Reference Detail

Ref Type Journal Article
PMID (29736026)
Authors Shen J, Ju Z, Zhao W, Wang L, Peng Y, Ge Z, Nagel ZD, Zou J, Wang C, Kapoor P, Ma X, Ma D, Liang J, Song S, Liu J, Samson LD, Ajani JA, Li GM, Liang H, Shen X, Mills GB, Peng G
Title ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade.
Journal Nature medicine
Vol
Issue
Date 2018 May 07
URL
Abstract Text ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer1,2. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression 3 , which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
D1838* nonsense loss of function - predicted ARID1A D1838* results in a premature truncation of the Arid1a protein at amino acid 1838 of 2285 (UniProt.org). D1838* has not been characterized, however, due to the effects of truncation mutations downstream of D1838 (PMID: 29736026), D1838* is predicted to lead to a loss of Arid1a protein function.
E1596* nonsense loss of function - predicted ARID1A E1596* results in a premature truncation of the Arid1a protein at amino acid 1596 of 2285 (UniProt.org). E1596* has not been characterized, however, due to the effects of truncation mutations downstream of E1596 (PMID: 26069190, PMID: 29736026), E1596* is predicted to lead to a loss of Arid1a protein function.
E1764* nonsense loss of function - predicted ARID1A E1764* results in a premature truncation of the Arid1a protein at amino acid 1764 of 2285 (UniProt.org). E1764* has not been characterized, however, due to the effects of truncation mutations downstream of E1764 (PMID: 29736026), E1764* is predicted to lead to a loss of Arid1a protein function.
E1776* nonsense loss of function - predicted ARID1A E1776* results in a premature truncation of the Arid1a protein at amino acid 1776 of 2285 (UniProt.org). E1776* has not been characterized, however, due to the effects of truncation mutations downstream of E1776 (PMID: 29736026), E1776* is predicted to lead to a loss of Arid1a protein function.
E1780* nonsense loss of function - predicted ARID1A E1780* results in a premature truncation of the Arid1a protein at amino acid 1780 of 2285 (UniProt.org). E1780* has not been characterized, however, due to the effects of truncation mutations downstream of E1780 (PMID: 29736026), E1780* is predicted to lead to a loss of Arid1a protein function.
G1450fs frameshift loss of function - predicted ARID1A G1450fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1450 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). G1450fs has not been characterized, however, due to the effects of truncation mutations downstream of G1450 (PMID: 26069190, PMID: 29736026), G1450fs is predicted to lead to a loss of Arid1a protein function.
G1848fs frameshift loss of function - predicted ARID1A G1848fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1848 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). G1848fs is associated with loss of Arid1a protein expression in a cell line in culture (PMID: 27486766), and due to the effects of other truncation mutations downstream of G1848 (PMID: 29736026), G1848fs is predicted to lead to a loss of Arid1a protein function.
K1071fs frameshift loss of function - predicted ARID1A K1071fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1071 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). K1071fs has not been characterized, however, due to the effects of truncation mutations downstream of K1071 (PMID: 26069190, PMID: 29736026), K1071fs is predicted to lead to a loss of Arid1a protein function.
L1092* nonsense loss of function - predicted ARID1A L1092* results in a premature truncation of the Arid1a protein at amino acid 1092 of 2285 (UniProt.org). L1092* has not been characterized, however, due to the effects of truncation mutations downstream of L1092 (PMID: 26069190, PMID: 29736026), L1092* is predicted to lead to a loss of Arid1a protein function.
M1318fs frameshift loss of function - predicted ARID1A M1318fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1318 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). M1318fs has not been characterized, however, due to the effects of truncation mutations downstream of M1318 (PMID: 26069190, PMID: 29736026), M1318fs is predicted to lead to a loss of Arid1a protein function.
Q1095* nonsense loss of function - predicted ARID1A Q1095* results in a premature truncation of the Arid1a protein at amino acid 1095 of 2285 (UniProt.org). Q1095* has not been characterized, however, due to the effects of truncation mutations downstream of Q1095 (PMID: 26069190, PMID: 29736026), Q1095* is predicted to lead to a loss of Arid1a protein function.
Q1131* nonsense loss of function - predicted ARID1A Q1131* results in a premature truncation of the Arid1a protein at amino acid 1131 of 2285 (UniProt.org). Q1131* has not been characterized, however, due to the effects of truncation mutations downstream of Q1131 (PMID: 26069190, PMID: 29736026), Q1131* is predicted to lead to a loss of Arid1a protein function.
Q1148* nonsense loss of function - predicted ARID1A Q1148* results in a premature truncation of the Arid1a protein at amino acid 1148 of 2285 (UniProt.org). Q1148* has not been characterized, however, due to the effects of truncation mutations downstream of Q1148 (PMID: 26069190, PMID: 29736026), Q1148* is predicted to lead to a loss of Arid1a protein function.
Q1212* nonsense loss of function - predicted ARID1A Q1212* results in a premature truncation of the Arid1a protein at amino acid 1212 of 2285 (UniProt.org). Q1212* has not been characterized, however, due to the effects of truncation mutations downstream of Q1212 (PMID: 26069190, PMID: 29736026), Q1212* is predicted to lead to a loss of Arid1a protein function.
