Inherited determinants of early recurrent somatic mutations in prostate cancer

Romanel, Alessandro; Garritano, Sonia; Stringa, Blerta; Blattner, Mirjam; Dalfovo, Davide; Chakravarty, Dimple; Soong, David; Cotter, Kellie A.; Petris, Gianluca; Dhingra, Priyanka; Gasperini, Paola; Cereseto, Anna; Elemento, Olivier; Sboner, Andrea; Khurana, Ekta; Inga, Alberto; Rubin, Mark A.; Demichelis, Francesca

doi:10.1038/s41467-017-00046-0

Cited by 26 publications

(24 citation statements)

References 42 publications

(69 reference statements)

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“…However, no significant association between SPOP mutations with ethnicity, clinical, or pathologic parameters was observed. Interestingly, Romanel et al identified a non-coding polymorphic allele at 7p14.3, associated with SPOP mutations through a hormone dependent DNA damage response [ 200 ]. This genetic predisposition may positively select for SPOP mutations in response to DNA damage.…”

Section: Genomic Landscape Of Advanced and Metastatic Castrate Resmentioning

confidence: 99%

Prostate Cancer Genomics: Recent Advances and the Prevailing Underrepresentation from Racial and Ethnic Minorities

Tan

Petrovics

Srivastava

2018

IJMS

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Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of male cancer deaths in the United States. Among African American (AA) men, CaP is the most prevalent malignancy, with disproportionately higher incidence and mortality rates. Even after discounting the influence of socioeconomic factors, the effect of molecular and genetic factors on racial disparity of CaP is evident. Earlier studies on the molecular basis for CaP disparity have focused on the influence of heritable mutations and single-nucleotide polymorphisms (SNPs). Most CaP susceptibility alleles identified based on genome-wide association studies (GWAS) were common, low-penetrance variants. Germline CaP-associated mutations that are highly penetrant, such as those found in HOXB13 and BRCA2, are usually rare. More recently, genomic studies enabled by Next-Gen Sequencing (NGS) technologies have focused on the identification of somatic mutations that contribute to CaP tumorigenesis. These studies confirmed the high prevalence of ERG gene fusions and PTEN deletions among Caucasian Americans and identified novel somatic alterations in SPOP and FOXA1 genes in early stages of CaP. Individuals with African ancestry and other minorities are often underrepresented in these large-scale genomic studies, which are performed primarily using tumors from men of European ancestry. The insufficient number of specimens from AA men and other minority populations, together with the heterogeneity in the molecular etiology of CaP across populations, challenge the generalizability of findings from these projects. Efforts to close this gap by sequencing larger numbers of tumor specimens from more diverse populations, although still at an early stage, have discovered distinct genomic alterations. These research findings can have a direct impact on the diagnosis of CaP, the stratification of patients for treatment, and can help to address the disparity in incidence and mortality of CaP. This review examines the progress of understanding in CaP genetics and genomics and highlight the need to increase the representation from minority populations.

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Section: Genomic Landscape Of Advanced and Metastatic Castrate Resmentioning

confidence: 99%

Prostate Cancer Genomics: Recent Advances and the Prevailing Underrepresentation from Racial and Ethnic Minorities

Tan

Petrovics

Srivastava

2018

IJMS

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“…More recent work has also suggested a genetic predisposition to this distinct subclass of PCA and this may be modulated by AR signaling and DNA repair alterations. 94…”

Section: Insights Into Genomic Complexitymentioning

confidence: 99%

The Genomics of Prostate Cancer: emerging understanding with technologic advances

Rubin

Demichelis

2018

Modern Pathology

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With the advent of next-generation sequencing technologies and large whole-exome and genome studies in prostate and other cancers, our understanding of the landscape of genomic alterations has dramatically been refined. In additional to well-known alterations in genomic regions involving 8p, 8q, 10q23, common ETS translocations and androgen receptor amplifications, newer technology have uncovered recurrent mutations in SPOP, FOXA1, MED12, IDH and complex large scale genomic alterations (eg, chromoplexy). This review surveys the enhanced landscape of genomic alterations in clinically localized and advanced prostate cancer.

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“…AR enhancer duplication [18,33,34] and RB1 exon 7-17 tandem duplication [106] leading to AR overexpression and RB1 protein loss respectively are relevant examples of events discovered through whole genome sequencing studies. Similarly, SNPs located in noncoding inter-or intragenic regions were shown to be associated with specific subtypes of prostate cancer and with disease aggressiveness [107][108][109][110] .…”

Section: Resultsmentioning

confidence: 99%

Evolution of the prostate cancer genome towards resistance

Lorenzin¹,

Demichelis²

2019

JTGG

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The clinical behavior of prostate cancer is highly heterogeneous, with most patients diagnosed with localized disease that successfully responds to surgery or radiotherapy or that can be followed by active surveillance. However, a fraction of men will relapse after initial treatment and eventually progress to an aggressive resistant form with metastasis spreading and high mortality, a state referred to as castration resistant prostate cancer (CRPC). The technological advances in next generation sequencing have enabled the deep genomic and epigenomic characterization of both the hormone naïve and CRPC states, leading to the definition of molecular subclasses of prostate cancer that could inform the clinicians on therapeutic strategies. These studies also shed light on the mechanisms driving resistance to therapy. CRPCs adapt to androgen receptor (AR) signaling impairment-which follows first-line therapies as androgen deprivation or AR targeting-by restoring the nuclear receptor signaling by means of multiple mechanisms. Alternatively, tumor cells might become resistant to targeted therapies by exploiting lineage plasticity and activating alternative pathways. This review will discuss the main mechanisms leading to the emergence of resistance to therapy in prostate cancer patients in the context of genomic and molecular features of CRPC and on their causal role in the development of resistance.

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Inherited determinants of early recurrent somatic mutations in prostate cancer

Cited by 26 publications

References 42 publications

Prostate Cancer Genomics: Recent Advances and the Prevailing Underrepresentation from Racial and Ethnic Minorities

Prostate Cancer Genomics: Recent Advances and the Prevailing Underrepresentation from Racial and Ethnic Minorities

The Genomics of Prostate Cancer: emerging understanding with technologic advances

Evolution of the prostate cancer genome towards resistance

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