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Mutations in thePIK3CAgene have recently been reported in different human neoplasms, including breast cancer. This paper reports the results of a systematic analysis ofPIK3CAmutations in different histological types of breast carcinoma. One hundred and eighty invasive breast carcinomas, comprising 74 ductal, 56 lobular, 22 mucinous, 20 medullary, and eight papillary, were selected on the basis of their histological type in a consecutive series of 780 breast cancers. Exons 1–20 of thePIK3CAgene were subjected to SSCP analysis followed by direct sequencing.PIK3CAmutations were observed in 46 (26%) of the 180 tumours examined: 23 (50%) mutations were located in exon 9, and 23 (50%) in exon 20. Mutations were frequent in lobular (46%), less frequent in ductal (22%), and uncommon in medullary (10%), mucinous (5%), and papillary tumours (12%) (p= 0.0002). Mutations in exon 9 were more frequent in lobular carcinomas (30% of cases) than in the other histological types (less than 5% of cases) (p= 0.00014). No significant differences were observed in the distribution of mutations in exon 20. There was no significant correlation betweenPIK3CAmutations and other clinicopathological and biological variables, including age, tumour size, lymph node metastases, oestrogen receptor (ER) status, progesterone receptor (PgR) status,p53gene mutations, and p53 protein expression. The findings indicate that in invasive breast carcinomas,PIK3CAalterations are mainly present in lobular and ductal tumours, whereas the other histological types, known to be associated with a favourable prognosis, show a very low incidence ofPIK3CAmutations. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.