Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage

Cancer. 1996 Feb 15;77(4):697-709. doi: 10.1002/(sici)1097-0142(19960215)77:4<697::aid-cncr16>3.0.co;2-w.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aneuploidy
  • BRCA1 Protein
  • BRCA2 Protein
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Breast Neoplasms, Male / genetics*
  • Breast Neoplasms, Male / mortality
  • Breast Neoplasms, Male / pathology
  • Cell Nucleus / pathology
  • Chromosome Mapping
  • Chromosomes, Human, Pair 13*
  • Chromosomes, Human, Pair 17*
  • DNA, Neoplasm / analysis
  • Diploidy
  • Disease-Free Survival
  • Female
  • Flow Cytometry
  • Genetic Linkage
  • Humans
  • Male
  • Middle Aged
  • Mitotic Index
  • Neoplasm Invasiveness
  • Neoplasm Proteins / analysis
  • Neoplasm Proteins / genetics*
  • Neoplasm Staging
  • Ovarian Neoplasms / genetics*
  • Ploidies
  • Recurrence
  • Reproducibility of Results
  • Retrospective Studies
  • Survival Rate
  • Transcription Factors / analysis
  • Transcription Factors / genetics*

Substances

  • BRCA1 Protein
  • BRCA2 Protein
  • DNA, Neoplasm
  • Neoplasm Proteins
  • Transcription Factors