Publication date: Available online 21 February 2020
Source: Human Pathology
Author(s): Carole Guillet, Markus Rechsteiner, Elisa Bellini, Matthias Choschzick, Linda Moskovszky, Konstantin Dedes, Bärbel Papassotiropoulos, Zsuzsanna Varga
ABSTRACT
Juvenile papillomatosis (JP), the so-called Swiss cheese disease is a rare benign breast disease of young adults. An association (up to 28 %) with breast-cancer within the family of affected patients has been reported. A multinodular cystic breast-mass lesion and calcifications characterizes JP in imaging studies. The histological picture is diverse and comprises multiple intraductal-papillomas, usual ductal hyperplasia (UDH), ductectasias, perifocal sclerosing adenosis and calcification. Patients with complete excision of JP lesions have an excellent follow-up; breast cancer develops only on a very low subset of patients. Molecular background of JP has not been investigated until now. In this study, we addressed mutational analysis of JP cases and correlated these results with follow-up and family-history in context with a comprehensive review of JP literature.
We identified 13 cases fulfilling the criteria of JP. All patients were female with a median-age of 38 years (26 to 50 years). Follow-up information was available in 11 of 13 patients. Sufficient paraffin embedded tissue and good DNA quality for next generation sequencing (NGS) was available in 10 patients. Paraffin blocks were microdissected in the area of intraductal proliferative disease, the tissue cores underwent NGS analysis using Oncomine Comprehensive Panel.
In 5 of 10 patients, we found PIK3CA mutations, in 2 of 10 patients AKT1 mutations in known hotspot regions. Further mutations in MET, FGFR3, PTEN, ATM, NF1 and GNAS genes were detected in individual patients. Some of these mutations were present at high allelic frequencies suggesting germ line mutations. 2 of 3 patients with positive family history had PIK3CA mutation; one patient with positive family history had an AKT1 mutation. One patient who subsequently developed invasive ductal carcinoma in the contralateral breast possibly had a germ line ATM mutation.
Our results confirm hotspot mutations in PIK3CA and AKT1 genes in JP associated with positive family history for breast cancer, although these mutations are not specific for JP. The genetic link between JP, positive family history and subsequent risk of breast cancer, needs further studies.
We identified 13 cases fulfilling the criteria of JP. All patients were female with a median-age of 38 years (26 to 50 years). Follow-up information was available in 11 of 13 patients. Sufficient paraffin embedded tissue and good DNA quality for next generation sequencing (NGS) was available in 10 patients. Paraffin blocks were microdissected in the area of intraductal proliferative disease, the tissue cores underwent NGS analysis using Oncomine Comprehensive Panel.
In 5 of 10 patients, we found PIK3CA mutations, in 2 of 10 patients AKT1 mutations in known hotspot regions. Further mutations in MET, FGFR3, PTEN, ATM, NF1 and GNAS genes were detected in individual patients. Some of these mutations were present at high allelic frequencies suggesting germ line mutations. 2 of 3 patients with positive family history had PIK3CA mutation; one patient with positive family history had an AKT1 mutation. One patient who subsequently developed invasive ductal carcinoma in the contralateral breast possibly had a germ line ATM mutation.
Our results confirm hotspot mutations in PIK3CA and AKT1 genes in JP associated with positive family history for breast cancer, although these mutations are not specific for JP. The genetic link between JP, positive family history and subsequent risk of breast cancer, needs further studies.
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