Molecular drivers of lobular carcinoma in situ

Logan, G; Dabbs, David J.; Lucas, Peter C.; Jankowitz, Rachel C.; Brown, Daniel D.; Clark, Beth Z.; Oesterreich, Steffi; McAuliffe, Priscilla F.

doi:10.1186/s13058-015-0580-5

Cited by 34 publications

(37 citation statements)

References 101 publications

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“…Further, there was no significant difference in the pattern of CDH1 mutations between LCIS and ILC samples. Previous studies with smaller sample sizes and different methodology have reported a higher frequency of CDH1 mutations in ILC (Logan et al., 2015); however, our findings are consistent with that of the most recent publication from The Cancer Genome Atlas Project, where CDH1 mutations were identified in 63% (80/127) of classic invasive lobular carcinomas (Ciriello et al., 2014, 2015).…”

Section: Discussionsupporting

confidence: 92%

Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships

et al. 2015

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Purpose Lobular carcinoma in situ (LCIS) has been proposed as a non-obligate precursor of invasive lobular carcinoma (ILC). Here we sought to define the repertoire of somatic genetic alterations in pure LCIS and in synchronous LCIS and ILC using targeted massively parallel sequencing. Methods DNA samples extracted from microdissected LCIS, ILC and matched normal breast tissue or peripheral blood from 30 patients were subjected to massively parallel sequencing targeting all exons of 273 genes, including the genes most frequently mutated in breast cancer and DNA repair-related genes. Single nucleotide variants and insertions and deletions were identified using state-of-the-art bioinformatics approaches. Results The constellation of somatic mutations found in LCIS (n=34) and ILC (n=21) were similar, with the most frequently mutated genes being CDH1 (56% and 66%, respectively), PIK3CA (41% and 52%, respectively) and CBFB (12% and 19%, respectively). Among 19 LCIS and ILC synchronous pairs, 14 (74%) had at least one identical mutation in common, including identical PIK3CA and CDH1 mutations. Paired analysis of independent foci of LCIS from 3 breasts revealed at least one common mutation in each of the 3 pairs (CDH1, PIK3CA, CBFB and PKHD1L1). Conclusion LCIS and ILC have a similar repertoire of somatic mutations, with PIK3CA and CDH1 being the most frequently mutated genes. The presence of identical mutations between LCIS-LCIS and LCIS-ILC pairs demonstrates that LCIS is a clonal neoplastic lesion, and provides additional evidence that at least some LCIS are non-obligate precursors of ILC.

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Section: Discussionsupporting

confidence: 92%

Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships

et al. 2015

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“…All cell lines grew without hormone supplements with engraftment rates between 30% and 100% with the exception of MDAMB231 cells, which grew only in 1 out of 26 grafts ( Figure 1B). The findings included ER + cell lines, such as the most widely studied MCF7 (Lee et al, 2015), HCC1428, ZR751, and MDAMB134VI, which is derived from a lobular carcinoma and does not seem to have been established in vivo previously (Logan et al, 2015), as well as the androgen receptor (AR) + MDAMB453 (Figures 1B, S1A, and S1B), which usually requires exogenous 5a-dihydrotestosterone (Ni et al, 2011). In vivo monitoring of engrafted mice by luminescence showed that the ER + cell lines grow exponentially ( Figure 1C).…”

Section: Intraductal Growth Of Breast Cancer Cell Linesmentioning

confidence: 99%

A Preclinical Model for ERα-Positive Breast Cancer Points to the Epithelial Microenvironment as Determinant of Luminal Phenotype and Hormone Response

et al. 2016

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Seventy-five percent of breast cancers are estrogen receptor α positive (ER⁺). Research on these tumors is hampered by lack of adequate in vivo models; cell line xenografts require non-physiological hormone supplements, and patient-derived xenografts (PDXs) are hard to establish. We show that the traditional grafting of ER⁺ tumor cells into mammary fat pads induces TGFβ/SLUG signaling and basal differentiation when they require low SLUG levels to grow in vivo. Grafting into the milk ducts suppresses SLUG; ER⁺ tumor cells develop, like their clinical counterparts, in the presence of physiological hormone levels. Intraductal ER⁺ PDXs are retransplantable, predictive, and appear genomically stable. The model provides opportunities for translational research and the study of physiologically relevant hormone action in breast carcinogenesis.

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“…Current biomarker data in LCIS are very limited [16]. There is some evidence to suggest the risk of subsequent invasive disease is associated with high Ki67 expression [17] and that increased expression of hsa-miR-375 contributes to lobular neoplastic progression [18].…”

Section: Introductionmentioning

confidence: 99%

PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression

et al. 2017

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BackgroundLobular carcinoma in situ (LCIS) is a non-invasive breast lesion that is typically found incidentally on biopsy and is often associated with invasive lobular carcinoma (ILC). LCIS is considered by some to be a risk factor for future breast cancer rather than a true precursor lesion. The aim of this study was to identify genetic changes that could be used as biomarkers of progression of LCIS to invasive disease using cases of pure LCIS and comparing their genetic profiles to LCIS which presented contemporaneously with associated ILC, on the hypothesis that the latter represents LCIS that has already progressed.MethodsSomatic copy number aberrations (SCNAs) were assessed by SNP array in three subgroups: pure LCIS, LCIS associated with ILC and the paired ILC. In addition exome sequencing was performed on seven fresh frozen samples of LCIS associated with ILC, to identify recurrent somatic mutations.ResultsThe copy number profiles of pure LCIS and LCIS associated with ILC were almost identical. However, four SCNAs were more frequent in ILC than LCIS associated with ILC, including gain/amplification of CCND1. CCND1 protein over-expression assessed by immunohistochemical analysis in a second set of samples from 32 patients with pure LCIS and long-term follow up, was associated with invasive recurrence (P = 0.02, Fisher’s exact test). Exome sequencing revealed that PIK3CA mutations were as frequent as CDH1 mutations in LCIS, but were not a useful biomarker of LCIS progression as they were as frequent in pure LCIS as in LCIS associated with ILC. We also observed heterogeneity of PIK3CA mutations and evidence of sub-clonal populations in LCIS irrespective of whether they were associated with ILC.ConclusionsOur data shows that pure LCIS and LCIS co-existing with ILC have very similar SCNA profiles, supporting the hypothesis that LCIS is a true precursor lesion. We have provided evidence that over-expression of CCND1 may identify a subgroup of patients with pure LCIS who are more likely to develop invasive disease, in contrast to PIK3CA mutations, which occur too early in lobular tumorigenesis to be informative.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0789-y) contains supplementary material, which is available to authorized users.

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Molecular drivers of lobular carcinoma in situ

Cited by 34 publications

References 101 publications

Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships

Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships

A Preclinical Model for ERα-Positive Breast Cancer Points to the Epithelial Microenvironment as Determinant of Luminal Phenotype and Hormone Response

PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression

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