In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P3-07-02-P3-07-02
Abstract:
Introduction: Metaplastic breast carcinomas (MBCs) and uterine carcinosarcomas (UCSs) are histologically similar, being often characterized by an admixture of adenocarcinoma areas with areas displaying sarcomatoid differentiation. We sought to investigate whether their histologic similarities would be paralleled by similar patterns of genetic alterations, and to determine whether the different histologic components of MBCs and UCSs would be clonally related. Methods: Whole exome sequencing (WES) data from 35 MBCs previously analyzed by our group and 57 UCSs from The Cancer Genome Atlas (TCGA) study were reanalyzed. Somatic single nucleotide variants were detected with MuTect and indels with Strelka, Varscan2, Scalpel and Lancet. Copy number alterations were inferred using FACETS and functional annotation of the non-synonymous somatic mutations, amplifications or homozygous deletions was performed. We further microdissected the histologically distinct components of 11 MBCs and six UCSs and subjected each component to WES. Clonal decomposition was performed using PyClone. Results: The most frequent somatic mutations identified in MBCs were TP53 (69%), PIK3CA (29%), FAT3 (26%) and PTEN (14%), whereas the most frequently mutated genes in UCSs were TP53 (84%), FBXW7 (35%), PIK3CA (29%), PTEN (15%) and PPP2R1A (15%). MBCs displayed a significantly higher frequency of mutations targeting FAT3 (26% vs 4%, P & lt;0.01), FAT1 (11% vs 0%, P & lt;0.05) and CHERP (11% vs 0%, P & lt;0.05) than UCSs. UCSs more frequently harbored mutations affecting FBXW7 (35% vs 0%; P & lt;0.01) and PPP2R1A (15% vs 0%, P & lt;0.05) than MBCs. MBCs and UCSs displayed similar copy number alteration profiles, with frequent gains/ amplification of 8q, 3q and 1q, and losses of 8p. Pathway analysis based on the genes targeted by somatic genetic alterations revealed that both MBCs and UCSs were underpinned by genetic alterations resulting in activation of similar pathways, including PI3K, p53, Wnt and Notch signaling. Analysis of the separate components of MBCs and UCSs revealed that the histologically distinct components of MBCs and UCSs are clonally-related, with a median of 71% (range 26%-93%) and 78% (range 30%-93%) of somatic mutations being shared by the distinct components in MBCs and UCSs, respectively. In MBCs, clonal TP53, NOTCH3, KMT2D, FAT4 and PIK3CA mutations and several copy number alterations were shared by the histologically distinct components. Mutations private to each of the histologically distinct components included PIK3R1, CHERP and MAPK14 mutations. The carcinomatous and sarcomatous components of UCSs shared clonal TP53, PIK3CA, CDKN2A, ITGB7 and FGFR2 mutations. Private KMT2B mutations were identified in the UCS carcinomatous components. PyClone analysis revealed that the clonally-related histologically distinct components of each case harbored intra-component genetic heterogeneity coupled with parallel evolution. Conclusions: Our findings support the contention that UCSs constitute the uterine counterpart of MBCs due to their similar histology and patterns of genetic alterations affecting the same signaling pathways (i.e. TP53, PI3K, Wnt and Notch). In each MBC and UCS analyzed here, the histologically distinct components were found to be clonally related. Citation Format: Da Cruz Paula A, Brown D, Geyer FC, Smith E, Pareja F, Papanastasiou AD, Fusco N, Marchio C, Brogi E, Wen HY, Vincent-Salomon A, Norton L, Weigelt B, Reis-Filho JS. Metaplastic breast carcinomas and uterine carcinosarcomas are histologically and genetically related [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-07-02.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.SABCS18-P3-07-02
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
