Chromothripsis-Mediated Small Cell Lung Carcinoma

被引：8

作者：

Rekhtman, Natasha ^{[1
]}

Tischfield, Sam E. ^{[2
]}

Febres-Aldana, Christopher A. ^{[1
,3
]}

Lee, Jake June-Koo ^{[4
]}

Chang, Jason C. ^{[1
]}

Herzberg, Benjamin O. ^{[4
,5
,6
]}

Selenica, Pier ^{[1
]}

Woo, Hyung Jun ^{[2
]}

Vanderbilt, Chad M. ^{[1
]}

Yang, Soo-Ryum ^{[1
]}

Xu, Fei ^{[1
]}

Bowman, Anita S. ^{[1
]}

da Silva, Edaise M. ^{[1
]}

Noronha, Anne Marie ^{[2
]}

Mandelker, Diana L. ^{[1
]}

Mehine, Miika ^{[1
,2
]}

Mukherjee, Semanti ^{[4
]}

Blanco-Heredia, Juan ^{[2
]}

Orgera, John J. ^{[2
]}

Nanjangud, Gouri J. ^{[7
]}

Baine, Marina K. ^{[1
]}

Aly, Rania G. ^{[1
]}

Sauter, Jennifer L. ^{[1
]}

Travis, William D. ^{[1
]}

Savari, Omid ^{[1
,8
]}

Moreira, Andre L. ^{[1
,9
]}

Falcon, Christina J. ^{[4
,10
]}

Bodd, Francis M. ^{[1
,10
]}

Wilson, Christina E. ^{[1
,10
]}

Sienty, Jacklynn V. ^{[4
,11
]}

Manoj, Parvathy ^{[4
]}

Sridhar, Harsha ^{[4
]}

Wang, Lu ^{[1
,12
]}

Choudhury, Noura J. ^{[4
,13
]}

Offin, Michael ^{[4
]}

Yu, Helena A. ^{[4
,13
]}

Quintanal-Villalonga, Alvaro ^{[4
]}

Berger, Michael F. ^{[1
,2
,3
]}

Ladanyi, Marc ^{[1
]}

Donoghue, Mark T. A. ^{[2
]}

Reis-Filho, Jorge S. ^{[1
,14
]}

Rudin, Charles M. ^{[4
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Pathol & Lab Med, 1275 York Ave, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10065 USA

[5] Columbia Univ, Irving Med Ctr, Dept Med, Div Hematol & Oncol, New York, NY USA

[6] Herbert Irving Comprehens Canc Ctr, New York, NY USA

[7] Mem Sloan Kettering Canc Ctr, Dept Mol Cytogenet Core Facil, New York, NY 10065 USA

[8] Case Western Reserve Univ, Univ Hosp Cleveland Med Ctr, Dept Pathol, Cleveland, OH USA

[9] NYU Grossman Sch Med, Grossman Sch Med, New York, NY USA

[10] Mem Sloan Kettering Canc Ctr, Druckenmiller Ctr Lung Canc Res, New York, NY 10065 USA

[11] NYU, Res Alliance, New York, NY 10003 USA

[12] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN USA

[13] Weill Cornell Med Coll, Dept Med, New York, NY USA

[14] AstraZeneca, Canc Biomarker Dev, Gaithersburg, MD USA

来源：

CANCER DISCOVERY | 2025年 / 15卷 / 01期

关键词：

EXTRACHROMOSOMAL DNA AMPLIFICATION; CANCER; MUTATIONS; GERMLINE; TUMORS; CONTRIBUTES; HISTORY; DAMAGE; GENES;

D O I：

10.1158/2159-8290.CD-24-0286

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here, we performed detailed clinicopathologic, genomic, and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis-massive, localized chromosome shattering-recurrently involving chromosome 11 or 12 and resulting in extrachromosomal amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors. Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers.Significance: Here, we provide the first detailed description of a unique SCLC subset lacking RB1/TP53 alterations and identify extensive chromothripsis and pathogenetic links to pulmonary carcinoids as its hallmark features. This work defines atypical SCLC as a novel entity among lung cancers, highlighting its exceptional histogenesis, clinicopathologic characteristics, and therapeutic vulnerabilities.See related commentary by Nadeem and Drapkin, p. 8

引用

页码：83 / 104

页数：22

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