Gynecologic-cancer analysis of ARID1A alterations detected in tissue and liquid biopsies.
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5593 Background: The tumor suppressor gene ARID1A is an emerging target for new cancer treatment strategies including ATR inhibition. This study aimed to describe the landscape of ARID1A alterations ( ARID1Amut) in gynecologic malignancies. Methods: Patients (pts) with a diagnosis of ovarian (OC) or uterine cancer (UC) of different histologies and comprehensive genomic profiling (CGP) by Foundation Medicine Inc. were included in this study. CGP of solid tissue biopsies (Tbx; FoundationOneCDx) included evaluation of genomic loss of heterozygosity (gLOH; gLOH-high as ≥16% as validated in OC), microsatellite instability (MSI), and tumor mutational burden (TMB; high as ≥10 mutations/Megabase). CGP of peripheral whole-blood liquid biopsies (Lbx; FoundationOneLiquidCDx) included evaluation of MSI and tumor fraction (TF), a measure of the relative quantity of circulating tumor DNA (ctDNA). TF was calculated by measures of aneuploidy and allele frequency and binned as TF < 1%, TF 1 to < 10%, or TF ≥10%. Results: Tbx Cohort: 5,778/30,212 (19.1%) cases were ARID1Amut. Pts had a median age of 63 (range 21-89) years. ARID1Amut were observed across many subtypes and most frequently in endometrial endometrioid (n = 3,052, 57.7%) and ovarian clear cell (n = 982, 57.6%) but rarely in serous (OC, n = 12,258, 2.8%; UC, n = 2,682, 8.9%). Pts frequently harbored more than one ARID1Amut (2,360/5,778, 40.8%). Of the 8,484 observed ARID1Amut, 97.6% were short variants (SV), 0.5% were deletions, and 1.9% were inactivating rearrangements. SV were primarily frameshifts (68.5%) and nonsense mutations (27.6%). The most frequent alterations observed were frameshifts at the D1860 codon. SV were predicted to be homozygous in 11.9%, heterozygous in 65.3%, or unknown zygosity in 22.8%. Overall, 16.6% of ARID1Amut cases with SV had at least one homozygous alteration. 6.6% of pts with homozygous ARID1Amut were MSI-high (MSI-H), while 39.4% of pts with only heterozygous or unknown zygosity ARID1Amut were MSI-H (p < 0.0001). Overall, 1,905 (33.0%) of ARID1Amut cases were MSI-H, and 2,183 (37.8%) were TMB high. For ARID1Amut cases with evaluable gLOH (n = 4745), the median gLOH was 2.7%, and 5.9% pts were gLOH-high. The most frequently altered co-occurring genes were PTEN (62.2%), PIK3CA (54.2%), and TP53 (27.6%). 8.7% of ARID1Amut also harbored a BRCA alteration. Lbx Cohort: 59/967 (6.1%) cases were ARID1Amut. 17 (28.8%) were MSI-H. Frequency of ARID1Amut increased as TF increased, with a detected frequency of 1.3%, 6.7%, and 14.0% among Lbx with TF < 1%, TF 1 to < 10%, or TF ≥10% respectively. Conclusions: ARID1Amut are observed across a variety of Gynecologial cancer subtypes but are enriched in clear cell and endometrioid histologies and detected in both tissue and liquid biopsies. ARID1Amut were not associated with elevated gLOH but were often MSI-H and TMB ≥10mut/Mb. Clinical trials targeting ARID1A may wish to consider the context of co-occuring biomarkers.Keywords:
ARID1A
Microsatellite Instability
Microsatellite Instability
MLH1
MSH2
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Microsatellite Instability
Lynch Syndrome
Uterine cancer
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Microsatellite Instability
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AIM: To investigate the role of DNA microsatellite instability (MSI) in gastric carcinogenesis by studying associations between MSI status, clinicopathological features, and loss of genetic loci. METHODS: Six microsatellite loci and loss of heterozygosity at APC, DCC, and MCC were analysed by polymerase chain reaction based methods in 53 cases of advanced gastric cancer. RESULTS: MSI was observed in 32.1% of gastric carcinomas (17/53) and 20% of foci of intestinal metaplasia (3/15). Seven gastric carcinomas (13.7%) were MSI-high (MSI-H) (three loci or more) and 10 (18.9%) were MSI-low (MSI-L) (one or two loci). The frequency of MSI-H was higher in intestinal (25.0%) than in diffuse carcinomas (3.7%) (p < 0.05). None of the MSI-H tumours showed loss of heterozygosity at APC, MCC, or DCC loci. CONCLUSIONS: MSI may have an important and early role in a subset of gastric cancers, particularly the intestinal type. The MSI-H subset of gastric cancer has features in common with its colorectal counterpart, whereas MSI-L and microsatellite stable cancers appear to develop through the loss of heterozygosity pathway.
Microsatellite Instability
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Microsatellite instability (MSI) seems to be important for the development of various human cancers including sporadic endometrial cancer. The aim of this study was evaluation of microsatellite instability in 20 postmenopausal women with endometrial adenocarcinoma in DNA samples obtained from cancer tissue and blood of the same patients. Control DNA was obtained from normal endometrial tissue (n=25). MSI was studied at five loci containing single- or dinucleotide repeat sequences and mapping to different chromosomal locations: BAT-25 (at locus 4q12), BAT-26 (2pl6), D2S123 (2pl6-p21), D5S346 (5q21-q22) and D17S250 (17q11.2-q12). No differences in the MSI frequencies between blood and cancer tissue obtained from patients were detected. The microsatellite instability status was significantly higher in endometrial cancer tissue [5/20 (25%)] as compared to control [3/25 (12%)] (p < 0.05). There were no significant differences between MSI presence in the subgroups assigned to the histological grades (p > 0.05). The results suggest that the microsatellite instability seems to be important in the development of sporadic endometrial cancer.
