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...

Nephroblastoma (Wilms' tumor; WT) is the most common renal tumor of childhood. To date, several genetic abnormalities predisposing to WT have been identified in rare overgrowth syndromes. Among them, abnormal methylation of the 11p15 region, GPC3 and DIS3L2 mutations, which are responsible for Beckwith-Wiedemann, Simpson-Golabi-Behmel and Perlman syndromes, respectively. However, the underlying cause of WT remains unknown in the majority of cases. We report three unrelated patients who presented with WT in addition to a constitutional 9q22.3 microdeletion and dysmorphic/overgrowth syndrome. The size of the deletions was variable (ie, from 1.7 to 8.9 Mb) but invariably encompassed the PTCH1 gene. Subsequently, we identified a somatic PTCH1 nonsense mutation in the renal tumor of one patient. In addition, by array comparative genomic hybridization method, we analyzed the DNA extracted from the blood samples of nine patients with overgrowth syndrome and WT, but did not identify any deleterious chromosomal imbalances in these patients. These findings strongly suggest that patients with constitutional 9q22.3 microdeletion have an increased risk of WT, and that PTCH1 have a role in the pathogenesis of nephroblastomas.

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