Mismatch Repair Proteins in Recurrent Prostate Cancer

Jarzen, John; Diamanduros, Andrew; Scarpinato, Karin

doi:10.1016/b978-0-12-407681-5.00002-7

Cited by 9 publications

(10 citation statements)

References 79 publications

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“…Most interestingly, four of seven hypermutated cases had complex structural rearrangements in MSH2 and MSH6 that were not detected by exome sequencing in the same samples, and would also not be expected to be detected by traditional exon-based Sanger sequencing methods. Several previous studies have reported MMR protein loss and MSI in both primary and advanced prostate cancers, but very few MMR mutations have been identified89101112131415. We speculate that technical limitations have led to an underestimation of MMR gene mutations in prostate cancer.…”

Section: Discussionmentioning

confidence: 83%

Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer

et al. 2014

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A hypermutated subtype of advanced prostate cancer was recently described, but prevalence and mechanisms have not been well-characterized. Here we find that 12% (7 of 60) of advanced prostate cancers are hypermutated, and that all hypermutated cancers have mismatch repair gene mutations and microsatellite instability (MSI). Mutations are frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1 epigenetic silencing. Our findings identify parallels and differences in the mechanisms of hypermutation in prostate cancer compared with other MSI-associated cancers.

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Section: Discussionmentioning

confidence: 83%

Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer

et al. 2014

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“…The key MMR proteins involved in the process of repair of DNA mismatch replication are MLH1, MSH2, MSH6, and PMS2 [ 7 , 8 , 10 , 11 ]. MSI is an extremely useful tool for the detection of families affected by hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, due to a defect in the DNA MMR system [ 10 – 12 ]. MSI occurs in GC associated not only with Lynch syndrome but also in sporadic GCs due to the somatic alteration of MMR genes promoter methylation [ 9 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Expression of Mismatch Repair Proteins in Early and Advanced Gastric Cancer in Poland

Karpińska-Kaczmarczyk

Lewandowska

Ławniczak

et al. 2016

Med Sci Monit

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BackgroundMutations in DNA of mismatch repair (MMR) genes result in failure to repair errors that occur during DNA replication in microsatellites, resulting in accumulation of frameshift mutations in these genes and leading to DNA mismatch replication errors and microsatellite instability. Gastric cancers (GCs) with high MSI (MSI-H) are a well-defined subset of carcinomas showing distinctive clinicopathological features. In this study we investigated the rate of MSI and the correlation between MSI status and clinicopathological features of GC.Material/MethodsThe study included 107 patients with GCs: 61 with advanced gastric cancers (AGC) and 46 with early gastric cancer (EGC). MSI deficiency in GCs was assessed by the immunohistochemical analysis of expression of MMR proteins – MLH1, MSH2, MSH6, and PMS2 – using formalin-fixed and paraffin-embedded tissue.ResultsA total of 6 (5.6%) MSI-H were observed. The loss of MMR proteins expression was associated with the intestinal type of GC in Lauren classification, and tubular and papillary architecture in WHO classification. There was no statistically significant association between negative MMR expression and other selected clinical parameters: age, sex, tumor location, depth of invasion (EGC and AGC), lymph nodes status, presence of the ulceration, and lymphocytic infiltrate.ConclusionsIn the present era of personalized medicine, the histological type of GC and MMR proteins status in cancer cells are very important for the proper surveillance of patients with familial GC and sporadic GCs, as well as for selecting the proper follow-up and treatment. Larger collaborative studies are needed to verify the features of MSI-H GCs in Poland.

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“…Specifically, early studies of primary PCa found chromosomal loss and instability at microsatellites, regions of the genome containing repeats of one nucleotide or groups of up to 5 [ 144 – 146 ]. The DNA repair pathway studied in early follow up investigations was mismatch repair [ 147 – 149 ], since this pathway is involved in correcting mistakes resulting from slippage at microsatellites during DNA replication [ 150 ]. In addition, loss of mismatch repair function has been associated with microsatellite instability [ 150 ].…”

Section: Resistance Mechanisms Not Related To Androgen Receptormentioning

confidence: 99%

“…The DNA repair pathway studied in early follow up investigations was mismatch repair [ 147 – 149 ], since this pathway is involved in correcting mistakes resulting from slippage at microsatellites during DNA replication [ 150 ]. In addition, loss of mismatch repair function has been associated with microsatellite instability [ 150 ]. When expression of proteins involved in mismatch repair, including MLH1, MSH2, MSH6, PMS1, and PMS2, were assessed by immunoblot in a panel of PCa cell lines, several cell lines had decreased expression of one or more of these proteins compared to HeLa cells that have normal mismatch repair function [ 147 ].…”

Section: Resistance Mechanisms Not Related To Androgen Receptormentioning

confidence: 99%

Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer

2016

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Prostate cancer (PCa) is the most widely diagnosed male cancer in the Western World and while low- and intermediate-risk PCa patients have a variety of treatment options, metastatic patients are limited to androgen deprivation therapy (ADT). This treatment paradigm has been in place for 75 years due to the unique role of androgens in promoting growth of prostatic epithelial cells via the transcription factor androgen receptor (AR) and downstream signaling pathways. Within 2 to 3 years of ADT, disease recurs—at which time, patients are considered to have castration-recurrent PCa (CR-PCa). A universal mechanism by which PCa becomes resistant to ADT has yet to be discovered. In this review article, we discuss underlying molecular mechanisms by which PCa evades ADT. Several major resistance pathways center on androgen signaling, including intratumoral and adrenal androgen production, AR-overexpression and amplification, expression of AR mutants, and constitutively-active AR splice variants. Other ADT resistance mechanisms, including activation of glucocorticoid receptor and impairment of DNA repair pathways are also discussed. New therapies have been approved for treatment of CR-PCa, but increase median survival by only 2-8 months. We discuss possible mechanisms of resistance to these new ADT agents. Finally, the practicality of the application of “precision oncology” to this continuing challenge of therapy resistance in metastatic or CR-PCa is examined. Empirical validation and clinical-based evidence are definitely needed to prove the superiority of “precision” treatment in providing a more targeted approach and curative therapies over the existing practices that are based on biological “cause-and-effect” relationship.

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Mismatch Repair Proteins in Recurrent Prostate Cancer

Cited by 9 publications

References 79 publications

Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer

Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer

Expression of Mismatch Repair Proteins in Early and Advanced Gastric Cancer in Poland

Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer

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