Lobular carcinomas in situ display intralesion genetic heterogeneity and clonal evolution in the progression to invasive lobular carcinoma

Ju Youn Lee, Michail Schizas, Felipe C. Geyer, Pier Selenica, Salvatore Piscuoglio, Rita A. Sakr, Charlotte K.Y. Ng, Jose V. Scarpa Carniello, Russell Towers, Dilip D. Giri, Victor P. de Andrade, Anastasios D. Papanastasiou, Agnes Viale, Reuben S. Harris, David B. Solit, Britta Weigelt, Jorge S. Reis-Filho, Tari A. King

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Purpose: Lobular carcinoma in situ (LCIS) is a preinvasive mutations present in 81% of the lesions. Forty-two percent lesion of the breast. We sought to define its genomic landscape, (18/43) of LCIS were found to be clonally related to synchro-whether intralesion genetic heterogeneity is present in LCIS, nous DCIS and/or ILCs, with clonal evolutionary patterns and the clonal relatedness between LCIS and invasive breast indicative of clonal selection and/or parallel/branched pro-cancers. gression. Intralesion genetic heterogeneity was higher among Experimental Design: We reanalyzed whole-exome LCIS clonally related to DCIS/ILC than in those nonclonally sequencing (WES) data and performed a targeted amplicon related to DCIS/ILC. A shift from aging to APOBEC-related sequencing validation of mutations identified in 43 LCIS and mutational processes was observed in the progression from 27 synchronous more clinically advanced lesions from 24 LCIS to DCIS and/or ILC in a subset of cases. patients [9 ductal carcinomas in situ (DCIS), 13 invasive Conclusions: Our findings support the contention that lobular carcinomas (ILC), and 5 invasive ductal carcinomas LCIS has a repertoire of somatic genetic alterations similar to (IDC)]. Somatic genetic alterations, mutational signatures, that of ILCs, and likely constitutes a nonobligate precursor of clonal composition, and phylogenetic trees were defined using breast cancer. Intralesion genetic heterogeneity is observed in validated computational methods. LCIS and should be considered in studies aiming to develop Results: WES of 43 LCIS lesions revealed a genomic profile biomarkers of progression from LCIS to more advanced similar to that previously reported for ILCs, with CDH1 lesions.

Original languageEnglish (US)
Pages (from-to)674-686
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number2
DOIs
StatePublished - Jan 15 2019

Bibliographical note

Funding Information:
J.S. Reis-Filho is funded in part by the Breast Cancer Research Foundation. S. Piscuoglio is funded by the Swiss National Science Foundation (Ambizione grant number PZ00P3_168165). R.S. Harris is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished McKnight University Professor, and an Investigator of the Howard Hughes Medical Institute. Research reported in this publication was supported in part by 2009 Komen Career Catalyst Award (T.A. King), 2012 Komen Investigator Initiated Research Award (T.A. King), Susan G. Komen for the Cure, and by a Cancer Center Support Grant of the NIH/NCI (grant no. P30CA008748).

Publisher Copyright:
© 2018 American Association for Cancer Research.

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