Somatic mutation and gain of copy number of PIK3CA in human breast cancer

Wu, Guojun; Xing, Mingzhao; Mambo, Elizabeth; Huang, Xin; Liu, Junwei; Guo, Zhen; Chatterjee, Aditi; Goldenberg, David; Gollin, Susanne M.; Sukumar, Saraswati; Trink, Barry; Sidransky, David

doi:10.1186/bcr1262

Cited by 205 publications

(164 citation statements)

References 18 publications

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“…Although the significance of this double mutant is unknown, PIK3CA double mutants have previously been described (2,6,13,21). In the study by Samuels et al (2), each of seven tumors contained two somatic alterations; several other groups have also reported double PIK3CA mutations (6, 13, 21).…”

Section: Discussionmentioning

confidence: 92%

PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme

Gallia¹,

Rand²,

Siu³

et al. 2006

Molecular Cancer Research

150

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The phosphatidylinositol 3-kinases (PI3K) are a family of enzymes that relay important cellular growth control signals. Recently, a large-scale mutational analysis of eight PI3K and eight PI3K-like genes revealed somatic mutations in PIK3CA, which encodes the p110A catalytic subunit of class IA PI3K, in several types of cancer, including glioblastoma multiforme. In that report, 4 of 15 (27%) glioblastomas contained potentially oncogenic PIK3CA mutations. Subsequent studies, however, showed a significantly lower mutation rate ranging from 0% to 7%. Given this disparity and to address the relation of patient age to mutation frequency, we examined 10 exons of PIK3CA in 73 glioblastoma samples by PCR amplification followed by direct DNA sequencing. Overall, PIK3CA mutations were found in 11 (15%) samples, including several novel mutations. PIK3CA mutations were distributed in all sample types, with 18%, 9%, and 13% of primary tumors, xenografts, and cell lines containing mutations, respectively. Of the primary tumors, PIK3CA mutations were identified in 21% and 17% of pediatric and adult samples, respectively. No evidence of PIK3CA gene amplification was detected by quantitative real-time PCR in any of the samples. This study confirms that PIK3CA mutations occur in a significant number of human glioblastomas, further indicating that therapeutic targeting of this pathway in glioblastomas is of value.Moreover, this is the first study showing PIK3CA mutations in pediatric glioblastomas, thus providing a molecular target in this important pediatric malignancy.

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Section: Discussionmentioning

confidence: 92%

PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme

Gallia¹,

Rand²,

Siu³

et al. 2006

Molecular Cancer Research

150

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“…1,2 Activating mutations in PIK3CA, which encodes the PI3K catalytic subunit, have been reported in approximately a quarter of breast tumors 3 and copy number gain of this gene has been identified in 1-14% of breast cancers. [4][5][6] Approximately one fifth of breast cancers are described as having loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression (range 4-48%) [6][7][8][9][10][11][12][13][14][15] and epigenetic silencing of the PTEN gene through promoter hypermethylation has been reported in 34% 16 and 48% 17 of breast cancers. Loss of heterozygosity at the PTEN locus is observed in 40% of invasive breast carcinomas 18,19 but mutations in this gene have only been identified in 2-9% of breast cancers 3,7,[20][21][22] suggesting that PTEN haploinsufficiency may have tumorigenic consequences.…”

mentioning

confidence: 99%

Comprehensive analysis of PTEN status in breast carcinomas

Jones

Bonnet

Sfar

et al. 2013

Intl Journal of Cancer

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PTEN plays a well-established role in the negative regulation of the PI3K pathway, which is frequently activated in several cancer types, including breast cancer. A nuclear function in the maintenance of chromosomal stability has been proposed for PTEN but is yet to be clearly defined. In order to improve understanding of the role of PTEN in mammary tumorigenesis in terms of a possible gene dosage effect, its PI3K pathway function and its association with p53, we undertook comprehensive analysis of PTEN status in 135 sporadic invasive ductal carcinomas. Four PTEN status groups were defined; complete loss (19/ 135, 14%), reduced copy number (19/135, 14%), normal (86/135, 64%) and complex (11/135, 8%). Whereas the PTEN complete loss status was significantly associated with estrogen receptor (ER) negativity (p50.006) and in particular the basal-like phenotype (p<0.0001), a reduced PTEN copy number was not associated with hormone receptor status or a particular breast cancer subtype. Overall, PI3K pathway alteration was suggested to be involved in 59% (79/134) of tumors as assessed by human epidermal growth factor receptor 2 overexpression, PIK3CA mutation or a complete loss of PTEN. A complex PTEN status was identified in a tumor subgroup which displayed a specific, complex DNA profile at the PTEN locus with a strikingly similar highly rearranged pan-genomic profile. All of these tumors had relapsed and were associated with a poorer prognosis in the context of node negative disease (p51.4 3 10 213 ) thus may represent a tumor subgroup with a common molecular alteration which could be targeted to improve clinical outcome.Alterations in phosphatidylinositol 3-kinase (PI3K) pathway components have been described in breast cancer and can lead to hyperactivation of the pathway. Human epidermal growth factor receptor 2 (HER2) overexpression is observed in 15% of breast cancers. 1,2 Activating mutations in PIK3CA, which encodes the PI3K catalytic subunit, have been reported in approximately a quarter of breast tumors 3 and copy number gain of this gene has been identified in 1-14% of breast cancers. [4][5][6] Approximately one fifth of breast cancers are described as having loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression (range 4-48%) 6-15 and epigenetic silencing of the PTEN gene through promoter hypermethylation has been reported in 34% 16 and 48% 17 of breast cancers. Loss of heterozygosity at the PTEN locus is observed in 40% of invasive breast carcinomas 18,19 but mutations in this gene have only been identified in 2-9% of breast cancers 3,7,[20][21][22] suggesting that PTEN haploinsufficiency may have tumorigenic consequences. 23,24 Indeed, complete loss of Pten has been reported to oppose tumor progression in vitro and in a prostate-specific mouse model through induction of p53-dependant cellular senescence. 25 In addition to its function as a negative regulator of the PI3K pathway, a nuclear role for PTEN has been proposed. It has been reported to control chromosomal integrity t...

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“…In a set of 292 breast tumors, the reported mutation rate of PIK3CA mutations was 26% (Saal et al 2005). In another study, 21% in 92 breast tumors (Wu et al, 2005). The vast majority of PIK3CA mutations (89%) occurs in exon 9 (helical) and exon 20 (kinase) (Campbell et al, 2004).…”

Section: Discussionmentioning

confidence: 97%

“…Yamaguchi (2001) suggested that PI3K signaling, via p110α, regulates invadopodia-mediated invasion and migration of breast cancer cells. Besides, several groups have initiated more comprehensive mutational analysis of PIK3CA in breast cancer (Campbell et al, 2004;Bachman et al, 2004;Lee et al, 2005;Levine et al, 2005;Saal et al, 2005;Wu et al, 2005). Scientists have reported that PIK3CA was the most commonly mutated oncogene yet discovered in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Scientists have reported that PIK3CA was the most commonly mutated oncogene yet discovered in breast cancer. PIK3CA mutations are valuable and have been detected in 8-40% of all human breast cancers Levine et al, 2005) and are observed in up to 50% of breast cancer cell lines (Wu et al, 2005;Hollestelle et al, 2007). PIK3CA mutations generrally arise late in tumorigenesis, just before or coincident with invasion (Samuels and Velculescu, 2004).…”

Section: Discussionmentioning

confidence: 99%

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