Genomic and mutational profiling of ductal carcinomas <i>in situ</i> and matched adjacent invasive breast cancers reveals intra‐tumour genetic heterogeneity and clonal selection

Hernández, L.; Wilkerson, Paul M.; Lambros, Maryou B.; Campion-Flora, Adriana; Rodrigues, Daniel Nava; Gauthier, Arnaud; Cabral, C.; Pawar, Vidya; Mackay, Alan; A’Hern, Roger; Marchiò, Caterina; Palacios, José; Natrajan, Rachael; Weigelt, Britta; Reis‐Filho, Jorge S.

doi:10.1002/path.3990

Cited by 144 publications

(157 citation statements)

References 52 publications

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“…To identify intratumoral heterogeneity, we microdissected and analyzed mutation status in more than 2,500 tumor foci of 81 tumors from patients with IDC who underwent prior surgery before chemotherapy, and 28.4% of tumors contained both mutant and wild-type foci. These findings are in accordance with the previous reports by Hernandez and colleagues (27) and Kalinsky and colleagues (28).…”

Section: Discussionsupporting

confidence: 94%

Favorable Prognostic Impact in Loss of TP53 and PIK3CA Mutations after Neoadjuvant Chemotherapy in Breast Cancer

Jiang

Bao

et al. 2014

Cancer Research

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We investigated the loss of somatic mutations in TP53 and PIK3CA in breast cancer tissue after neoadjuvant chemotherapy (NCT) and the clinical relevance of the observed mutation profiles. Samples were derived from three cohorts: Cohort 1 consisting of 206 patients undergoing NCT with matched pre-and postchemotherapy tumor tissues; Cohort 2 consisting of 158 additional patients undergoing NCT; and Cohort 3, consisting of 81 patients undergoing chemotherapy with prechemotherapy tumor tissues. In the first cohort, somatic mutations in TP53 or PIK3CA were identified in 24.8% of the pre-NCT tumor samples but in only 12.1% of the post-NCT tumor samples (P < 0.001). Patients with initial TP53 and PIK3CA mutations who became negative for the mutations after NCT had a higher Miller-Payne score (P ¼ 0.008), improved disease-free survival, and improved overall survival than those with no change or the opposite change. The association of loss of mutations in TP53 and PIK3CA and improved survival was successfully validated in the second cohort. In addition, 28.4% of the tumors showed intratumoral heterogeneity of somatic mutations in TP53 or PIK3CA, whereas 71.6% were homogeneous, either with or without the mutations. Our data reveal the novel concept that chemotherapy may reduce mutation frequency in patients with breast cancer. Furthermore, the loss of somatic mutations in TP53 and PIK3CA may be translated to biomarkers for prognosis via further verification, which may optimize the choice of sequential therapy and improve patient survival. Cancer Res; 74(13); 3399-407. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 94%

Favorable Prognostic Impact in Loss of TP53 and PIK3CA Mutations after Neoadjuvant Chemotherapy in Breast Cancer

Jiang

Bao

et al. 2014

Cancer Research

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“…The continuous improvements of next-generation sequencing (NGS) technologies currently allow the analysis of hundreds of genes in just one population of cells, or even in one single cell (96,97). Such application has opened a new window in the genomic field where a mutational, time-based lineage tree can now be delineated for a specific subtype of cancer considered to be highly aggressive.…”

Section: Breast Cancer Stem Cells and Next-generation Sequencingmentioning

confidence: 99%

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

Paula

Lopes

2017

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“…Given these observations, there is significant interest in finding genes that promote the invasive progression of early-stage tumors (3). Previous studies have sought molecular alterations present in invasive tumors but not DCIS, leading to the identification of hundreds of genomic and gene-expression alterations specifically associated with invasive cancers (4)(5)(6). However, it is unclear if genes that are amplified or up-regulated in invasive cancers also functionally drive DCIS invasion.…”

mentioning

confidence: 99%

SMARCE1 is required for the invasive progression of in situ cancers

Sokol

Feng

Jin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Advances in mammography have sparked an exponential increase in the detection of early-stage breast lesions, most commonly ductal carcinoma in situ (DCIS). More than 50% of DCIS lesions are benign and will remain indolent, never progressing to invasive cancers. However, the factors that promote DCIS invasion remain poorly understood. Here, we show that SMARCE1 is required for the invasive progression of DCIS and other early-stage tumors. We show that SMARCE1 drives invasion by regulating the expression of secreted proteases that degrade basement membrane, an ECM barrier surrounding all epithelial tissues. In functional studies, SMARCE1 promotes invasion of in situ cancers growing within primary human mammary tissues and is also required for metastasis in vivo. Mechanistically, SMARCE1 drives invasion by forming a SWI/SNF-independent complex with the transcription factor ILF3. In patients diagnosed with early-stage cancers, SMARCE1 expression is a strong predictor of eventual relapse and metastasis. Collectively, these findings establish SMARCE1 as a key driver of invasive progression in early-stage tumors.T he past two decades have brought an exponential increase in the diagnosis of early-stage breast lesions, most commonly ductal carcinoma in situ (DCIS). DCIS remains encapsulated within the ductal-lobular architecture of mammary epithelium; in contrast, invasive breast cancers have escaped this architecture by breaking through the basement membrane, a layer of ECM rich in collagen (IV) and laminins that separates epithelial tissues from the adjacent stromal microenvironment ( Fig. S1A) (1). This distinction has a critical impact on patient prognosis: whereas women with DCIS show no reduction in survival 5 y after diagnosis, those with invasive cancers have a 15-74% reduction in 5-y survival rates depending on the extent of tumor invasion at diagnosis (2). Given these observations, there is significant interest in finding genes that promote the invasive progression of early-stage tumors (3). Previous studies have sought molecular alterations present in invasive tumors but not DCIS, leading to the identification of hundreds of genomic and gene-expression alterations specifically associated with invasive cancers (4-6). However, it is unclear if genes that are amplified or up-regulated in invasive cancers also functionally drive DCIS invasion. In large part, the difficulty in addressing this question can be traced to a paucity of experimental systems that model cancer invasion within a microenvironment that faithfully replicates human breast tissue.The treatment of early-stage cancers remains an unresolved issue. Women with early-stage breast cancers-which include DCIS and stage I tumors that have not entered the lymph nodesare typically treated by lumpectomy followed by localized radiation. However, recurrence with metastasis occurs in a significant fraction of women with stage I cancers; if such tumors could be prospectively identified, it would be possible to preemptively adopt a more aggressive therapy. Conver...

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Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra‐tumour genetic heterogeneity and clonal selection

Cited by 144 publications

References 52 publications

Favorable Prognostic Impact in Loss of TP53 and PIK3CA Mutations after Neoadjuvant Chemotherapy in Breast Cancer

Favorable Prognostic Impact in Loss of TP53 and PIK3CA Mutations after Neoadjuvant Chemotherapy in Breast Cancer

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

SMARCE1 is required for the invasive progression of in situ cancers

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