9, Netto GJ1,6, Yang ES2,6, Varambally S11,12,13, Sonpavde G14.

Author information

1

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.

2

Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.

3

Shodhaka Life Sciences Private Limited, Bengaluru, India.

4

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

5

Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.

6

O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.

7

Institute of Bioinformatics and Applied Biotechnology (IBAB), Biotech Park, Electronic City, Bengaluru, 560100, Karnataka, India.

8

Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, 48202, USA.

9

Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

10

Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA.

11

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. svarambally@uabmc.edu.

12

O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. svarambally@uabmc.edu.

13

Informatics Institute, University of Alabama at Birmingham, Birmingham, AL, USA. svarambally@uabmc.edu.

14

Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA. GuruP_Sonpavde@DFCI.HARVARD.EDU.

Abstract

Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting tumor heterogeneity. We have performed multi-omic profiling of the kinome in bladder cancer patients with the goal of identify therapeutic targets. Our analyses revealed amplification, overexpression, and elevated kinase activity of P21 (RAC1) activated kinase 4 (PAK4) in a subset of Bladder cancer (BLCA). Using bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, we observed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, protein tyrosine kinase 6 (PTK6), upon treatment with a PAK4 inhibitor and RNA interference of PAK4. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared with either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.

PMID:

 

32231273

 

DOI:

 

10.1038/s41388-020-1275-7

PUBLICATION IN INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY

Int J Surg Pathol. 2020 Mar 19:1066896920912485. doi: 10.1177/1066896920912485. [Epub ahead of print]

A Novel COL1A1-CAMTA1 Rearrangement in Cranial Fasciitis.

Jebastin Thangaiah J1, Vickery J2, Selwanes W3, Al-Haddad E3, Perry KD1, Palanisamy N1, Poulik JM3, Williamson SR1,2, Chitale DA1, Shehata BM3.

Author information

1

Henry Ford Health System, Detroit, MI, USA.

2

Wayne State University, Detroit, MI, USA.

3

Children's Hospital of Michigan, Detroit, MI, USA.

Abstract

Cranial fasciitis is an uncommon benign fibroblastic tumor, generally histologically identical to nodular fasciitis. It develops almost exclusively in children. Cranial fasciitis manifests clinically as a painless rapidly growing solitary nodule in the head and neck area, frequently eroding the underlying bone. Thus, this entity is often confused with aggressive lesions such as sarcomas, both clinically and radiologically. Histopathologic examination is essential to differentiate between cranial fasciitis and fibrohistiocytic or even sarcomatous lesions observed in children. In this article, we present a case of cranial fasciitis with intracranial extension in a 2-year-old boy. Although USP6 rearrangement has recently been recognized as a recurring alteration in nodular fasciitis, we present a novel COL1A1-CAMTA1 fusion in this lesion.

KEYWORDS:

CAMTA1; COL1A1; USP6; cranial fasciitis; familial adenomatous polyposis; molecular pathology; β-catenin

PMID:

 

32192385

 

DOI:

 

10.1177/1066896920912485

Publication in Nature Communications

Nat Commun. 2020 Jan 20;11(1):384. doi: 10.1038/s41467-019-14184-0.

Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer.

Tiwari R1, Manzar N1, Bhatia V1, Yadav A1, Nengroo MA2, Datta D2, Carskadon S3, Gupta N4, Sigouros M5, Khani F6, Poutanen M7, Zoubeidi A8, Beltran H9, Palanisamy N3, Ateeq B10.

Author information

1

Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP, 208016, India.

2

Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, UP, 226031, India.

3

Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, 48202, USA.

4

Department of Pathology, Henry Ford Health System, Detroit, MI, 48202, USA.

5

Division of Medical Oncology, Weill Cornell Medicine, New York, NY, 10065, USA.

6

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.

7

Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland.

8

Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.

9

Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.

10

Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP, 208016, India. bushra@iitk.ac.in.

Abstract

Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for adjuvant therapies.

PMID:

 

31959826

 

DOI:

 

10.1038/s41467-019-14184-0

Publication in Cancers

Cancers (Basel). 2020 Jan 3;12(1). pii: E127. doi: 10.3390/cancers12010127.

High-Throughput Label-Free Isolation of Heterogeneous Circulating Tumor Cells and CTC Clusters from Non-Small-Cell Lung Cancer Patients.

Zeinali M1,2,3, Lee M1,2, Nadhan A1,2, Mathur A1,2, Hedman C4, Lin E1,2, Harouaka R5, Wicha MS5, Zhao L6, Palanisamy N7, Hafner M3, Reddy R8, Kalemkerian GP5, Schneider BJ5, Hassan KA5, Ramnath N5,9, Nagrath S1,2.

