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

Sakr, Rita A.; Schizas, Michail; Carniello, Jose V. Scarpa; Ng, Charlotte K.Y.; Piscuoglio, Salvatore; Giri, Dilip; Andrade, Victor Piana de; Brot, Marina De; Lim, Raymond S.; Towers, Russell; Weigelt, Britta; Reis‐Filho, Jorge S.; King, Tari A.

doi:10.1016/j.molonc.2015.11.001

Cited by 44 publications

(34 citation statements)

References 50 publications

(68 reference statements)

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“…It did, however, show that activating PIK3CA mutations are as common in LCIS as CDH1 mutations. Activating PIK3CA mutations are well-described in both ILC and IDC, occurring in 48% of ILC (as the second most common mutations after CDH1 ) and 33% of IDC [47, 48]. PIK3CA mutations have previously been reported by Christgen et al [49] in 1/3 patients with LCIS associated with ILC and by Sakr et al [48] in 7/19 patients.…”

Section: Discussionmentioning

confidence: 99%

“…Activating PIK3CA mutations are well-described in both ILC and IDC, occurring in 48% of ILC (as the second most common mutations after CDH1 ) and 33% of IDC [47, 48]. PIK3CA mutations have previously been reported by Christgen et al [49] in 1/3 patients with LCIS associated with ILC and by Sakr et al [48] in 7/19 patients. We confirmed the frequency of PIK3CA mutations in a larger set of LCIS by Sanger sequencing, which revealed no difference in the frequency of PIK3CA mutations in inv-cLCIS compared to pure-cLCIS.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…In recent years, targeted capture and MPS technologies have been widely used in clinical practice and have got satisfactory results15232425262728. To this end, we designed the gene panel contains 118 genes which are reported to be associated with leukoencephalopathies, not only contains genes associated with genetic leukoencephalopathy, but also mitochondrial disease, cerebral cortical degenerative disorders, etc.…”

Section: Discussionmentioning

confidence: 99%

The use of targeted genomic capture and massively parallel sequencing in diagnosis of Chinese Leukoencephalopathies

Wang

Yin

et al. 2016

Sci Rep

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Leukoencephalopathies are diseases with high clinical heterogeneity. In clinical work, it’s difficult for doctors to make a definite etiological diagnosis. Here, we designed a custom probe library which contains the known pathogenic genes reported to be associated with Leukoencephalopathies, and performed targeted gene capture and massively parallel sequencing (MPS) among 49 Chinese patients who has white matter damage as the main imaging changes, and made the validation by Sanger sequencing for the probands’ parents. As result, a total of 40.8% (20/49) of the patients identified pathogenic mutations, including four associated with metachromatic leukodystrophy, three associated with vanishing white matter leukoencephalopathy, three associated with mitochondrial complex I deficiency, one associated with Globoid cell leukodystrophy (or Krabbe diseases), three associated with megalencephalic leukoencephalopathy with subcortical cysts, two associated with Pelizaeus-Merzbacher disease, two associated with X-linked adrenoleukodystrophy, one associated with Zellweger syndrome and one associated with Alexander disease. Targeted capture and MPS enables to identify mutations of all classes causing leukoencephalopathy. Our study combines targeted capture and MPS technology with clinical and genetic diagnosis and highlights its usefulness for rapid and comprehensive genetic testing in the clinical setting. This method will also expand our knowledge of the genetic and clinical spectra of leukoencephalopathy.

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“…Mutations in CDH1 have been identified in up to 56% of cases of LCIS, with matching CDH1 mutations in adjacent ILBC 52 55. Frequent mutations are also found in PIK3CA and CBFB in LCIS with shared mutations in 71% of coexistent ILBC indicating that the lesions are clonally related 52. Another study by the same group identified 169 genes that were differentially expressed in the progression pathway from normal epithelium to LCIS to ILBC; interestingly there was enrichment for genes located on 16q and 1q, sites of common copy number changes in lobular carcinoma 56.…”

Section: Lobular Breast Tumorigenesis With Cdh1 Defectmentioning

confidence: 97%

Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect

et al. 2018

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Recent studies have reported germline mutations in cases of lobular breast cancer (LBC) not associated with the classical hereditary diffuse gastric cancer syndrome. A multidisciplinary workgroup discussed genetic susceptibility, pathophysiology and clinical management of hereditary LBC (HLBC). The team has established the clinical criteria for screening and results' interpretation, and created consensus guidelines regarding genetic counselling, breast surveillance and imaging techniques, clinicopathological findings, psychological and decisional support, as well as prophylactic surgery and plastic reconstruction. Based on a review of current evidence for the identification of HLBC cases/families, genetic testing is recommended in patients fulfilling the following criteria: (A) bilateral LBC with or without family history of LBC, with age at onset<50 years, and (B) unilateral LBC with family history of LBC, with age at onset <45 years. In asymptomatic mutant carriers, breast surveillance with clinical examination, yearly mammography, contrast-enhanced breast MRI and breast ultrasonography (US) with 6-month interval between the US and the MRI should be implemented as a first approach. In selected cases with personal history, family history of LBC and mutations, prophylactic mastectomy could be discussed with an integrative group of clinical experts. Psychodecisional support also plays a pivotal role in the management of individuals with or without germline alterations. Ultimately, the definition of a specific protocol for genetic screening and ongoing coordinated management of patients with HLBC is crucial for the effective surveillance and early detection of LBC.

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

Cited by 44 publications

References 50 publications

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

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

The use of targeted genomic capture and massively parallel sequencing in diagnosis of Chinese Leukoencephalopathies

Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect

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