Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations

Ali, Siraj M.; Pal, Sumanta K.; Wang, Kai; Palma, Norma Alonzo; Sanford, Eric M.; Bailey, Mark; He, Jie; Elvin, Julia A.; Chmielecki, Juliann; Squillace, Rachel M.; Dow, Edward; Morosini, Deborah; Buell, Jamie; Yelensky, Roman; Lipson, Doron; Frampton, Garrett M.; Howley, Peter; Ross, Jeffrey S.; Stephens, Philip J.; Miller, Vincent A.

doi:10.1634/theoncologist.2015-0241

Cited by 70 publications

(52 citation statements)

References 27 publications

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“…All of these mutations were validated by Sanger sequencing. Among the 11 frequently mutated genes, FAT1, HRAS, NOTCH1, TP53 and PIK3CA have been found to be frequently mutated in penile cancer, 18,[20][21][22][23] whereas the remaining six genes were newly discovered as frequently mutated genes for this type of cancer. In addition, less frequent alterations in our series also included known penile cancer-related genes (e.g., NFE2L2).…”

Section: Somatic Mutations In Penile Carcinomamentioning

confidence: 99%

“…Somatic mutations in the PIK3CA , HRAS , KRAS and STK11 genes have been previously identified in penile carcinoma samples, suggesting a potential role of the phosphatidylinositol 3‐kinase or Ras pathway . In addition, TP53 alterations, EGFR amplification and CSN1 mutation are frequent in primary penile tumor/lymph node metastases . However, the etiology of penile cancer is largely unknown, and the current knowledge of the involved genetic alterations remains limited.…”

Section: Introductionmentioning

confidence: 99%

“…18,19,21 In addition, TP53 alterations, EGFR amplification and CSN1 mutation are frequent in primary penile tumor/lymph node metastases. 20,22,23 However, the etiology of penile cancer is largely unknown, and the current knowledge of the involved genetic alterations remains limited. In particular, molecular heterogeneity in cancer across ethnics is probable but poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Mutational landscape of penile squamous cell carcinoma in a Chinese population

Wang

Chen

et al. 2019

Intl Journal of Cancer

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Penile squamous cell carcinoma (PSCC) is a malignancy that affects the skin and tissues of the penis, but the knowledge of pathogenesis and carcinogenesis is limited. Here, we characterize the PSCC genomic landscape using whole‐exome sequencing. Of the 30 paired blood and tumor samples, we identified recurrent mutations in 11 genes; confirmed previous findings for FAT1 (4/30), HRAS (4/30), NOTCH1 (4/30), TP53 (3/30) and PIK3CA (3/30); and revealed novel candidate driver genes [CASP8 (4/30), SLITRK2 (3/30), FLG (3/30) and TRRAP (3/30)]. Our in vitro experiments suggested CASP8 was involved in mediating TRAIL‐induced apoptosis of penile cancer cell lines. We also observed the frequently altered pathways for potential therapeutic implications: alterations in the Notch (30% of sample altered), RTK–RAS (26.7% altered) and Hippo (23.3% altered) pathways accounted for over 50% of tumors. The frequently altered genes (>10%) in these pathways were proved to be expressed in penile tumors by immunohistochemistry assay. These findings provide new insight into the mutational and pathway landscapes of PSCC and suggest potential novel therapeutic opportunities for this malignancy.

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Section: Somatic Mutations In Penile Carcinomamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutational landscape of penile squamous cell carcinoma in a Chinese population

Wang

Chen

et al. 2019

Intl Journal of Cancer

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“…67,68 Hence, the results indicate that EGFR activation has a key role in the development of the tumor and suggest that EGFR-targeted therapy may have antitumor activity in PeCa, reinforcing the clinical trials results. [68][69][70][71] However, to better understand this association, prospective studies investigating larger samples sizes are needed to perform the molecular characterization and viral genotyping in countries presenting high incidence of PeCa.…”