Microsatellite Instability
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Microsatellite Instability
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Abstract AT-rich interactive domain-containing protein 1A (ARID1A) is a subunit of the SWI-SNF chromatin-remodeling complex, which is considered to perform a tumor suppressor function. Somatic mutations of ARID1A were reported to be detected in about 50% of colorectal cancer (CRC), but loss of expression seems vary according to tissue type and microsatellite instability (MSI) status. So, we designed this study to identify the frequency of loss of ARID1A expression and its clinical relevance in CRC and gastric cancer (GC) of Korean patients. Immunohistochemistry for ARID1A was performed using tissue microarray blocks containing 197 CRCs and 275 SCs, and paired normal mucosa. Data on MSI status were available in 178 of 197 CRCs and 233 of 275 GCs. Clinicopathological data of the patients were collected and analyzed. We identified 12 (12/197, 6.1%) CRCs showing loss of ARID1A expression, all of which were microsatellite stable. In 178 CRCs with identified MSI status, 3 (1.7%) MSI-H and 6 (3.4%) MSI-L tumors showed normal expression of ARID1A, contrary to MSS tumors (ARID1A loss: 10/169, 5.9%). Among GCs, 8.0% (22/275) showed loss of ARID1A expression and 6.4% (15/233) were MSI-H. Tumors with loss of ARID1A expression accounted for 13.3% (2/13) of GCs with MSI-H whereas 5.0% (11/207) of GCs with MSS. However, there was no association between ARID1A expression and MSI status in both CRCs (p=0.754) and SCs (p=0.200). Expression of ARID1A in paired normal mucosal epithelial cells was normal in all patients. Clinicopathological factors were not associated with ARID1A expression in both cancers except that CRCs with loss of ARID1A expression showed less frequent lymphatic invasion than those with normal expression (25.0% vs. 69.0%, p=0.003). There was no association between ARID1A expression and 3-year disease-free survival or 5-year overall survival in both cancers. In this study population, loss of ARID1A expression was uncommon and not relevant to MSI-H tumors. Its clinical implication for the prognosis of CRC and GC patients seems to need further studies with more accumulated data. Citation Format: Soo Young Lee, Duck-Woo Kim, Hye Seung Lee, Myong Hoon Ihn, Heung-Kwon Oh, Sung-Bum Kang. ARID1A expression and its relation with microsatellite instability and clinicopathological characteristics in colorectal and gastric cancers of Korean patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4673. doi:10.1158/1538-7445.AM2014-4673
ARID1A
Microsatellite Instability
Tissue microarray
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Abstract Microsatellite instability at mono‐ and dinucleotide repeats is the hallmark of the hereditary non‐polyposis cancer syndrome (HNPCC) and is related to deficient DNA mismatch repair. In contrast, a distinct form of microsatellite instability at selective tetranucleotide repeats (EMAST or elevated microsatellite alterations at selected tetranucleotides) was described in several non‐HNPCC cancer types. EMAST is probably unrelated to mismatch repair defects. We investigated the frequency of microsatellite instability at mononucleotide, dinucleotide and tetranucleotide repeats in a series of 75 ovarian carcinomas (53 serous and 22 non‐serous). Microsatellite analysis was carried out using 5 mono‐ and dinucleotide markers from the National Cancer Institute Consensus Panel and 6 tetranucleotide markers, which have been reported as frequently unstable in the literature. High frequency of microsatellite instability (MSI‐H) at mono‐ and dinucleotide repeats was observed in 9% and a low frequency (MSI‐L) in 21% of serous carcinomas. MSI‐H was detected in 4% and MSI‐L in 18% of non‐serous carcinomas. Nine percent of serous carcinomas showed instability at multiple and 9% at single tetranucleotide loci. All non‐serous carcinomas were stable at tetranucleotide loci. In summary, EMAST ( e.g. , tumors with tetranucleotide instability without concomitant MSI‐H) was observed in 13% of ovarian serous carcinomas. All EMAST positive tumors were of advanced stage. We conclude that EMAST occurs as a distinct form of microsatellite instability in ovarian cancer. EMAST seems to be particularly frequent in advanced serous carcinomas. Its clinical significance needs to be investigated. © 2004 Wiley‐Liss, Inc.
Microsatellite Instability
Serous carcinoma
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Deficient DNA mismatch repair (dMMR) is a rare molecular disorder found in 20-30 % of endometrial tumors. Laboratory identification of dMMR/microsatellite instability (MSI) has a high diagnostic value, since these impairments are considered as biomarkers of endometrial adenocarcinoma. They help to identify patients at high risk of Lynch syndrome, evaluate the disease prognosis, and estimate the efficacy of immune checkpoint inhibitors and their combinations. This review details current concepts of MSI diagnostics and discusses its predictive value in patients with endometrial cancer. It also describes a new diagnostic algorithm for the detection of dMMR and MSI.
Microsatellite Instability
Lynch Syndrome
Identification
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Microsatellite instability (MSI) is involved in the pathogenesis of about 30% of endometrial cancer cases. In accumulating data from the past few years MSI is shown to have both clinical and prognostic value. In the present work we are discussing the components and molecular mechanisms of functioning of the mismatch repair system (MMR). MSI is a hallmark of endometrial tumors with DNA MMR deficiency. We summarized the main pathways for accumulating mutations in coding and non-coding DNA sequences, which is a result of errors during replication of microsatellite tandem repeats. A few studies rising valuable conclusions about the correlation between MSI and endometrial cancer are revised.
Microsatellite Instability
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