Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer

Rodrigues, Daniel Nava; Rescigno, Pasquale; Liu, David; Wang, Yuan; Carreira, Suzanne; Lambros, Maryou; Seed, George; Mateo, Joaquín; Riisnaes, Ruth; Mullane, Stephanie A.; Margolis, Claire A.; Miao, Diana; Miranda, Susana; Dolling, David; Clarke, Matthew; Bertan, Claudia; Boysen, Gunther; Ferreira, Ana; Sharp, Adam; Figueiredo, Ines; Keliher, Daniel; AlDubayan, Saud H.; Burke, Kelly P.; Sumanasuriya, Semini; Fontes, Mariane; Bianchini, Diletta; Mendes, Larissa Sena Teixeira; Mouw, Kent W.; Schweizer, Michael T.; Pritchard, Colin C.; Salipante, Stephen J.; Taplin, Mary‐Ellen; Beltran, Himisha; Rubin, Mark A.; Cieślik, Marcin; Robinson, Dan R.; Heath, Elizabeth; Schultz, Nikolaus; Armenia, Joshua; Abida, Wassim; Scher, Howard I.; Lord, Christopher J.; D’Andrea, Alan D.; Sawyers, Charles L.; Chinnaiyan, Arul M.; Alimonti, Andrea; Nelson, Peter S.; Drake, Charles G.; Allen, Eliezer M. Van; Bono, Johann S. de

doi:10.1172/jci125184

Cited by 49 publications

(24 citation statements)

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“… 34 While a study suggests favourable responses to ADT, others have found that MMR-deficient patients develop castration-resistant disease earlier than the MMR-proficient ones. 35 , 36 These differences in outcomes between studies may be related to the limited number of patients included and the different assays used to detect these alterations (targeted sequencing vs. immunohistochemistry). Further studies are needed to completely elucidate the clinical implications of these and other DDR alterations in prostate cancer.…”

Section: Clinical Implications Of Ddr Gene Alterations In Prostate Camentioning

confidence: 99%

Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer

et al. 2020

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Over the past years, several studies have demonstrated that defects in DNA damage response and repair (DDR) genes are present in a significant proportion of patients with prostate cancer. These alterations, particularly mutations in BRCA2, are known to be associated with an increased risk of developing prostate cancer and more aggressive forms of the disease. There is growing evidence that certain DDR gene aberrations confer sensitivity to poly-(ADP ribose) polymerase inhibitors and/or platinum chemotherapy, while other defects might identify cases that are more likely to benefit from immune checkpoint inhibition. The potential prognostic impact and relevance for treatment selection together with the decreasing costs and broader accessibility to next-generation sequencing have already resulted in the increased frequency of genetic profiling of prostate tumours. Remarkably, almost half of all DDR genetic defects can occur in the germline, and prostate cancer patients identified as mutation carriers, as well as their families, will require appropriate genetic counselling. In this review, we summarise the current knowledge regarding the biology and clinical implications of DDR defects in prostate cancer, and outline how this evidence is prompting a change in the treatment landscape of the disease.

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Section: Clinical Implications Of Ddr Gene Alterations In Prostate Camentioning

confidence: 99%

Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer

et al. 2020

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“…In advanced prostate cancer, where two clinical trials testing response to immune checkpoint blockade in unselected patients have failed [80, 81], a report from de Bono and colleagues evaluated the diagnosis of MMRd using a variety of assays including IHC, MSI by PCR, MSI by targeted panel NGS of MMR pathway genes, and MSI by exome sequencing (WES) assay [82]. Their results showed that the PCR-based assay of MSI was more likely to give discordant (presumed false-positive) results when compared to the results of the NGS-based tests.…”

Section: Genomic Instability Neoantigens and Immunotherapy Responsementioning

confidence: 99%

Neoantigens and genome instability: impact on immunogenomic phenotypes and immunotherapy response

Mardis

2019

Genome Med

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The resurgence of immune therapies in cancer medicine has elicited a corresponding interest in understanding the basis of patient response or resistance to these treatments. One aspect of patient response clearly lies in the genomic alterations that are associated with cancer onset and progression, including those that contribute to genomic instability and the resulting creation of novel peptide sequences that may present as neoantigens. The immune reaction to these unique ‘non-self’ peptides is frequently suppressed by the tumor itself, but the use of checkpoint blockade therapies, personalized vaccines, or a combination of these treatments may elicit a tumor-specific immune response that results in cell death. Massively parallel sequencing, coupled with different computational analyses, provides unbiased identification of the germline and somatic alterations that drive cancer development, and of those alterations that lead to neoantigens. These range from simple point mutations that change single amino acids to complex alterations, such as frameshift insertion or deletion mutations, splice-site alterations that lead to exon skipping, structural alterations that lead to the formation of fusion proteins, and other forms of collateral damage caused by genome instability that result in new protein sequences unique to the cancer. The various genome instability phenotypes can be identified as alterations that impact DNA replication or mismatch repair pathways or by their genomic signatures. This review provides an overview of current knowledge regarding the fundamentals of genome replication and of both germline and somatic alterations that disrupt normal replication, leading to various forms of genomic instability in cancers, to the resulting generation of neoantigens and, ultimately, to immune-responsive and resistant phenotypes.

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“…By contrast to p110α and similar to p110β overexpression of p110γ transform cells in vitro, this process still needs upstream signaling input since mutating the Gβγ-binding site on p110γ or p101 severely affects the cell transforming efficiency [54,193]. Nonetheless, copy number gain or increased expression levels rather than mutations were associated with various patients’ tumors such as leukemia and medulloblastoma, as well as breast, liver, pancreatic, ovarian, clear-cell renal carcinoma or prostate cancer [52,152,194,195,196,197]. It is worth mentioning that recurrent mutations of the PIK3CG gene were reported to occur in a considerable number of patients suffering from biliary cancer, metastatic prostate cancer or renal cell carcinoma although the functional consequences remain to be established [50,198,199,200].…”

Section: Biological Functions Of Pi3kγmentioning

confidence: 99%

Function, Regulation and Biological Roles of PI3Kγ Variants

Nürnberg

Beer‐Hammer

2019

Biomolecules

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Phosphatidylinositide 3-kinase (PI3K) γ is the only class IB PI3K member playing significant roles in the G-protein-dependent regulation of cell signaling in health and disease. Originally found in the immune system, increasing evidence suggest a wide array of functions in the whole organism. PI3Kγ occur as two different heterodimeric variants: PI3Kγ (p87) and PI3Kγ (p101), which share the same p110γ catalytic subunit but differ in their associated non-catalytic subunit. Here we concentrate on specific PI3Kγ features including its regulation and biological functions. In particular, the roles of its non-catalytic subunits serving as the main regulators determining specificity of class IB PI3Kγ enzymes are highlighted.

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Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer

Abstract: In Table 2, the mutation for patient no. 11 in the column labeled "cDNA, aa change" is incorrect. The correct mutation is NM_002524.4:c.182A>G; NRAS p.(Q61R). The JCI regrets the error.

Cited by 49 publications

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Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer

Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer

Neoantigens and genome instability: impact on immunogenomic phenotypes and immunotherapy response

Function, Regulation and Biological Roles of PI3Kγ Variants

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