Reference Detail

Ref Type Journal Article
PMID (28765325)
Authors Weigelt B, Comino-Méndez I, de Bruijn I, Tian L, Meisel JL, García-Murillas I, Fribbens C, Cutts R, Martelotto LG, Ng CKY, Lim RS, Selenica P, Piscuoglio S, Aghajanian C, Norton L, Murali R, Hyman DM, Borsu L, Arcila ME, Konner J, Reis-Filho JS, Greenberg RA, Robson ME, Turner NC
Title Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 21
Date 2017 Nov 01
URL
Abstract Text Purpose: Resistance to platinum-based chemotherapy or PARP inhibition in germline BRCA1 or BRCA2 mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether BRCA1/2 reversion mutations could be identified in circulating cell-free DNA (cfDNA) of patients with ovarian or breast cancer previously treated with platinum and/or PARP inhibitors.Experimental Design: cfDNA from 24 prospectively accrued patients with germline BRCA1 or BRCA2 mutations, including 19 patients with platinum-resistant/refractory ovarian cancer and five patients with platinum and/or PARP inhibitor pretreated metastatic breast cancer, was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of BRCA1 and BRCA2 Functional studies were performed to assess the impact of the putative BRCA1/2 reversion mutations on BRCA1/2 function.Results: Diverse and often polyclonal putative BRCA1 or BRCA2 reversion mutations were identified in cfDNA from four patients with ovarian cancer (21%) and from two patients with breast cancer (40%). BRCA2 reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a patient with breast cancer who did not respond to treatment and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function.Conclusions: Putative BRCA1/2 reversion mutations can be detected by cfDNA sequencing analysis in patients with ovarian and breast cancer. Our findings warrant further investigation of cfDNA sequencing to identify putative BRCA1/2 reversion mutations and to aid the selection of patients for PARP inhibition therapy. Clin Cancer Res; 23(21); 6708-20. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
E29Sfs*2 frameshift loss of function - predicted BRCA1 E29Sfs*2 indicates a shift in the reading frame starting at amino acid 29 and terminating 2 residues downstream causing a premature truncation of the 1863 aa Brca1 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), E29Sfs*2 is predicted to result in a loss of Brca1 protein function; however, the corresponding cDNA change has been demonstrated to act as a reversion mutation in the context of a specific inactivating BRCA1 mutation, leading to restoration of the BRCA1 open reading frame and wild-type protein function, as demonstrated by induction of Brca1 foci formation following ionizing irradiation in vitro and association with acquired resistance to platinum-based chemotherapy (PMID: 28765325). Y
I1318Lfs*7 frameshift loss of function - predicted BRCA1 I1318Lfs*7 indicates a shift in the reading frame starting at amino acid 1318 and terminating 7 residues downstream causing a premature truncation of the 1863 aa Brca1 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), I1318Lfs*7 is predicted to result in a loss of Brca1 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA1 mutation, potentially leading to restoration of the BRCA1 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy (PMID: 28765325). Y
K38Sfs*12 frameshift loss of function - predicted BRCA1 K38Sfs*12 indicates a shift in the reading frame starting at amino acid 38 and terminating 12 residues downstream causing a premature truncation of the 1863 aa Brca1 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), K38Sfs*12 is predicted to result in a loss of Brca1 protein function; however, the corresponding cDNA change has been demonstrated to act as a reversion mutation in the context of a specific inactivating BRCA1 mutation, leading to restoration of the BRCA1 open reading frame and wild-type protein function, as demonstrated by induction of Brca1 foci formation following ionizing irradiation in vitro and association with acquired resistance to platinum-based chemotherapy (PMID: 28765325). Y
N1309Ifs*9 frameshift loss of function - predicted BRCA1 N1309Ifs*9 indicates a shift in the reading frame starting at amino acid 1309 and terminating 9 residues downstream causing a premature truncation of the 1863 aa Brca1 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), N1309Ifs*9 is predicted to result in a loss of Brca1 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA1 mutation, potentially leading to restoration of the BRCA1 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy (PMID: 28765325). Y
