To characterize the prevalence of BRCA mutations and characteristics of BRCA carriers in China and to update the clinical recommendations for BRCA testing, we conducted a wide screen for BRCA mutations using next‐generation sequencing (NGS). A total of 4,034 Chinese subjects were screened for germline BRCA1/2 mutations, including 2,991 breast cancer patients and 1,043 healthy individuals from the community enrolled as controls. We developed an NGS‐based approach to perform BRCA1/2 screening. BRCA mutations were identified in 9.1% (232/2,560) of cases with at least one risk factor, in 3.5% (15/431) of sporadic patients and in 0.38% (4/1,043) of healthy controls. The mutation frequency ranged from 8.9 to 15.2% in cohorts with a single risk factor to 16.6–100% in groups with multiple risk factors. We identified 70 novel BRCA mutations. A high frequency of BRCA1 c.5470_5477del was detected, accounting for 13.9% (16/115) of the BRCA1 mutations detected in our study. Clinical characteristics such as family history, invasive carcinoma, negative human epidermal growth factor receptor 2 (HER2), high Ki67 index, lymph node status, and high tumour grade were closely related to BRCA mutations. BRCA2 carriers had poorer disease‐free survival among HER2‐ or hormone receptor‐positive patients (hazard ratio = 1.892; 95% confidence interval: 1.132–3.161; p = 0.013). This study shows that BRCA mutation carriers could be frequently identified among breast cancer patients with multiple risk factors. Importantly, we established an NGS‐based pipeline for BRCA1/2 testing in clinical practice and strongly suggest that breast cancer patients of premier‐ and moderate‐grade risks receive BRCA1/2 mutations testing in China.

Purpose: BATF2, a novel IFN-stimulated gene, inhibits tumor cell proliferation, invasion, and migration. The objectives of this study were to determine how BATF2 expression is associated with colorectal cancer progression and patient outcome, to investigate how BATF2 overexpression inhibits hepatocyte growth factor (HGF)/MET signaling, and to elucidate the rationale for combining MET inhibitors with IFN. Experimental Design: BATF2 expression in colorectal cancer tissues was determined and correlated with colorectal cancer patient prognosis. Cultured colorectal cancer cells were used to investigate the effects of BATF2 overexpression on the malignant phenotype of colorectal cancer cells and HGF/MET signaling. Tumor xenograft models were used to validate the effects of BATF2 on colorectal cancer xenograft growth and assess the efficacy of the combination of MET inhibitors with IFNs in colorectal cancer. Results: In colorectal cancer tissues, BATF2 was found to be significantly downregulated, and its expression negatively correlated with MET expression. Decreased BATF2 expression was associated with progression and shorter patient survival in colorectal cancer. BATF2 overexpression promoted apoptosis and inhibited proliferation, migration, and invasion in colorectal cancer cells, as well as dramatically blunted tumor xenograft growth. In addition, MET inhibitors in combination with IFNβ produced synergistic cytotoxicity both in vitro and in vivo. Conclusions: Together, these novel findings suggest that BATF2, a tumor suppressor gene, is a potent negative regulator of HGF/MET signaling in colorectal cancer and may serve as a prognostic tumor marker. Furthermore, these results provide a rationale for combining MET inhibitors with IFNs in preclinical trials. Clin Cancer Res; 21(7); 1752–63. ©2015 AACR.

Plasma extracellular vesicles (EVs) have been reported to be a promising source of diagnostic and prognostic biomarkers in various cancers. However, further research in this area is needed due to the limitations of circulating extracellular vesicles detection methods. Using the Single Molecule array (SiMoa) technology, we developed two extracellular vesicle detection assays, CD9-CD63 and PD-L1-CD63, to determine circulating universal EVs and PD-L1 positive EVs, respectively. A total of 164 diffuse large B-cell lymphoma (DLBCL) patients were retrospectively included in this study. Compared with healthy volunteers (n = 25), elevated CD9-CD63 and PD-L1-CD63 signals were detected in the plasma of DLBCL patients (n = 164). High CD9-CD63 signals was associated with molecular subtype, extranodal site and treatment response in DLBCL. A high PD-L1-CD63 signal was also associated with certain clinical features, including extranodal site and treatment response. CD9-CD63 and PD-L1-CD63 signals were found to be important prognostic factors for both progression-free and overall survival. Furthermore, PD-L1-positive EVs were found in all patients, though PD-L1 protein expression was positive in only 35.4% (17/48) of tumor biopsies. No correlation was found between circulating PD-L1+ EVs and soluble PD-L1 (sPD-L1) levels. Our results show that plasma universal EV and PD-L1-positive EV levels are significantly elevated in DLBCL and might serve as biomarkers for predicting survival outcomes in DLBCL patients.