Author information

1

Chemical Engineering, University of Michigan, 2800 Plymouth Road, NCRC, Building 20-3rd Floor, Ann Arbor, MI 48109, USA.

2

Biointerfaces Institute, University of Michigan, 2800 Plymouth Road, NCRC B10-A184, Ann Arbor, MI 48109, USA.

3

Institute for Medical Technology of Heidelberg University & University of Applied Sciences Mannheim, Paul-Wittsack-Straße 10, 68163 Mannheim, Germany.

4

Molecular, Cellular, and Developmental Biology, University of Michigan, 1105 North University Avenue, 2220 Biological Science Building, Ann Arbor, MI 48109, USA.

5

Department of Internal Medicine, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI 48109, USA.

6

Biostatistics Department, University of Michigan, Ann Arbor, MI 48109, USA.

7

Department of Urology, Henry Ford Health System, 1 Ford Place, Room 2D26, Detroit, MI 48202, USA.

8

Department of Surgery, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI 48109, USA.

9

Veterans Administration Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105, USA.

Abstract

(1) Background: Circulating tumor cell (CTC) clusters are emerging as clinically significant harbingers of metastases in solid organ cancers. Prior to engaging these CTC clusters in animal models of metastases, it is imperative for technology to identify them with high sensitivity. These clusters often present heterogeneous surface markers and current methods for isolation of clusters may fall short. (2) Methods: We applied an inertial microfluidic Labyrinth device for high-throughput, biomarker-independent, size-based isolation of CTCs/CTC clusters from patients with metastatic non-small-cell lung cancer (NSCLC). (3) Results: Using Labyrinth, CTCs (PanCK+/DAPI+/CD45-) were isolated from patients (n = 25). Heterogeneous CTC populations, including CTCs expressing epithelial (EpCAM), mesenchymal (Vimentin) or both markers were detected. CTCs were isolated from 100% of patients (417 ± 1023 CTCs/mL). EpCAM- CTCs were significantly greater than EpCAM+ CTCs. Cell clusters of ≥2 CTCs were observed in 96% of patients-of which, 75% were EpCAM-. CTCs revealed identical genetic aberrations as the primary tumor for RET, ROS1, and ALKgenes using fluorescence in situ hybridization (FISH) analysis. (4) Conclusions: The Labyrinth device recovered heterogeneous CTCs in 100% and CTC clusters in 96% of patients with metastatic NSCLC. The majority of recovered CTCs/clusters were EpCAM-, suggesting that these would have been missed using traditional antibody-based capture methods.

KEYWORDS:

CTC clusters; circulating tumor cells (CTCs); epithelial-to-mesenchymal transition (EMT); inertial microfluidics; non-small-cell lung cancer (NSCLC)

PMID:

31947893

PMCID:

PMC7016759

DOI:

10.3390/cancers12010127

கக்கத்தில் வைத்து வளர்த்த பிள்ளை

துக்கத்தில்

பக்கத்தில்

இல்லை

Publication in Modern Pathology

Mod Pathol. 2019 Dec 19. doi: 10.1038/s41379-019-0424-4. [Epub ahead of print]

Next-generation sequencing implicates oncogenic roles for p53 and JAK/STAT signaling in microcystic adnexal carcinomas.

Chan MP1,2,3, Plouffe KR4,5,6, Liu CJ4,5, Palanisamy N7, Carskadon S7, Zhao L8, Nazarian RM9, Durham AB10,11, Johnson TM10,11, Andea AA4,10,11, Patel RM4,10,11, Lowe L4,10,11, Fullen DR4,10,11, Brown NA4, Tomlins SA4,11,5,6, Udager AM4,5, Harms PW12,13,14,15.

Author information

1

Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. mpchan@med.umich.edu.

2

Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. mpchan@med.umich.edu.

3

Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA. mpchan@med.umich.edu.

4

Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.

5

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.

6

Strata Oncology, Ann Arbor, MI, USA.

7

Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA.

8

Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.

9

Dermatopathology Unit, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

10

Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.

11

Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.

12

Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. paulharm@med.umich.edu.

13

Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. paulharm@med.umich.edu.

14

Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA. paulharm@med.umich.edu.

15

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. paulharm@med.umich.edu.

