Clonal relationships between lobular carcinoma in situ and other breast malignancies

Begg, Colin B.; Ostrovnaya, Irina; Carniello, Jose V. Scarpa; Sakr, Rita A.; Giri, Dilip; Towers, Russell; Schizas, Michail; Brot, Marina De; Andrade, Victor Piana de; Mauguen, Audrey; Seshan, Venkatraman; King, Tari A.

doi:10.1186/s13058-016-0727-z

Cited by 35 publications

(28 citation statements)

References 45 publications

(49 reference statements)

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“…Whole‐exome sequencing has the potential to greatly reduce the diagnostic uncertainty, but it would not necessarily eliminate it. Indeed in an earlier study by our group that used whole‐exome sequencing to assess the evidence of clonal relationships between pre‐malignant lesions (lobular carcinoma in situ ) and invasive breast cancers several cases were observed with a single shared somatic mutation, rendering the evidence for clonality equivocal . Finally, our statistical testing is based on the premise that the probability of a matching mutation in two independently occurring tumors is the square of the relative frequency of the given mutation in breast cancers generally.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed in an earlier study by our group that used whole-exome sequencing to assess the evidence of clonal relationships between premalignant lesions (lobular carcinoma in situ) and invasive breast cancers several cases were observed with a single shared somatic mutation, rendering the evidence for clonality equivocal. 52 Finally, our statistical testing is based on the premise that the probability of a matching mutation in two independently occurring tumors is the square of the relative frequency of the given mutation in breast cancers generally. However, matches are more likely if host characteristics of the patient influence these probabilities, a phenomenon that will occur if somatic mutational patterns are influenced by the germline.…”

Section: Tumor Markers and Signaturesmentioning

confidence: 99%

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Contralateral breast cancers: Independent cancers or metastases?

Begg

Ostrovnaya

Geyer

et al. 2017

Intl Journal of Cancer

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A cancer in the contralateral breast in a woman with a previous or synchronous breast cancer is typically considered to be an independent primary tumor. Emerging evidence suggests that in a small subset of these cases the second tumor represents a metastasis. We sought to investigate the issue using massively parallel sequencing targeting 254 genes recurrently mutated in breast cancer. We examined the tumor archives at Memorial Sloan Kettering Cancer Center for the period 1995-2006 to identify cases of contralateral breast cancer where surgery for both tumors was performed at the Center. We report results from 49 patients successfully analyzed by a targeted massively parallel sequencing assay. Somatic mutations and copy number alterations were defined by state-of-the-art algorithms. Clonal relatedness was evaluated by statistical tests specifically designed for this purpose. We found evidence that the tumors in contralateral breasts were clonally related in three cases (6%) on the basis of matching mutations at codons where somatic mutations are rare. Clinical data and the presence of similar patterns of gene copy number alterations were consistent with metastasis for all three cases. In three additional cases, there was a solitary matching mutation at a common PIK3CA locus. The results suggest that a subset of contralateral breast cancers represent metastases rather than independent primary tumors. Massively parallel sequencing analysis can provide important evidence to clarify the diagnosis. However, given the inter-tumor mutational heterogeneity in breast cancer, sufficiently large gene panels need to be employed to define clonality convincingly in all cases.

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Section: Discussionmentioning

confidence: 99%

Section: Tumor Markers and Signaturesmentioning

confidence: 99%

Contralateral breast cancers: Independent cancers or metastases?

Begg

Ostrovnaya

Geyer

et al. 2017

Intl Journal of Cancer

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“…LCIS and invasive lobular carcinomas (ILC) are phenotypically and genetically similar. Both lesions are preferentially of the luminal-A molecular subtype [i.e., estrogen receptor (ER)positive, HER2-negative, low-grade, and low-proliferation] and harbor recurrent gains of 1q and losses of 16q, encompassing the CDH1 gene locus, as well as recurrent CDH1 somatic mutations (1,(3)(4)(5)(6)(7). In fact, loss of E-cadherin, the protein product of the CDH1 gene, is a hallmark feature of these lesions (3,6) and has been shown to result in the development of ILCs in conditional mouse models (8).…”

Section: Introductionmentioning

confidence: 99%

Lobular Carcinomas In Situ Display Intralesion Genetic Heterogeneity and Clonal Evolution in the Progression to Invasive Lobular Carcinoma

Lee

Schizas

Geyer

et al. 2019

Clinical Cancer Research

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

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“…The study conducted by Colin B.Begg et al [13] has reiterated the fact that LCIS is a precursor of both the lobular and the invasive ductal carcinoma, showing that in LCIS there are genetic alterations such as gain or loss of function of certain genes that are also found in the lobular and invasive ductal carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Contralateral Prophylactic Mastectomies: Correlations between Primary Tumor and Histological Findings of Controlateral Breast

Vitale¹

2017

CSROA

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Clonal relationships between lobular carcinoma in situ and other breast malignancies

Cited by 35 publications

References 45 publications

Contralateral breast cancers: Independent cancers or metastases?

Contralateral breast cancers: Independent cancers or metastases?

Lobular Carcinomas In Situ Display Intralesion Genetic Heterogeneity and Clonal Evolution in the Progression to Invasive Lobular Carcinoma

Contralateral Prophylactic Mastectomies: Correlations between Primary Tumor and Histological Findings of Controlateral Breast

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