A case series of extraneural metastatic glioblastoma at Memorial Sloan Kettering Cancer Center

Abstract Background Extraneural metastasis of glioma is a rare event, often occurring in patients with advanced disease. Genomic alterations associated with extraneural glioma metastasis remain incompletely understood. Methods Ten patients at Memorial Sloan Kettering Cancer Center diagnosed with extraneural metastases of glioblastoma (9 patients) and gliosarcoma (1 patient) from 2003 to 2018 were included in our analysis. Patient characteristics, clinical course, and genomic alterations were evaluated. Results Patient age at diagnosis ranged from 14 to 73, with 7 men and 3 women in this group. The median overall survival from initial diagnosis and from diagnosis of extraneural metastasis was 19.6 months (range 11.2 to 57.5 months) and 5 months (range 1 to 16.1 months), respectively. The most common site of extraneural metastasis was bone, with other sites being lymph nodes, dura, liver, lung, and soft tissues. All patients received surgical resection and radiation, and 9 patients received temozolomide, with subsequent chemotherapy appropriate for individual cases. 1 patient had an Ommaya and then ventriculoperitoneal shunt placed, and 1 patient underwent craniectomy for cerebral edema associated with a brain abscess at the initial site of resection. Genomic analysis of primary tumors and metastatic sites revealed shared and private mutations with a preponderance of tumor suppressor gene alterations, illustrating clonal evolution in extraneural metastases. Conclusions Several risk factors emerged for extraneural metastasis of glioblastoma and gliosarcoma, including sarcomatous dedifferentiation, disruption of normal anatomic barriers during surgical resection, and tumor suppressor gene alterations. Next steps with this work include validation of these genomic markers of glioblastoma metastases in larger patient populations and the development of preclinical models. This work will lead to a better understanding of the molecular mechanisms of metastasis to develop targeted treatments for these patients.

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Genetic determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo

10.1101/2020.04.13.036921 ◽

2020 ◽

Author(s):

Giorgia Foggetti ◽

Chuan Li ◽

Hongchen Cai ◽

Jessica A. Hellyer ◽

Wen-Yang Lin ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Growth ◽

Lung Adenocarcinoma ◽

Tumor Suppressor Gene ◽

Suppressor Gene ◽

Genetic Alterations ◽

Putative Tumor Suppressor ◽

Lung Adenocarcinomas ◽

Gene Alterations

AbstractCancer genome sequencing has uncovered substantial complexity in the mutational landscape of tumors. Given this complexity, experimental approaches are necessary to establish the impact of combinations of genetic alterations on tumor biology and to uncover genotype-dependent effects on drug sensitivity. In lung adenocarcinoma, EGFR mutations co-occur with many putative tumor suppressor gene alterations, however the extent to which these alterations contribute to tumor growth and their response to therapy in vivo has not been explored experimentally. By integrating a novel mouse model of oncogenic EGFR-driven Trp53-deficient lung adenocarcinoma with multiplexed CRISPR–Cas9-mediated genome editing and tumor barcode sequencing, we quantified the effects of inactivation of ten putative tumor suppressor genes. Inactivation of Apc, Rb1, or Rbm10 most strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 – which are the strongest drivers of tumor growth in an oncogenic Kras-driven model – reduced EGFR-driven tumor growth. These results are consistent with the relative frequency of these tumor suppressor gene alterations in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduces the sensitivity of EGFR-driven Trp53-deficient tumors to the EGFR inhibitor osimertinib. Importantly, in human EGFR/TP53 mutant lung adenocarcinomas, mutations in the KEAP1 pathway correlated with decreased time on tyrosine kinase inhibitor treatment. Our study highlights how genetic alterations can have dramatically different biological consequences depending on the oncogenic context and that the fitness landscape can shift upon drug treatment.