The advent of targeted therapies for oncogenic mutations has led to a major paradigm shift in the management of non-small cell lung cancer (NSCLC). Molecular targets, such as epidermal growth factor receptor (EGFR)-activating mutations in the region of exons 18 through 21 are the most common oncogenic driver in NSCLC. Classical activating mutations, such as in-frame deletions in exon 19 and point mutations in exon 21 (L858R), are strong predictors for good clinical response to the approved EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, low frequency mutations occurring within exon 20 (ex20ins) have poorer responses to first/second generation EGFR-TKIs. Moreover, patients with NSCLC harboring EGFR ex20ins are known to have poorer prognosis than those with other EGFR-TKI sensitive mutations, leading to unmet clinical need of novel specific therapeutic options. Rapid changes in molecular diagnostics identifying specific causes have hastened the translation of diagnostic recommendations into clinical practice. Emergence of treatment strategies targeting EGFR ex20ins, such as newer EGFR-TKIs with increased specificity and novel approaches using bispecific monoclonal antibodies, may hold promising therapeutic options in the near future. In this review, we describe the structural, molecular characteristics, and detection strategies of EGFR ex20ins mutations and summarize the latest clinical data on approved treatments and emerging therapies for patients with NSCLC harboring EGFR ex20ins mutations. Further, we will discuss the response heterogeneity of ex20ins mutations to new drugs and acquired drug resistance mechanisms.

Primary breast diffuse large B-Cell lymphoma: a population-based study from 1975 to 2014 Primary breast diffuse large B-Cell lymphoma: a population-based study from 1975 to 2014

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare mesenchymal neoplasm that mainly harbors NCOA1-3 rearrangements with partner genes ESR1 or GREB1. Here, we explored 23 UTROSCTs by targeted RNA sequencing. The association between molecular diversity and clinicopathologic features was investigated. The mean age of our cohort was 43 years (23–65 y). Only 15 patients (65%) were originally diagnosed with UTROSCTs. Mitotic figures ranged from 1 to 7/10 high power fields, of primary tumors and increased from 1 to 9/10 high power fields in recurrent tumors. Five types of gene fusions were identified in these patients, including GREB1::NCOA2 (n=7), GREB1::NCOA1 (n=5), ESR1::NCOA2 (n=3), ESR1::NCOA3 (n=7), and GTF2A1::NCOA2 (n=1). To our knowledge, our group included the largest cohort of tumors with GREB1::NCOA2 fusions. Recurrences were most common in patients with GREB1::NCOA2 fusion (57%), followed by 40% (GREB1::NCOA1), 33% (ESR1::NCOA2), and 14% (ESR1::NCOA3). The recurrent patient who harbored an ESR1::NCOA2 fusion was characterized by extensive rhabdoid features. Both of the recurrent patients who harbored GREB1::NCOA1 and ESR1::NCOA3 had the largest tumor sizes in their own gene alteration groups, and another recurrent GREB1::NCOA1 patient had extrauterine involvement. The GREB1-rearranged patients were of older age, larger tumor size, and higher stage than non-GREB1-rearranged patients (P=0.004, 0.028, and 0.016, respectively). In addition, the GREB1-rearranged tumors presented more commonly as intramural masses rather than non-GREB1-rearranged tumors presenting as polypoid/submucosal masses (P=0.021). Microscopically, nested and whorled patterns were frequently seen in GREB1-rearranged patients (P=0.006). Of note, estrogen receptor expression was weaker than progesterone receptor in all 12 GREB1-rearranged tumors, whereas the similar staining intensity of estrogen receptor and progesterone receptor was observed in all 11 non-GREB1-rearranged tumors (P<0.0001). This study demonstrated that UTROSCTs were present at a younger age in the Chinese population. The genetic heterogeneity of UTROSCTs was correlated with variable recurrence rate. Tumors with GREB1::NCOA2 fusions are more likely to recur compared with those with other genetic alterations.