Abstract

Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its infiltrative growth and histopathologic overlap with benign adnexal tumors, often posing challenges to both diagnosis and management. Understanding the molecular underpinnings of microcystic adnexal carcinoma may allow for more accurate diagnosis and identify potential targetable oncogenic drivers. We characterized 18 microcystic adnexal carcinomas by targeted, multiplexed PCR-based DNA next-generation sequencing of the coding sequence of over 400 cancer-relevant genes. The majority of cases had relatively few (less than 8) prioritized somatic mutations, and lacked an ultraviolet (UV) signature. The most recurrent mutation was TP53 inactivation in four (22%) tumors. Frame-preserving insertions affecting the kinase domain of JAK1 were detected in three (17%) cases, and were nonoverlapping with TP53 mutations. Seven (39%) cases demonstrated copy number gain of at least one oncogene. By immunohistochemistry, p53 expression was significantly higher in microcystic adnexal carcinomas with TP53 mutations compared with those without such mutations and syringomas. Similarly, phospho-STAT3 expression was significantly higher in microcystic adnexal carcinomas harboring JAK1 kinase insertions compared with those with wild-type JAK1 and syringomas. In conclusion, microcystic adnexal carcinomas are molecularly heterogeneous tumors, with inactivated p53 or activated JAK/STAT signaling in a subset. Unlike most other nonmelanoma skin cancers involving sun-exposed areas, most microcystic adnexal carcinomas lack evidence of UV damage, and hence likely originate from a relatively photo-protected progenitor population in the dermis. These findings have implications for the biology, diagnosis, and treatment of microcystic adnexal carcinomas, including potential for therapeutic targeting of p53 or the JAK/STAT pathway in advanced tumors.

PMID:

 

31857679

 

DOI:

 

10.1038/s41379-019-0424-4

Publication in Diagnostics

Diagnostics (Basel). 2019 Dec 11;9(4). pii: E219. doi: 10.3390/diagnostics9040219.

A Hierarchical Machine Learning Model to Discover Gleason Grade-Specific Biomarkers in Prostate Cancer.

Hamzeh O1, Alkhateeb A1, Zheng JZ1, Kandalam S2, Leung C3, Atikukke G4, Cavallo-Medved D2, Palanisamy N5, Rueda L1.

Author information

1

School of Computer Science, University of Windsor, 401 Sunset Ave, Windsor, ON N9B 3P4, Canada.

2

Department of Biomedical Sciences, University of Windsor, 401 Sunset Ave, Windsor, ON N9B 3P4, Canada.

3

Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON N6A 5C1, Canada.

4

ITOS Oncology Inc., 1453 Prince Rd, Ste: 4125, Windsor, ON N9C 3Z4, Canada.

5

Department of Urology, Henry Ford Health System, One Ford Place, Detroit, MI 48202, USA.

Abstract

(1) Background:One of the most common cancers that affect North American men and men worldwide is prostate cancer. The Gleason score is a pathological grading system to examine the potential aggressiveness of the disease in the prostate tissue. Advancements in computing and next-generation sequencing technology now allow us to study the genomic profiles of patients in association with their different Gleason scores more accurately and effectively. (2) Methods: In this study, we used a novel machine learning method to analyse gene expression of prostate tumours with different Gleason scores, and identify potential genetic biomarkers for each Gleason group. We obtained a publicly-available RNA-Seq dataset of a cohort of 104 prostate cancer patients from the National Center for Biotechnology Information's (NCBI) Gene Expression Omnibus (GEO) repository, and categorised patients based on their Gleason scores to create a hierarchy of disease progression. A hierarchical model with standard classifiers in different Gleason groups, also known as nodes, was developed to identify and predict nodes based on their mRNA or gene expression. In each node, patient samples were analysed via class imbalance and hybrid feature selection techniques to build the prediction model. The outcome from analysis of each node was a set of genes that could differentiate each Gleason group from the remaining groups. To validate the proposed method, the set of identified genes were used to classify a second dataset of 499 prostate cancer patients collected from cBioportal. (3) Results: The overall accuracy of applying this novel method to the first dataset was 93.3%; the method was further validated to have 87% accuracy using the second dataset. This method also identified genes that were not previously reported as potential biomarkers for specific Gleason groups. In particular, PIAS3 was identified as a potential biomarker for Gleason score 4 + 3 = 7, and UBE2V2 for Gleason score 6. (4) Insight: Previous reports show that the genes predicted by this newly proposed method strongly correlate with prostate cancer development and progression. Furthermore, pathway analysis shows that both PIAS3 and UBE2V2 share similar protein interaction pathways, the JAK/STAT signaling process.

KEYWORDS:

Gleason score detection; classification; next generation sequencing; prostate cancer; supervised learning; transcriptomics

PMID:

 

31835700

 

DOI:

 

10.3390/diagnostics9040219