Q1479* nonsense loss of function - predicted ARID1A Q1479* results in a premature truncation of the Arid1a protein at amino acid 1479 of 2285 (UniProt.org). Q1479* has not been characterized, however, due to the effects of truncation mutations downstream of Q1479 (PMID: 26069190, PMID: 29736026), Q1479* is predicted to lead to a loss of Arid1a protein function.
Q1741* nonsense loss of function - predicted ARID1A Q1741* results in a premature truncation of the Arid1a protein at amino acid 1741 of 2285 (UniProt.org). Q1741* has not been characterized, however, due to the effects of truncation mutations downstream of Q1741 (PMID: 26069190, PMID: 29736026), Q1741* is predicted to lead to a loss of Arid1a protein function.
Q1856* nonsense loss of function - predicted ARID1A Q1856* results in a premature truncation of the Arid1a protein at amino acid 1856 of 2285 (UniProt.org). Q1856* has not been biochemically characterized, however, due to the effects of truncation mutations downstream of Q1856 (PMID: 29736026), Q1856* is predicted to lead to a loss of Arid1a protein function.
Q1894* nonsense loss of function - predicted ARID1A Q1894* results in a premature truncation of the Arid1a protein at amino acid 1894 of 2285 (UniProt.org). Q1894* has not been characterized, however, due to the effects of truncation mutations downstream of Q1894 (PMID: 29736026), Q1894* is predicted to lead to a loss of Arid1a protein function.
R1446* nonsense loss of function - predicted ARID1A R1446* results in a premature truncation of the Arid1a protein at amino acid 1446 of 2285 (UniProt.org). R1446* has not been characterized, however, due to the effects of truncation mutations downstream of R1446 (PMID: 26069190, PMID: 29736026), R1446* is predicted to lead to a loss of Arid1a protein function.
R1528* nonsense loss of function - predicted ARID1A R1528* results in a premature truncation of the Arid1a protein at amino acid 1528 of 2285 (UniProt.org). R1528* has not been characterized, however, due to the effects of truncation mutations downstream of R1528 (PMID: 26069190, PMID: 29736026), R1528* is predicted to lead to a loss of Arid1a protein function.
R1721* nonsense loss of function - predicted ARID1A R1721* results in a premature truncation of the Arid1a protein at amino acid 1721 of 2285 (UniProt.org). R1721* has not been characterized, however, due to the effects of truncation mutations downstream of R1721 (PMID: 26069190, PMID: 29736026), R1721* is predicted to lead to a loss of Arid1a protein function.
R1721fs frameshift loss of function - predicted ARID1A R1721fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1721 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). R1721fs has not been characterized, however, due to the effects of truncation mutations downstream of R1721 (PMID: 26069190, PMID: 29736026), R1721fs is predicted to lead to a loss of Arid1a protein function.
R1722* nonsense loss of function - predicted ARID1A R1722* results in a premature truncation of the Arid1a protein at amino acid 1722 of 2285 (UniProt.org). R1722* has not been characterized, however, due to the effects of truncation mutations downstream of R1722 (PMID: 26069190, PMID: 29736026), R1722* is predicted to lead to a loss of Arid1a protein function.
R1989* nonsense loss of function - predicted ARID1A R1989* results in a premature truncation of the Arid1a protein at amino acid 1989 of 2285 (UniProt.org). R1989* is associated with loss of Arid1a protein expression in culture and therefore, is predicted to confer a loss of function on the Arid1a protein (PMID: 29736026).
S1248* nonsense loss of function - predicted ARID1A S1248* results in a premature truncation of the Arid1a protein at amino acid 1248 of 2285 (UniProt.org). S1248* has not been characterized, however, due to the effects of truncation mutations downstream of S1248 (PMID: 26069190, PMID: 29736026), S1248* is predicted to lead to a loss of Arid1a protein function.
V1561fs frameshift loss of function - predicted ARID1A V1561fs results in a change in the amino acid sequence of the Arid1a protein beginning at aa 1561 of 2285, likely resulting in premature truncation of the functional protein (UniProt.org). V1561fs has not been characterized, however, due to the effects of truncation mutations downstream of V1561 (PMID: 26069190, PMID: 29736026), V1561fs is predicted to lead to a loss of Arid1a protein function.
W1545* nonsense loss of function - predicted ARID1A W1545* results in a premature truncation of the Arid1a protein at amino acid 1545 of 2285 (UniProt.org). W1545* has not been characterized, however, due to the effects of truncation mutations downstream of W1545 (PMID: 26069190, PMID: 29736026), W1545* is predicted to lead to a loss of Arid1a protein function.
W1670* nonsense loss of function - predicted ARID1A W1670* results in a premature truncation of the Arid1a protein at amino acid 1670 of 2285 (UniProt.org). W1670* has not been characterized, however, due to the effects of truncation mutations downstream of W1670 (PMID: 26069190, PMID: 29736026), W1670* is predicted to lead to a loss of Arid1a protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ARID1A loss colon cancer predicted - sensitive unspecified PD-L1 antibody Preclinical - Cell line xenograft Actionable In a preclinical study, ARID1A-deficient colon cancer xenograft models demonstrated an increased response to treatment with an anti-PD-L1 antibody compared to controls (PMID: 29736026). 29736026
ARID1A loss ovarian cancer predicted - sensitive unspecified PD-L1 antibody Preclinical Actionable In a preclinical study, an ARID1A-deficient orthotopic ovarian cancer mouse model treated with a PD-L1 antibody demonstrated improved survival and greater decreased tumor volume compared to those treated with control (PMID: 29736026). 29736026