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Fanconi Anemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Since the cloning of the first Fanconi anemia-related gene (FANCC) in 1992, a total of 22 genes (i.e., FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN, FANCO, FANCP, FANCQ, FANCR/RAD51, FANCS, FANCT, FANCU, FANCV, and FANCW) have been isolated and characterized by using complementation analysis of cell lines from affected patients, positional cloning, biochemical purification, and sequencing analysis (Table 73.1). These genes encode components of the FA (or FA/BRCA) pathway that work in coordination to repair DNA damage and ensure genome stability [5]. Homozygous or compound heterozygous mutations in 20 of these genes (except for FANCB and FANCR/RAD51), or heterozygous mutations in FANCR/RAD51, or hemizygous mutations in X-chromosome-linked FANCB result in nonfunctional proteins that cause disruption in the FA pathway, compromise DNA damage repair, and induce various chromosome breaks (Figure 73.1) [6–9].
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Genetics: a genetically heterogeneous disorder, 13 genes have been identified to date, which define the respective FA complementation groups: FANCA (includes the previously designated FANCH), FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG (XRCC9), FANCI (KIAA1794), FANCJ (BRIP1), FANCL (PHF9), FANCM, FANCN ( PALB2), and FANCO ( RAD51C). All the FA subtypes are autosomal recessive disorders, except for FANCB which is X-linked. The products of the genes FANC- A, C, E, F, G, L are part of a nuclear complex which regulate the monoubiquitination of FANCD2 during the S phase of the cell cycle or after DNA damage by crosslinking agents (e.g. mitomycin C, diepoxybutane (DEB), cisplatin), which targets FANCD2 to BRCA1 nuclear foci containing BRCA2 (FANCD1) and RAD51. The FA/BRCA pathway (FANCD1-BRCA2, FANCJ-BRIP1, FANCN-PALB2) is implicated in the repair of DNA damage. The diagnosis first relies on the finding of increased chromosomal breakage or rearrangements when a patient’s cell culture is exposed to diepoxybutane (DEB) or radial figures when exposed to mitomycin C (MMC).
The evolving landscape of PARP inhibitors in castration-resistant prostate cancer: a spotlight on treatment combinations
Published in Expert Review of Clinical Pharmacology, 2022
Benjamin A. Teply, Emmanuel S. Antonarakis
These investigators subsequently expanded the study to a randomized phase II portion, termed the TOPARP-B trial [29]. In this portion of the study, men were first screened for the presence of a potential sensitizing gene alterations for PARP inhibition and only those men with these underlying mutations were treated (i.e. only a biomarker-positive population). For this study, the included genes were: BRCA1, BRCA2, ATM, CDK12, PALB2, ARID1A, ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, MSH2, NBN, RAD50, and WRN. Patients were randomized to either 300 mg or 400 mg doses of olaparib, given orally twice daily. Ninety-eight men were treated, and the most commonly mutated genes were BRCA2 (n = 30), ATM (n = 21), and CDK12 (n = 21). Using the same composite overall response criteria as in the TOPARP-A study, 47% (43 of 92) of men had a response to olaparib, which included 34% by PSA50 criteria and 20% by RECIST 1.1 criteria. However, the responses varied by gene subgroup, with the highest rates of response being in those with BRCA1 or BRCA2 alterations (83%). Median radiographic progression-free survival also varied by subgroup, with the best outcomes reported in the BRCA1 or BRCA2 group at 8.3 months. Overall, the TOPARP-B studied confirmed the activity of olaparib in men with prostate cancer and importantly demonstrated that the underlying biology of the tumor is predictive of response.
Olaparib and rucaparib for the treatment of DNA repair-deficient metastatic castration-resistant prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Benjamin L. Maughan, Emmanuel S. Antonarakis
Because the efficacy of olaparib in the overall unselected population was not sufficient, the TOPARP-B trial was conducted in biomarker-positive patients using a two-dose pick-the-winner design where each dose cohort was independently assessed for the primary endpoint [11]. This was an open-label randomized phase 2 clinical trial. Eligible patients with mCRPC must have had a known pathogenic mutation or homozygous deletion in a HRR gene (BRCA1, BRCA2, ATM, CDK12, PALB2, ARID1A, ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, NBN, RAD50 and WRN). Progression on at least one chemotherapy regimen was required. Patients could not have previously been exposed to platinum chemotherapy, PARPi, cyclophosphamide or mitoxantrone. Patients were randomized 1:1 to olaparib 300 mg or 400 mg twice daily. The primary endpoint was ORR, as defined identically in the TOPARP-A trial. The primary purpose of this trial was to validate the predictive gene panel for PARPi. If both cohorts were determined to be successful as assessed by the primary endpoint then the DNA damage gene panel would be considered validated in predicting response to PARPi.
Investigational PARP inhibitors for the treatment of biliary tract cancer: spotlight on preclinical and clinical studies
Published in Expert Opinion on Investigational Drugs, 2021
Rutika Mehta, Anthony C Wood, James Yu, Richard Kim
Through extensive genome sequencing, multiple other genes have now been identified that play a role in DDR and specifically HRR. These have been identified in different tumor types and while this list is not absolute; some version of this list is being increasingly used to define DDR or HR deficiency (HRD) or BRCAness in cancers. These genes include ATM, ATR, BAP1, BRCA1, BRCA2, CDK12, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, PALB2, NBS1, WRN, RAD51C, RAD51D, MRE11A, CHEK1, BLM, RAD51B, and BRIP1 [21]. But with the vast number of genes involved in the DDR pathway, it can be difficult to predict which mutations are clinically significant and potentially targetable [31,32]. Additionally, epigenetic phenomena that influence gene expression are not routinely accounted for [33]. To get around these dilemma alternative detection methods have been developed to identify tumors that may possess a BRCA-like HRD phenotype. Loss of heterozygosity (LOH) is an allelic imbalance in which a previously heterozygous locus becomes homozygous as the result of the genetic loss of one allele. This type of chromosomal damage is commonly seen in HRD tumors as error-prone repair processes play a more prominent role in the DDR [34].