Characterization of familial non-BRCA1/2 breast tumors by loss of heterozygosity and immunophenotyping.
OBJECTIVE
Since the identification of BRCA1 and BRCA2, there has been no major breast cancer susceptibility gene discovered by linkage analysis in breast cancer families. This has been attributed to the heterogeneous genetic basis for the families under study. Recent studies have indicated that breast tumors arising in women carrying a BRCA1 mutation have distinct histopathologic, immunophenotypic, and genetic features. To a lesser extent, this is also true for breast tumors from BRCA2 carriers. This indicates that it might be possible to decrease the genetic heterogeneity among families in which BRCA1 and BRCA2 have been excluded with high certainty (BRCAx families) if distinct subgroups of BRCAx-related breast tumors could be identified.


METHODS
Loss of heterozygosity (LOH) analysis with at least one marker per chromosomal arm (65 markers) was used to characterize 100 breast tumors derived from 92 patients from 42 selected BRCAx families. In addition, the immunophenotype of 10 markers was compared with that of 31 BRCA1- and 21 BRCA2-related breast tumors.


CONCLUSIONS
The BRCAx-related tumors were characterized by more frequent LOH at 22q relative to sporadic breast cancer (P < 0.02), and differed significantly from BRCA1- and BRCA2-related tumors in their positivity for Bcl2. However, cluster analyses of the combined data (LOH and immunohistochemistry) did not result in subgroups that would allow meaningful subclassification of the families. On chromosomes 2, 3, 6, 12, 13, 21, and 22, we found markers at which LOH occurred significantly more frequent among the tumors from patients belonging to a single family than expected on the basis of overall LOH frequencies. Nonetheless, linkage analysis with markers for the corresponding regions on chromosomes 12, 21, and 22 did not reveal significant logarithm of the odds.
Center for Human and Clinical Genetics, Department of Pathology, Leiden University Medical Center, Rotterdam, the Netherlands. R.A.Oldenburg@lumc.nl
Rogier A
RA
Oldenburg
Karin
K
Kroeze-Jansema
Hanne
H
Meijers-Heijboer
Cristi J
CJ
van Asperen
Nicoline
N
Hoogerbrugge
Inge
I
van Leeuwen
Hans F A
HF
Vasen
Anne-Marie
AM
Cleton-Jansen
Jaennelle
J
Kraan
Jeanine J
JJ
Houwing-Duistermaat
Hans
H
Morreau
Cees J
CJ
Cornelisse
Peter
P
Devilee
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D016000:Cluster Analysis; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008126:Lod Score; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D008875:Middle Aged; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53