Mucinous breast carcinomas lack PIK3CA and AKT1 mutations

Kehr, Elizabeth; Jorns, Julie M.; Ang, Daphne; Warrick, Andrea; Neff, Tanaya; Degnin, Michelle; Lewis, Rebecca; Beadling, Carol; Corless, Christopher L.; Troxell, Megan L.

doi:10.1016/j.humpath.2012.03.012

Cited by 39 publications

(30 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[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. 1,8,16,19 In this study, we demonstrated a 50% frequency of PIK3CA point mutations in usual ductal hyperplasia and columnar cell lesions across 62 lesions, representing the largest series to date.…”

Section: Discussionmentioning

confidence: 93%

“…Lesions were screened for known hotspot point mutations using a multiplexed mass spectroscopy-based approach with a panel covering 643 common activating point mutations in 53 known cancer genes, including 58 hotspot substitutions in the PIK3CA gene, along with coverage of other breast cancer genes such as AKT1, ERBB2, PIK3R1, and TP53; identified mutations were sequence confirmed. [19][20][21]27,28 The final study group included 192 breast lesions successfully genotyped from 75 patients, as follows (Supplementary Table 1A and B): 62 usual ductal hyperplasia/columnar cell lesion, 14 atypical ductal hyperplasia/flat epithelial atypia, 16 lobular neoplasias, 21 DCIS, 37 invasive carcinomas, 6 lymph node metastases, and 36 other lesions (papillomas, mixed histology, and from patients with recurrent cancer).…”

Section: Patients and Genotypingmentioning

confidence: 99%

“…[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.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

et al. 2014

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Patients and Genotypingmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…In other studies (Kononen et al, 1998;Davies et al, 2002;Cheang et al, 2008;Gollamudi et al, 2010;Kan et al, 2010), BRAF mutations were identified only in breast cancer cell lines and other primary tumours, but not in breast cancer patients. AKT1 mutations have been identified in 1-8% of breast carcinomas, in which they occur early (Dunlap et al, 2010); however, mucinous breast carcinomas have been reported to lack AKT1 mutations (Kehr et al, 2012). In a triple-negative breast cancer study, no HRAS mutation was found (Martin et al, 2012); however, 1 of 45 papillary breast neoplasm cases exhibited an HRAS mutation (Troxell et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Mutational Analysis of Key EGFR Pathway Genes in Chinese Breast Cancer Patients

Lin

Yang²,

Liu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Background: The epidermal growth factor receptor (EGFR) is a potential therapeutic target for breast cancer treatment; however, its use does not lead to a marked clinical response. Studies of non-small cell lung cancer and colorectal cancer showed that mutations of genes in the PIK3CA/AKT and RAS/RAF/MEK pathways, two major signalling cascades downstream of EGFR, might predict resistance to EGFR-targeted agents. Therefore, we examined the frequencies of mutations in these key EGFR pathway genes in Chinese breast cancer patients. Methods: We used a high-throughput mass-spectrometric based cancer gene mutation profiling platform to detect 22 mutations of the PIK3CA, AKT1, BRAF, EGFR, HRAS, and KRAS genes in 120 Chinese women with breast cancer. Results: Thirteen mutations were detected in 12 (10%) of the samples, all of which were invasive ductal carcinomas (two stage I, six stage II, three stage III, and one stage IV). These included one mutation (0.83%) in the EGFR gene (rs121913445-rs121913432), three (2.50%) in the KRAS gene (rs121913530, rs112445441), and nine (7.50%) in the PIK3CA gene (rs121913273, rs104886003, and rs121913279). No mutations were found in the AKT1, BRAF, and HRAS genes. Six (27.27%) of the 22 genotyping assays called mutations in at least one sample and three (50%) of the six assays queried were found to be mutated more than once. Conclusions: Mutations in the EGFR pathway occurred in a small fraction of Chinese breast cancers. However, therapeutics targeting these potential predictive markers should be investigated in depth, especially in Oriental populations.

show abstract

“…It has been shown that PIK3CA pathway aberrations are common in breast cancer [30]. PIK3CA mutations are reported to be presented in approximately 25% of breast cancer cases, especially in the estrogen-receptor positive (ER + ) and human epidermal growth factor receptor 2 (HER2)-overexpressing (HER2 + ) subtypes [31,32]; however, the frequency of PIK3CA mutations in hormone dependent breast cancer cell lines was much higher, 39% [30]. This breast cancer subtype specifi city showed that PIK3CA mutations and other PI3K pathway aberrations may play a distinct role in the pathogenesis and cell proliferation of the disease [32].…”

Section: Discussionmentioning

confidence: 99%

PIK3CA rs7640662 (C/G) single nucleotide polymorphism lacks association with breast cancer cases in Persians

Mir¹,

Harati‐Sadegh²,

Ahmadinia³

et al. 2015

Interventional Medicine and Applied Science

View full text Add to dashboard Cite

Phosphatidylinositol-3-kinase (PI3K) is a group of enzymes involved in cellular growth, proliferation, diff erentiation, cell motility, intracellular traffi cking, and survival that play very important roles in developing breast cancer. PIK3CA is a gene that encodes α catalytic subunit of this enzyme. A common polymorphism of PIK3CA, rs7640662 (C/G), was analyzed, and its association to breast cancer cases was determined. In this study, DNA was extracted from peripheral blood samples of 278 women suff ering from breast cancer and 128 healthy women. Tetra-primer amplifi cation refractory mutation system polymerase chain reaction (T-ARMS-PCR) method was performed to genotype rs7640662. P values and ODD ratios were measured using SPSS. P value less than 0.05 and ODD ratios more than 1 were considered as signifi cant. All ODD ratios were less than 1, and P values were more than 0.05 showing that rs7640662 (C/G) and breast cancer are not signifi cantly associated. However, the genotypes observed in the Persian population, as an ancient population living in the Middle East, was signifi cantly diff erent from the genotypes reported by HapMap for Asian populations. As a conclusion, rs7640662 was not associated with the risk of breast cancer in a Persian population; however, it was observed that heterozygote (GC) is the most common genotypes in both case and control samples.

show abstract

Mucinous breast carcinomas lack PIK3CA and AKT1 mutations

Cited by 39 publications

References 26 publications

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

Mutational Analysis of Key EGFR Pathway Genes in Chinese Breast Cancer Patients

PIK3CA rs7640662 (C/G) single nucleotide polymorphism lacks association with breast cancer cases in Persians

Contact Info

Product

Resources

About