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ING1 and p53 tumor suppressor gene alterations in adenocarcinomas of the esophagogastric junction

Cancer Letters ◽

10.1016/s0304-3835(02)00635-3 ◽

2003 ◽

Vol 192 (1) ◽

pp. 109-116 ◽

Cited By ~ 18

Author(s):

Yasuo Hara ◽

Zuoyu Zheng ◽

Susan C Evans ◽

Dickran Malatjalian ◽

D.Christie Riddell ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Esophagogastric Junction ◽

Suppressor Gene ◽

P53 Tumor Suppressor ◽

P53 Tumor Suppressor Gene ◽

Gene Alterations

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O-006 LKB1 Tumor suppressor gene alterations in lung adenocarcinomas

Lung Cancer ◽

10.1016/s0169-5002(05)80138-2 ◽

2005 ◽

Vol 49 ◽

pp. S6

Author(s):

M. Tang ◽

B. Angulo ◽

E. Conde ◽

J. Carretero ◽

P. Medina ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Suppressor Gene ◽

Lkb1 Tumor Suppressor ◽

Lung Adenocarcinomas ◽

Gene Alterations

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Role of the p16 tumor suppressor gene in cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.3.1197 ◽

1998 ◽

Vol 16 (3) ◽

pp. 1197-1206 ◽

Cited By ~ 399

Author(s):

W H Liggett ◽

D Sidransky

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Human Cancer ◽

Suppressor Gene ◽

Premalignant Lesions ◽

Early Event ◽

Cyclin Dependent Kinase ◽

Primary Tumors

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.

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Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders

Blood ◽

10.1182/blood.v85.2.552.552 ◽

1995 ◽

Vol 85 (2) ◽

pp. 552-565 ◽

Cited By ~ 440

Author(s):

DM Knowles ◽

E Cesarman ◽

A Chadburn ◽

G Frizzera ◽

J Chen ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Gene Rearrangement ◽

Molecular Genetic ◽

Suppressor Gene ◽

Lymphoproliferative Disorders ◽

Ebv Infection ◽

P53 Tumor Suppressor Gene ◽

Single Form ◽

Gene Alterations

Abstract The posttransplantation lymphoproliferative disorders (PT-LPDs) are a morphologically heterogeneous group of Epstein-Barr virus (EBV)-driven lymphoid proliferations of varying clonal composition. Some PT-LPDs regress after a reduction in immunosuppression, while others progress in spite of aggressive therapy. Previously defined morphologic categories do not correlate with clonality, and neither morphology nor clonality has reliably predicted the clinical behavior of PT-LPDs. We investigated 28 PT-LPD lesions occurring in 22 patients for activating alterations involving the bcl-1, bcl-2, c-myc, and H-, K- and N-ras proto-oncogenes and for mutations involving the p53 tumor suppressor gene. We correlated the results of these studies with the morphology of the lesions, their clonality based on Ig heavy and light chain gene rearrangement analysis, and the presence and clonality of EBV infection. We found that the PT-LPDs are divisible into three distinct categories as follows: (1) plasmacytic hyperplasia: most commonly arise in the oropharynx or lymph nodes, are nearly always polyclonal, usually contain multiple EBV infection events or only a minor cell population infected by a single form of EBV, and lack oncogene and tumor suppressor gene alterations; (2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma: may arise in lymph nodes or various extranodal sites, are nearly always monoclonal, usually contain a single form of EBV, and lack oncogene and tumor suppressor gene alterations; and (3) immunoblastic lymphoma or multiple myeloma: present with widely disseminated disease, are monoclonal, contain a single form of EBV, and contain alterations of one or more oncogene or tumor suppressor genes (N-ras gene codon 61 point mutation, p53 gene mutation, or c-myc gene rearrangement). The PT-LPDs are divisible into three categories exhibiting distinct morphologic and molecular genetic characteristics. Alterations involving the N-ras and c-myc proto- oncogenes and the p53 tumor suppressor gene may play an important role in the development and/or progression of the PT-LPDs.

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