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Jiang, Xiao; O'Neill, Amanda; Smith, Katherine R.; Lai, Zhongwu; Carss, Keren; Wang, Quanli; Petrovski, Slavé
doi: 10.1002/gcc.23042pmid: 35394676
As an essential regulator of DNA damage, ataxia‐telangiectasia mutated (ATM) gene has been widely studied in oncology. However, the independent effects of ATM missense variants and protein‐truncating variants (PTVs) on neoplasms have not been heavily studied. Whole‐exome sequencing data and the clinical health records of 394,694 UK Biobank European participants were used in this analysis. We mined genetic associations from gene‐level and variant‐level phenome‐wide association studies, and conducted a variant‐level conditional association study to test whether the effects of ATM missense variants on neoplasms were independent of ATM PTV carrier status. The gene‐level PTV collapsing analysis was consistent with established ATM PTV literature showing that the aggregated impact of 286 ATM PTVs significantly (p < 2 × 10−9) associated with 31 malignant neoplasm phenotypes. Of 773 distinct protein‐coding variants in ATM, three individual missense variants significantly (p < 2 × 10−9) associated with nine phenotypes. Remarkably, although the nine phenotypes were tumor‐related, none overlapped the established ATM PTV‐linked malignancies. A subsequent conditional analysis identified that the missense signals were acting independently of the known clinically relevant ATM PTVs.
Wang, Wenxian; Gu, Xiaodong; Si, Jinfei; Pu, Xingxiang; Wang, Liping; Chen, Huafei; Xu, Chunwei; Zhang, Xiaoyan; Yuan, Hongling; Lou, Guangyuan; Shao, Lan; Zhang, Gu; Song, Zhengbo
Xu, Bin; Chen, Jie‐Fu; Sarungbam, Judy; Tickoo, Satish; Dickson, Brendan C.; Reuter, Victor E.; Antonescu, Cristina R.
doi: 10.1002/gcc.23046pmid: 35430756
Tumors with NUTM1 fusions occur predominantly in the thoracic cavity and head and neck region. However, recent literature expanded the location of NUTM1‐translocated malignancy to soft tissue, brain, and visceral organs. In this study, we describe the first series of six NUTM1‐translocated carcinomas and sarcomas occurring in the genitourinary tract. The sites of origin were kidney (n = 2), bladder (n = 3), and penis (n = 1). All tumors occurred in adulthood (range: 30–78 years). The histologic features were heterogeneous, showing epithelial, spindle cell, or primitive small blue round cell morphology. Glandular architecture, keratinization, rhabdoid cells, or myxoid‐to‐edematous stromal component were also noted. In three cases, features were in keeping with a carcinoma (two from kidney and one from bladder), whereas the remaining three were classified as malignant undifferentiated neoplasm (MUN)/sarcoma. Fusion partners detected in four cases tested by either FISH and/or RNA sequencing were BRD4 in two kidney tumors, MXD1 in a bladder sarcoma, and MXD4 in a penile sarcoma. NUT immunostain showed diffuse spiculated positivity in five cases. Immunopositivity for various cytokeratins was noted in two tumors. The outcome of NUTM1‐rearranged genitourinary malignancy was dismal: four of five cases with follow‐up developed distant metastasis, and three suffered disease‐specific death. In conclusion, NUTM1‐rearranged carcinoma and sarcoma can affect the genitourinary tract, including kidney, bladder, and penis. Histologic features and keratin immunoexpression are highly variable. A NUTM1‐fusion positive malignancy may be included in the differential diagnosis of a MUN of the genitourinary tract given the dismal outcome and the existing BET‐targeted therapy for tumors with BRD3/4::NUTM1 fusion.
Bochtler, Tilmann; Wohlfromm, Timothy; Hielscher, Thomas; Stichel, Damian; Pouyiourou, Maria; Kraft, Bianca; Neumann, Olaf; Endris, Volker; Deimling, Andreas; Stenzinger, Albrecht; Krämer, Alwin
doi: 10.1002/gcc.23047pmid: 35430765
Satgunaseelan, Laveniya; Strbenac, Dario; Willet, Cali; Chew, Tracy; Sadsad, Rosemarie; Wykes, James; Low, Tsu‐Hui (Hubert); Cooper, Wendy A.; Lee, C. Soon; Palme, Carsten E.; Yang, Jean Y. H.; Clark, Jonathan R.; Gupta, Ruta
doi: 10.1002/gcc.23076pmid: 35670448
Argani, Pedram; Matoso, Andres; Gross, John M.; Zhang, Yanming; SoRelle, Jeffrey A.; Gagan, Jeffrey; Antonescu, Cristina R.; Palsgrove, Doreen
doi: 10.1002/gcc.23053pmid: 35521683
We report the first case of a primary renal undifferentiated sarcoma harboring an SS18::POU5F1 gene fusion. The patient was a 38 year‐old male diagnosed with a 5 cm renal tumor which invaded the adrenal gland and extended into the renal vein. Microscopically, the neoplasm had a predominantly undifferentiated round cell morphology, with areas of rhabdoid and spindle cell growth. Similar to the previously reported cases with this fusion, by immunohistochemistry the neoplasm expressed S100 protein and epithelial markers (diffuse EMA, focal cytokeratin), suggesting the possibility of a myoepithelial phenotype. This report documents another example of a fusion‐positive undifferentiated soft tissue sarcoma occurring as a primary renal neoplasm, adding to the already broad list of such entities. It highlights the crucial role of molecular analysis in establishing a specific diagnosis given the overlapping morphology and immunophenotypes such entities may exhibit.
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The incidence of primary and acquired BRAF mutations is low in non‐small cell lung cancer (NSCLC), with limited demographic and treatment outcome data available for this patient population. We evaluated lung cancer samples with programmed cell death ligand 1 (PD‐L1) information extracted from 12 051 cases (cohort A) of lung cancer from OncoPanscan™‐based sequencing of tissue (Genetron Health) and conducted retrospective multicenter data analysis using the database of Zhejiang Cancer Hospital and four other centers (cohort B, including 73 primary BRAF mutation and 14 acquired BRAF mutation cases) to compare treatment outcomes of patient groups with primary and acquired BRAF mutations. In cohort A, after propensity score analysis, 165 samples of NSCLC with BRAF mutations were screened along with 165 paired non‐BRAF mutation samples. We observed no significant differences in the proportion of samples with ≥1% PD‐L1 between BRAF and non‐BRAF mutant groups. The median progression‐free survival (mPFS) period in 13 patients with primary BRAF mutations receiving BRAF tyrosine kinase inhibitors (BRAF‐TKIs) was 7.0 months. The group with primary BRAF mutations receiving immune checkpoint inhibitor (ICI) combination chemotherapy had better PFS than those administered ICI monotherapy (14.77 months vs. 5.0 months, p = 0.025) and similar results were obtained for OS (unreached vs. 20.3 months, p = 0.013). For acquired BRAF mutations, mPFS of BRAF‐TKI, ICI‐based, and chemotherapy‐based regimens were 3.8, 1.5, and 1.9 months, respectively. Therefore, for patients with the primary BRAF V600E mutation, targeted therapy or immunochemotherapy could serve as effective treatment choices, while for those with acquired BRAF V600E, targeted drug therapy may remain the preferred solution in China.