Genomic Catastrophe (Chromothripsis and Polyploidy) Correlates With Tumor Distribution in Extrauterine High-grade Serous Carcinoma

Abstract

Most extrauterine high-grade serous carcinomas (HGSCs) are thought to develop first in the distal fallopian tube. Most models of HGSC assume origin from relatively stable, noninvasive serous tubal intraepithelial carcinomas. However, widespread tumor involvement in the absence of a serous tubal intraepithelial carcinoma could occur after catastrophic genomic events (CGEs; such as chromothripsis or polyploidy). Twenty-six HGSCs assigned to fallopian tube (n = 9, group 1) and/or ovary (n = 9, group 2), and primary peritoneal (n = 8, group 3) were assessed by microarray (Oncoscan). CGEs were identified in 15/26 (57.7%); chromothripsis-like pattern in 13/26 (50.0%) and polyploidy in 6/26 (23.1%). CGE was seen in 4/9 (44.4%), 9/9 (100%), and 2/8 (25%) cases in groups 1. 2, and 3, respectively. Overall, CGEs were seen in 9/9 (100%) cases with grossly evident ovarian parenchymal involvement versus 6/17 (35.3%) without ( P = 0.0024). Ovarian size (measured on the long axis) correlated with CGE positivity ( P = 0.016). CGEs are significantly more common in HGSCs with ovarian parenchymal involvement compared with those limited to the fallopian tube and/or extraovarian tissues. These associations suggest geographically different tumor growth patterns and support the subdivision of HGSCs according to not only the stage but also tumor distribution. They have implications for clinical and pathologic presentation, trajectory of tumor evolution, and in the case of primary peritoneal HGSCs, potentially unique precursors to tumor transitions that could inform or influence cancer prevention efforts.

Figure 1.

Representative histologic images from cases (see Table 1). A) 0.3cm HGSC in the fallopian tube with STIC and without evidence of chromothripsis (Case 2); B) Small 0.6 cm Stage IA carcinoma of the fallopian tube with STIC and chromothripsis (Case 4); C) Primary peritoneal HGSC without evidence of chromothripsis (Case 23); D) Large ovarian tumor mass with numerous chromosomes exhibiting chromothriptic events (Case 16). E) STIC associated with a p53 signature, coexisting with extensive peritoneal carcinomatosis (Case 9). Serous tubal intraepithelial lesion (STIL) with a low proliferative index associated with a primary peritoneal HGSC (Case 25). Both the STIL and the peritoneal tumor were null for p53 staining by immunohistochemistry.

Figure 2.

A) OncoScan output for case 13, with chromothripsis detected in chromosomes 1–8, 10–12, 14–19, and X. B) Comparison of different chromosome types involved by chromothripsis in the BWH cohort. C) Chromothripsis and polyploidy detected by microarray in Group 1 and Group 2 cases.

Figure 3.

Graphic distribution of largest ovarian size (measured along the longest axis) between CGE positive and negative HGSCs (Mann-Whitney p = 0.016).