Loss of heterozygosity of p53, BRCA1, VHL, and estrogen receptor genes in breast carcinoma: correlation with related protein products and morphologic features.
Correlation of loss of heterozygosity (LOH) of p53, BRCA1, VHL, and estrogen receptor (ER) genes with the expression of related protein products and morphologic features predictive of aggressive biologic behavior was investigated to determine the significance of LOH in these genes. DNA from 35 formalin-fixed, paraffin-embedded breast carcinomas was obtained by microdissection of histologic sections. LOH was determined by polymerase chain reaction (PCR) using primers TP53, D3S1038, D17S855, and ESR for p53, VHL, BRCA1, and ER genes, respectively. p53, ER, and progesterone receptor (PR) protein expression was evaluated by immunohistochemistry. Morphologic evaluation included histologic type, and histologic and nuclear grades. TP53 LOH was identified in 13 (52%), BRCA1 LOH in 3 (17%), VHL LOH in 1 (4%), and ER LOH in 4 (21%) of 25, 17, 24, and 19 informative cases, respectively. p53 and ER protein expression was identified in 20 (57%) and 25 (71%) cases, respectively. TP53 LOH directly correlated with both high histologic and nuclear grade (P<0.01). BRCA1, VHL, and ER LOH was not frequent enough for correlation to morphologic features. Although 4 of 4 ER and 7 of 13 p53 LOH cases expressed related proteins, LOH did not correlate with protein expression. TP53 LOH may be an event contributing to aggressive biologic behavior since it is strongly associated with high histologic and nuclear grade. Missense or nonsense mutations may explain the absence of detectable p53 protein in 6 of 13 cases with p53 LOH. All 4 ER LOH cases expressed ER protein. BRCA1 and VHL LOH is infrequent in sporadic breast carcinoma.
Otis
Christopher N
CN
Department of Pathology, Baystate Medical Center, Tufts University School of Medicine, Springfield, MA 01199, USA.
Krebs
Patricia A
PA
Albuquerque
Ana
A
Quezado
Martha M
MM
San Juan
Xavier
X
Sobel
Mark E
ME
Merino
Maria J
MJ
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D019398:Genes, BRCA1; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008025:Ligases / Q000235:genetics* / Q000378:metabolism; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human