Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage.
BACKGROUND
The purpose of this investigation was to determine if there are pathobiologic differences between BRCA1-related and BRCA2-related hereditary breast cancer (HBC) and non-HBC.


METHODS
On the basis of linkage to chromosomes 17q or 13q and/or the presence of ovarian and male breast cancer, HBC families were classified as either "BRCA1-related" (26 families, 90 breast cancer pathology cases) or "Other" (26 families, 85 cases), in which most BRCA2 cases were likely to reside. Cases were compared with 187 predominantly non-HBC cases. Tumors were assessed for histologic type, grade, and ploidy and S-phase fraction by quantitative DNA flow cytometry. Clinical presentation and available follow-up data were obtained.


RESULTS
BRCA1-related and Other HBC patients each presented at lower stage (P = 0.003) and earlier age than non-HBC patients (mean, 42.8 years and 47.1 years vs. 62.9 years, P = 0.0001). Compared with non-HBC, invasive BRCA1-related HBC had a lower diploidy rate (13% vs. 35%; P = 0.002), lower mean aneuploid DNA index (1.53 vs. 1.73; P= 0.002), and strikingly higher proliferation rates (mitotic grade 3; odds ratio [OR]= 4.42; P= 0.001; aneuploid mean S-phase fraction 16.5% vs. 9.3%, P < 0.0001). Other HBC patients, including patients in two BRCA2- linked families, had more tubular-lobular group (TLG) carcinomas (OR = 2.56, P = 0.007). All trends were independent of age. A nonsignificant trend toward better crude survival in both HBC groups was age- and stage-dependent. Compared with Other HBC, BRCA1-related HBC patients had fewer recurrences (P = 0.013), a trend toward lower specific death rates, and fared no worse than breast cancer patients at large. Other HBC patients, despite neutral prognostic indicators, fared worse.


CONCLUSIONS
BRCA1-related HBCs are more frequently aneuploid and have higher tumor cell proliferation rates compared with Other HBC. Despite these adverse prognostic features, BRCA1-related HBC patients have paradoxically lower recurrence rates than Other HBC patients. The excess of TLG cancers in the "Other" HBC group may be associated with BRCA2 linkage.
Marcus
J N
JN
Department of Pathology, Creighton University School of Medicine, Omaha, Nebraska, USA.
Watson
P
P
Page
D L
DL
Narod
S A
SA
Lenoir
G M
GM
Tonin
P
P
Linder-Stephenson
L
L
Salerno
G
G
Conway
T A
TA
Lynch
H T
HT
D000328:Adult; D000782:Aneuploidy; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002467:Cell Nucleus / Q000473:pathology; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13; D002886:Chromosomes, Human, Pair 17; D004273:DNA, Neoplasm / Q000032:analysis; D004171:Diploidy; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics*; D011003:Ploidies; D012008:Recurrence; D015203:Reproducibility of Results; D012189:Retrospective Studies; D015996:Survival Rate; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D014157:Transcription Factors