Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair

Sulkowski, Parker L.; Sundaram, Ranjini K.; Oeck, Sebastian; Corso, Christopher D.; Liu, Yanfeng; Noorbakhsh, Seth; Niger, Monica; Boeke, Marta; Ueno, Daiki; Kalathil, Aravind N.; Bao, Xun; Li, Jing; Shuch, Brian; Bindra, Ranjit S.; Glazer, Peter M.

doi:10.1038/s41588-018-0170-4

Cited by 168 publications

(142 citation statements)

References 20 publications

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“…For example, deleterious variants in non-BRCA HRR genes such as ATM, PALB2, and RAD51 lead to functional HRR deficiency and sensitivity to PARP inhibition. Outside of canonical HRR pathway genes, mutations in Krebs cycle genes such as IDH1 or FH lead to oncometabolite production that results in reduced expression of HRR gene activity (52,53). In addition, mutations in key chromatin regulators, such as ARID1A (54) and BAP1 (55,56), give way to an HRD phenotype via loss of sustained DDR signaling and ubiquitylation activity that is needed in DSB repair.…”

Section: Clinical Studiesmentioning

confidence: 99%

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Pilié

Byers

O’Connor

et al. 2019

Clinical Cancer Research

283

206

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A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. Although PARP inhibitors as a class display many similarities, critical differences in structure can translate into differences in tolerability and antitumor activity that have important implications for the clinic. Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small-cell lung cancer. In this article, we highlight the key similarities and differences between individual PARP inhibitors and their implications for the clinic. We discuss data that currently support clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers, toward broader populations of patients through the use of novel biomarkers of homologous recombination repair deficiency (HRD), as well as predictive biomarkers rooted in mechanisms of sensitivity outside of HRD. We also explore the potential application of PARP inhibitors in earlier treatment settings, including neoadjuvant, adjuvant, and even chemoprevention approaches. Finally, we focus on promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non-DDR-targeted agents that induce "chemical BRCAness."

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Section: Clinical Studiesmentioning

confidence: 99%

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Pilié

Byers

O’Connor

et al. 2019

Clinical Cancer Research

283

206

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“…The FH gene, located on chromosome region 1q42.1, is a tumor suppressor gene that encodes the enzyme fumarate hydratase (fumarase), which plays a role in both the tricarboxylic acid (TCA) cycle in mitochondria, as well as the Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1068 9-019-00155 -3) contains supplementary material, which is available to authorized users. response to DNA double strand breaks in the nucleus [3,9]. Somatic inactivation of the second allele can be demonstrated in most, but not all, HLRCC-related tumors [2,[10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Renal cell carcinoma in young FH mutation carriers: case series and review of the literature

et al. 2019

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Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant syndrome caused by heterozygous pathogenic germline variants in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and an increased risk of developing renal cell carcinoma (RCC), which is usually adult-onset. HLRCC-related RCC tends to be aggressive and can metastasize even when the primary tumor is small. Data on children and adolescents are scarce. Herein, we report two patients from unrelated Dutch families, with HLRCC-related RCC at the ages of 15 and 18 years, and a third patient with an FH mutation and complex renal cysts at the age of 13. Both RCC's were localized and successfully resected, and careful MRI surveillance was initiated to monitor the renal cysts. One of the patients with RCC subsequently developed an ovarian Leydig cell tumor. A review of the literature identified 10 previously reported cases of HLRCC-related RCC in patients aged younger than 20 years, five of them presenting with metastatic disease. These data emphasize the importance of recognizing HLRCC in young patients to enable early detection of RCC, albeit rare. They support the recommendations from the 2014 consensus guideline, in which genetic testing for FH mutations, and renal MRI surveillance, is advised for HLRCC family members from the age of 8-10 years onwards.

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“…Mutations in these genes result in the accumulation of fumarate and succinate, which stabilize HIF and shift cell metabolism towards aerobic glycolysis. In addition to this metabolic shift, the loss of function of TCA cycle genes leads to subsequent build-up of their associated oncometabolites, which in turn have inhibitory effects on ␣-ketoglutarate (␣KG)-dependent dioxygenases [38,39]. Preclini-cal data suggest that pathogenic mutations in FH or SDH lead to suppression of specific ␣KG-dependent dioxygenases, KDM4A and KDM4B, and indirectly subsequent deficient DNA DSB repair in the HRR pathway [38].…”

Section: Metabolic Genesmentioning

confidence: 99%

Genomic Instability in Kidney Cancer: Etiologies and Treatment Opportunities

Pilié

2019

KCA

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Genomic instability is a hallmark of cancer, allowing for cancer initiation, proliferation, and progression through the accumulation of driver mutations. This instability seen in cancer arises due to a variety of factors in the cancer cell itself as well as in the cell's environment, including endogenous and exogenous stressors leading to DNA damage in the setting of deficiency in DNA damage response (DDR). While genomic instability is beneficial to cancer cell growth and survival, it also creates targetable vulnerabilities in the cell. Kidney cancer displays low to moderate genomic instability, yet does not have frequent mutations in canonical DDR genes and is not typically responsive to DNA damaging therapies. In this review, the etiology of genomic instability in kidney cancer, with a primary focus on clear cell renal cell carcinoma (ccRCC) histology, is discussed; and, pre-clinical data supporting the use of agents targeting DDR in ccRCC is summarized with associated progress towards clinical applications.

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Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair

Cited by 168 publications

References 20 publications

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Renal cell carcinoma in young FH mutation carriers: case series and review of the literature

Genomic Instability in Kidney Cancer: Etiologies and Treatment Opportunities

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