S1596Nfs*25 frameshift loss of function - predicted BRCA1 S1596Nfs*25 indicates a shift in the reading frame starting at 1596 and terminating 25 residues downstream causing a premature truncation of the 1863 aa Brca1 protein (UniProt.org). S1596Nfs*25 has not been characterized, however, other BRCT domain deletions downstream of S1596 are destabilizing (PMID: 14534301), thus S1596Nfs*25 is predicted to lead to a loss of Brca1 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA1 mutation, potentially leading to restoration of the BRCA1 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy (PMID: 28765325). Y
T37Qfs*13 frameshift loss of function - predicted BRCA1 T37Qfs*13 indicates a shift in the reading frame starting at amino acid 37 and terminating 13 residues downstream causing a premature truncation of the 1863 aa Brca1 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), T37Qfs*13 is predicted to result in a loss of Brca1 protein function; however, the corresponding cDNA change has been demonstrated to act as a reversion mutation in the context of a specific inactivating BRCA1 mutation, leading to restoration of the BRCA1 open reading frame and wild-type protein function, as demonstrated by induction of Brca1 foci formation following ionizing irradiation in vitro and association with acquired resistance to platinum-based chemotherapy (PMID: 28765325). Y
A248Sfs*15 frameshift loss of function - predicted BRCA2 A248Sfs*15 indicates a shift in the reading frame starting at amino acid 248 and terminating 15 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), A248Sfs*15 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
D244Efs*10 frameshift loss of function - predicted BRCA2 D244Efs*10 indicates a shift in the reading frame starting at amino acid 244 and terminating 10 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), D244Efs*10 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
D244Rfs*7 frameshift loss of function - predicted BRCA2 D244Rfs*7 indicates a shift in the reading frame starting at amino acid 244 and terminating 7 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), D244Rfs*7 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
E260Sfs*15 frameshift loss of function - predicted BRCA2 E260Sfs*15 indicates a shift in the reading frame starting at amino acid 260 and terminating 15 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), E260Sfs*15 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
I247_E254del deletion unknown BRCA2 I247_E254del results in the deletion of 8 amino acids of the Brca2 protein from amino acids 247 to 254 (UniProt.org). I247_E254del has not been characterized in the scientific literature and therefore, its effect on Brca2 protein function is unknown; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
I247Kfs*2 frameshift loss of function - predicted BRCA2 I247Kfs*2 indicates a shift in the reading frame starting at amino acid 247 and terminating 2 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), I247Kfs*2 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
I247Yfs*8 frameshift loss of function - predicted BRCA2 I247Yfs*8 indicates a shift in the reading frame starting at amino acid 247 and terminating 8 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), I247Yfs*8 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
N136_L139del deletion unknown BRCA2 N136_L139del results in the deletion of 4 amino acids of the Brca2 protein from amino acids 136 to 139 (UniProt.org). N136_L139del has not been characterized in the scientific literature and therefore, its effect on Brca2 protein function is unknown; however, the corresponding cDNA change has been demonstrated to act as a reversion mutation in the context of a specific inactivating BRCA1 mutation, leading to restoration of the BRCA1 open reading frame and wild-type protein function, as demonstrated by interaction with Palb2 and Rad51 similar to wild-type Brca2 levels in culture and association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
N243Kfs*3 frameshift loss of function - predicted BRCA2 N243Kfs*3 indicates a shift in the reading frame starting at amino acid 243 and terminating 3 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), N243Kfs*3 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
N255Tfs*21 frameshift loss of function - predicted BRCA2 N255Tfs*21 indicates a shift in the reading frame starting at amino acid 255 and terminating 21 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), N255Tfs*21 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
