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. 2018 Apr 15;24(8):1965-1973.
doi: 10.1158/1078-0432.CCR-17-2655. Epub 2017 Nov 27.

Small-Cell Carcinomas of the Bladder and Lung Are Characterized by a Convergent but Distinct Pathogenesis

Matthew T Chang #  1   2   3 , Alexander Penson #  1   2 , Neil B Desai  4 , Nicholas D Socci  5   6 , Ronglai Shen  2 , Venkatraman E Seshan  2 , Ritika Kundra  6 , Adam Abeshouse  6 , Agnes Viale  6 , Eugene K Cha  7 , Xueli Hao  8 , Victor E Reuter  8 , Charles M Rudin  4 , Bernard H Bochner  7 , Jonathan E Rosenberg  4   9 , Dean F Bajorin  4   9 , Nikolaus Schultz  2   6 , Michael F Berger  6   8 , Gopa Iyer  4   9 , David B Solit  1   4   6   9 , Hikmat A Al-Ahmadie  10 , Barry S Taylor  11   2   6
Affiliations

Small-Cell Carcinomas of the Bladder and Lung Are Characterized by a Convergent but Distinct Pathogenesis

Matthew T Chang et al. Clin Cancer Res. .

Abstract

Purpose: Small-cell carcinoma of the bladder (SCCB) is a rare and aggressive neuroendocrine tumor with a dismal prognosis and limited treatment options. As SCCB is histologically indistinguishable from small-cell lung cancer, a shared pathogenesis and cell of origin has been proposed. The aim of this study is to determine whether SCCBs arise from a preexisting urothelial carcinoma or share a molecular pathogenesis in common with small-cell lung cancer.Experimental Design: We performed an integrative analysis of 61 SCCB tumors to identify histology- and organ-specific similarities and differences.Results: SCCB has a high somatic mutational burden driven predominantly by an APOBEC-mediated mutational process. TP53, RB1, and TERT promoter mutations were present in nearly all samples. Although these events appeared to arise early in all affected tumors and likely reflect an evolutionary branch point that may have driven small-cell lineage differentiation, they were unlikely the founding transforming event, as they were often preceded by diverse and less common driver mutations, many of which are common in bladder urothelial cancers, but not small-cell lung tumors. Most patient tumors (72%) also underwent genome doubling (GD). Although arising at different chronologic points in the evolution of the disease, GD was often preceded by biallelic mutations in TP53 with retention of two intact copies.Conclusions: Our findings indicate that small-cell cancers of the bladder and lung have a convergent but distinct pathogenesis, with SCCBs arising from a cell of origin shared with urothelial bladder cancer. Clin Cancer Res; 24(8); 1965-73. ©2017 AACRSee related commentary by Oser and Jänne, p. 1775.

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Conflict of interest statement

Conflict of interest disclosure: The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1. Mutational burden of SCCB
a) The somatic mutational burden of SCCBs, other genitourinary cancers, and both pulmonary non-small cell adenocarcinomas and small cell carcinomas. Box represents interquartile range (IQR); upper whisker extends from hinge to largest value ≤1.5x IQR b) Mutational signatures in SCCB patients with WES or WGS data (includes three TCGA small cell bladder samples, see Methods), urothelial tumors, and small cell lung cancers (bottom). Patients 06 and 23 possessed a polymerase η-associated AID mutational signature, as indicated. c) Pattern of lesions in TP53, RB1, the TERT promoter, and other effectors of cell cycle regulation in SCCBs and urothelial carcinomas (as labeled, UC inferred from TCGA data). d) Commonly mutated genes in SCCB, UC, and small cell lung cancers (dark blue, light blue, and red respectively) are grouped based on their alteration frequency being predominantly associated with either histology, organ, or cancer type alteration patterns (asterisk, nominal p-value < 0.05; Fisher exact test, error bars represent one standard deviation using the binomial distribution).
Fig. 2
Fig. 2. Genome doubling as a function of TP53 aberrations
a) Total, allele-specific, and integer copy number segmentation inferred from whole-exome sequencing (chromosomes 1-22; top, middle, bottom) of a representative SCCB genome is shown (patient 61T). Hallmark lesions are indicated (yellow). b) The overall burden of CNAs as a function of tumor ploidy in both SCCBs and urothelial carcinomas (points are individual tumors, SCCBs are those with black border). GD-positive tumors are in red. GD-positive tumors have both higher ploidy and elevated levels of CNAs genome-wide. c) GD as a function of TP53 mutational and zygosity status (biallelic missense with inset representing underlying mechanism; asterisk, p-value < 10−4, Fisher exact test). d) A representative tumor possessing two independent TP53 mutations (patient 70, R280T and E271K) that could be phased, reads spanning both mutant sites indicate that the mutations were in trans. Inset, targeting sequencing coverage of reads spanning both mutations are shown indicating the near absence of reads harboring both mutant alleles.
Fig. 3
Fig. 3. Heterogeneous evolutionary histories
a) Genome doubling (GD) can arise at different points in the chronology of tumor development as indicated by the fraction of somatic mutations present at diagnosis that arose before and after GD (error bars represent one standard deviation using the binomial distribution; 10 patients shown are those with ≥20 somatic mutations in regions of balanced tetraploidy). b) While in some tumors, APOBEC-associated mutagenesis is constant before and after GD, in others it either accelerates or ebbs after a genome doubling indicating the pressure of a given mutagenic process is not constant in SCCB evolution. c) Integrated analysis of mutational event timing in a typical SCCB (patient 61) indicates that multiple mutant copies of cardinal lesions are present after a late GD event that is preceded by most the APOBEC-induced somatic mutational burden. d) Coincident urothelial (not otherwise specified – NOS) and small cell (SC) histologies from a single patient with mixed histology disease (left) and the corresponding lesion-specific somatic mutations (right). e) Schematic of the evolution of SCCBs in which a founding lesion that initiates cellular transformation precedes the cardinal RB1/TP53 lesions that define a branch point of the small cell histology that may or may not co-exist with a second minor population of a distinct histology with its own lesions.
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