PIK3CA Mutations in <i>In situ</i> and Invasive Breast Carcinomas

Miron, Alexander; Váradi, Mária; Carrasco, Daniel R.; Li, Hailun; Luongo, Lauren; Kim, Hee Jung; Park, So Yeon; Cho, Eun Yoon; Lewis, Gretchen; Kehoe, Sarah M.; Iglehart, J. Dirk; Dillon, Deborah; Allred, D. Craig; MacConaill, Laura E.; Gelman, Rebecca; Polyák, Kornélia

doi:10.1158/0008-5472.can-08-2660

Cited by 113 publications

(98 citation statements)

References 17 publications

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“…The prevalence of PIK3CA mutations in this cohort (55%) is somewhat higher than that previously reported for DCIS (17-48%) 7,8,14,15,38,39 and invasive breast cancers (25-36%). 4,5,40,41 The relatively small number of cases included in this and other DCIS each studies (involving between six and 202 cases), 7,8,14,15,38,39 may account for the variation in prevalence.…”

Section: Discussioncontrasting

confidence: 75%

“…4,5,40,41 The relatively small number of cases included in this and other DCIS each studies (involving between six and 202 cases), 7,8,14,15,38,39 may account for the variation in prevalence. Alternatively, the high read-depth of our targeted sequencing may have led to increased detection rates compared with exome or Sanger studies: four DCIS cases had a PIK3CA variant frequency of o20%, which could have been missed by less sensitive methods.…”

Section: Discussionmentioning

confidence: 93%

“…[1][2][3][4][5] However, little is known about the mutational profile of ductal carcinoma in situ (DCIS). Studies have addressed mutations of individual genes [6][7][8][9][10][11][12][13] but until very recently, assessment of a broad panel of genes in DCIS has not been performed, largely due the challenges in obtaining DNA from DCIS cases compatible with highly multiplexed methodologies. To date, whole genome or whole exome sequencing has been performed in only 45 published DCIS cases in total, all using DNA from fresh frozen tissue.…”

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confidence: 99%

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Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

et al. 2017

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The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n = 20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P = 0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P = 0.005), including a significant positive association with amplification or gain of ERBB2 (Po 0.05). The association between TP53 mutation and ERBB2 amplification was confirmed in a wider DCIS cohort using p53 immunohistochemistry as a surrogate marker for TP53 mutations (P = 0.03). RUNX1 mutations and MAP2K4 copy number loss were novel findings in DCIS. Frequent copy number alterations included gains on 1q, 8q, 17q, and 20q and losses on 8p, 11q, 16q, and 17p. Patterns of genomic alterations observed in DCIS were similar to those previously reported for invasive breast cancers, with all DCIS having at least one bona fide breast cancer driver event. However, an increase in GATA3 mutations and fewer copy number changes were noted in DCIS compared with invasive carcinomas. The role of such alterations as prognostic and predictive biomarkers in DCIS is an avenue for further investigation.

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Section: Discussioncontrasting

confidence: 75%

Section: Discussionmentioning

confidence: 93%

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confidence: 99%

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Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

et al. 2017

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“…[14][15][16][17] Accumulating evidence suggests that PIK3CA point mutations may also be common in other proliferative breast lesions such as benign papillomas and columnar cell lesions. [18][19][20][21][22][23] Prior studies have failed to identify PIK3CA mutations in histologically normal breast tissue, even with the same sensitive methods employed here.…”

Section: Discussionmentioning

confidence: 99%

“…3,12,13 We and other groups have previously shown that the PIK3CA genotype is concordant between ductal carcinoma in situ (DCIS) and concurrent invasive carcinoma in 66-100% of tested samples. [14][15][16][17] However, several small studies suggest that pre-neoplastic or benign breast lesions, such as papillomas, radial scars, or columnar cell lesions, may also very frequently harbor PIK3CA mutations. [18][19][20][21][22][23] The goal of this study was to systematically screen a large number of hyperplastic and putative precursor breast lesions, along with accompanying carcinomas for known activating mutations in PIK3CA and other key signaling molecules.…”

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confidence: 99%

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

et al. 2014

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The phosphatidylinositol-3-kinase pathway is one of the most commonly altered molecular pathways in invasive breast carcinoma, with phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) mutations in 25% of invasive carcinomas. Ductal carcinoma in situ (DCIS), benign papillomas, and small numbers of columnar cell lesions harbor an analogous spectrum of PIK3CA and AKT1 mutations, yet there is little data on usual ductal hyperplasia and atypical ductal and lobular neoplasias. We screened 192 formalin-fixed paraffin-embedded breast lesions from 75 patients for point mutations using a multiplexed panel encompassing 643 point mutations across 53 genes, including 58 PIK3CA substitutions. PIK3CA point mutations were identified in 31/62 (50%) proliferative lesions (usual ductal hyperplasia and columnar cell change), 10/14 (71%) atypical hyperplasias (atypical ductal hyperplasia and flat epithelial atypia), 7/16 (44%) lobular neoplasias (atypical lobular hyperplasia and lobular carcinoma in situ), 10/21 (48%) DCIS, and 13/37 (35%) invasive carcinomas. In genotyping multiple lesions of different stage from the same patient/specimen, we found considerable heterogeneity; most notably, in 12 specimens the proliferative lesion was PIK3CA mutant but the concurrent carcinoma was wild type. In 11 additional specimens, proliferative epithelium and cancer contained different point mutations. The frequently discordant genotypes of usual ductal hyperplasia/columnar cell change and concurrent carcinoma support a role for PIK3CA-activating point mutations in breast epithelial proliferation, perhaps more so than transformation. Further, these data suggest that proliferative breast lesions are heterogeneous and may represent non-obligate precursors of invasive carcinoma. Keywords: atypical ductal hyperplasia; breast carcinoma; columnar cell change; PIK3CA; usual ductal hyperplasia The phosphatidylinositol-3-kinase pathway is one of the most commonly mutated pathways in invasive breast carcinoma. Activating mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are present in B25% of invasive carcinomas and are present in an even higher percentage (on the order of 40%) of low-grade estrogen receptorpositive carcinomas (luminal A intrinsic subtype). 1-10 PIK3CA mutations cluster in 'hotspots' in exon 9 (helical domain, E542K and E545K) and exon 20 (kinase domain, H1047R/L). [1][2][3][4][5][6][7][8][9][10] In addition, this pathway is activated by mutations in the plekstrinhomology domain of AKT1 in B5% of breast carcinomas, by the loss of the phosphatase PTEN (phosphatase and tensin homolog on chromosome 10), or rarely by amplification or alterations in other regulatory subunits, and is a target of active drug development. [8][9][10][11] In recent large studies of estrogen receptor-positive tumors, the presence of activating PIK3CA hotspot point mutations has been paradoxically associated with more favorable outcome as compared with breast carcinomas with wild-type PIK3CA. 3,12,13 We and other groups have previously s...

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Correlation of Breast Cancer Axillary Lymph Node Metastases With Stem Cell Mutations

et al. 2013

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PIK3CA Mutations in In situ and Invasive Breast Carcinomas

Cited by 113 publications

References 17 publications

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

Correlation of Breast Cancer Axillary Lymph Node Metastases With Stem Cell Mutations

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