N257Efs*19 frameshift loss of function - predicted BRCA2 N257Efs*19 indicates a shift in the reading frame starting at amino acid 257 and terminating 19 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), N257Efs*19 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
N257Kfs*17 frameshift loss of function - predicted BRCA2 N257Kfs*17 indicates a shift in the reading frame starting at amino acid 257 and terminating 17 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), N257Kfs*17 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
N272Kfs*2 frameshift loss of function - predicted BRCA2 N272Kfs*2 indicates a shift in the reading frame starting at amino acid 272 and terminating 2 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), N272Kfs*2 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
R245_D252del deletion unknown BRCA2 R245_D252del results in the deletion of 8 amino acids of the Brca2 protein from amino acids 245 to 252 (UniProt.org). R245_D252del has not been characterized in the scientific literature and therefore, its effect on Brca2 protein function is unknown; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
T256Kfs*19 frameshift loss of function - predicted BRCA2 T256Kfs*19 indicates a shift in the reading frame starting at amino acid 256 and terminating 19 residues downstream causing a premature truncation of the 3418 amino acid Brca2 protein (UniProt.org). Due to the loss of most known functional domains (UniProt.org), T256Kfs*19 is predicted to result in a loss of Brca2 protein function; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
V130_N136delinsD indel unknown BRCA2 V130_N136delinsD results in a deletion of seven amino acids of the Brca2 protein from amino acids 130 to 136, combined with the insertion of an aspartate (D) at the same site (UniProt.org). V130_N136delinsD has not been characterized in the scientific literature and therefore, its effect on Brca2 protein function is unknown; however, the corresponding cDNA change has been predicted to act as a reversion mutation in the context of a specific inactivating BRCA2 mutation, potentially leading to restoration of the BRCA2 open reading frame and wild-type protein function, as demonstrated by association with acquired resistance to platinum-based chemotherapy and a PARP inhibitor (PMID: 28765325). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRCA2 D244Efs*10 BRCA2 D244Rfs*7 BRCA2 D252Vfs*24 BRCA2 E260Sfs*15 BRCA2 I247_E254del BRCA2 I247Yfs*8 BRCA2 N255Tfs*21 BRCA2 N257Efs*19 BRCA2 R245_D252del BRCA2 T256Kfs*19 breast cancer predicted - resistant Carboplatin + Olaparib Case Reports/Case Series Actionable In a clinical case study, a breast cancer patient harboring BRCA2 D252Vfs*24 progressed while being treated with Carboplatin and a PARP inhibitor, and via cell-free DNA testing was found to have acquired nine somatic reversion mutations, BRCA2 D244Efs*10, BRCA2 D244Rfs*7, BRCA2 E260Sfs*15, BRCA2 I247_E254del, BRCA2 I247Yfs*8, BRCA2 N255Tfs*21, BRCA2 N257Efs*19, BRCA2 R245_D252del, BRCA2 T256Kfs*19, which restored the open reading frame, resulting in wild-type BRCA2 protein function (PMID: 28765325). 28765325
BRCA1 E23Vfs*17 BRCA1 E29Sfs*2 BRCA1 K38Sfs*12 ovarian cancer predicted - resistant Carboplatin Case Reports/Case Series Actionable In a clinical case study, an ovarian cancer patient harboring BRCA1 E23Vfs*17 progressed while being treated with platinum-based chemotherapy, and via cell-free DNA testing was found to have acquired somatic reversion mutations, BRCA1 E29Sfs*2 and BRCA1 K38Sfs*12, which restored the open reading frame, resulting in wild-type BRCA1 protein function (PMID: 28765325). 28765325
BRCA1 E23Vfs*17 BRCA1 T37Qfs*13 ovarian cancer predicted - resistant Carboplatin Case Reports/Case Series Actionable In a clinical case study, an ovarian cancer patient harboring BRCA1 E23Vfs*17 progressed while being treated with platinum-based chemotherapy, and via cell-free DNA testing was found to have acquired a somatic reversion mutation, BRCA1 T37Qfs*13, which restored the open reading frame, resulting in wild-type BRCA1 protein function (PMID: 28765325). 28765325
BRCA2 N136_L139del BRCA2 N136Ifs*16 BRCA2 V130_N136delinsD breast cancer predicted - resistant Talazoparib Case Reports/Case Series Actionable In a clinical case study, a patient with breast cancer harboring the germline mutation, BRCA2 N136Ifs*16, acquired two BRCA2 reversion mutations, V130_N136delinsD and N136_L139del, as detected in cell-free DNA post treatment with Paraplatin (carboplatin), and subsequently, did not respond to treatment with Talazoparib (BMN-673) (PMID: 28765325). 28765325