mentioning

confidence: 99%

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

Macedo

Silva

Nogueira³

et al. 2020

Molecular Carcinogenesis

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The incidence of penile cancer (PeCa) is increasing worldwide, however, the highest rates are reported in underdeveloped countries. The molecular mechanisms that underly the onset and progression of these tumors are still unclear. Therefore, our goal was to determine the genome-wide copy number alterations and the involvement of human papiloma virus (HPV) (TP53 and RB1), inflammatory (COX2 and EGFR), and PI3K/AKT pathway (AKT1, AKT2, EGFR, ERBB3, ERBB4, PIK3CA, and PTEN) associated genes in patients with PeCa from a high incidence region in Brazil (Maranhão). HPV genotyping was performed by nest-PCR and genome sequencing, copy number alterations (CNAs) by array comparative genomic hybridization and gene copy number status, gene, and protein expression by quantitative polymerase chain reaction, reverse transcriptasequantitative polymerase chain reaction, and immunohistochemistry, respectively.HPV genotyping revealed one of the highest frequencies of HPV reported in PeCa, affecting 96.4% of the cases. The most common CNAs observed were located at the HPV integration sites, such as 2p12-p11.2 and 14q32.33, where Abbreviations: aCGH, array comparative genomic hybridization; CNA, copy number alteration; Cq, quantification cycle; FFPE, formalin-fixed paraffin-embedded; HPV, human papiloma virus;HrHPV, High risk HPV; IHCi, mmunohistochemistry; PCR, polymerase chain reaction; PeCa, penile cancer; qPCR, quantitative polymerase chain reaction; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction; TMA, tissue microarray. ADAM 6, KIAA0125, LINC00226, LINC00221, and miR7641-2, are mapped. Increased copy number of ERBB3 and EGFR genes were observed in association with COX2 and EGFR overexpression, reinforcing the role of the inflammatory pathway in PeCa, and suggesting anti-EGFR and anti-COX2 inhibitors as promising therapies for PeCa. Additionally, TP53 and RB1 messenger RNA downregulation was observed, suggesting the occurrence of other mechanisms for repression of these oncoproteins, in addition to the canonical HPV/TP53/RB1 signaling pathway. Our data reinforce the role of epigenetic events in abnormal gene expression in HPV-associated carcinomas and suggest the pivotal role of HPV driving CNAs and controlling gene expression in PeCa. K E Y W O R D Scarcinoma of the penis, genomic alterations, human papillomavirus, molecular markers

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“…Molecular alterations in PeCa have been described only recently by our group and others [19,[21][22][23][24][25][26][27][28][29][30]. Interestingly, contrary to the findings described in breast and prostate cancers, AR mRNA is down-expressed in PeCa [19].…”

Section: Introductionmentioning

confidence: 64%

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor

et al. 2018

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Androgen receptor (AR) is a member of the steroid and nuclear family receptor that acts as transcription factor. AR signaling plays pivotal role in the development and progression of prostate cancer. However, the role of AR in penile cancer (PeCa) is poorly explored. Our previous molecular studies unveiled frequent AR mRNA loss in PeCa, which was further predicted as a major driver alteration in this neoplasm. Herein, we assessed the AR protein expression in 59 usual PeCa tissues and 42 surrounding normal tissues (SNT) by immunohistochemistry using a tissue microarray. In a paired analysis, we found a total absence of nuclear AR expression in PeCa while 95.2% of SNT samples presented strong nuclear AR expression (P < 0.001). Interestingly, 17 of 42 PeCa presented weak or moderate cytoplasmic AR staining, contrasting with 5 of 42 SNT (P = 0.008). Increased levels of AR cytoplasmic expression were related with poor prognosis features including advanced clinical staging (P = 0.044), compromised surgical margins (P = 0.005), and pathological inguinal node status (P = 0.047). Furthermore, AR cytoplasmic expression was also related with shorter overall survival (P = 0.032). In conclusion, the frequent loss of nuclear AR protein levels suggests a potential function in PeCa development. Based on this result, the androgen deprivation therapy is not indicated for PeCa patients. In addition, the AR cytoplasmic expression found in a significant number of cases (40.5%) showed prognostic value and pathways activated by the non-genomic AR signaling may represent a promising therapeutic strategy.

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Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations

Cited by 70 publications

References 27 publications

Mutational landscape of penile squamous cell carcinoma in a Chinese population

Mutational landscape of penile squamous cell carcinoma in a Chinese population

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor

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