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Modifiers of risk of hereditary breast and ovarian cancer

Nature Reviews Cancer volume 2, pages 113–123 (2002)Cite this article

Key Points

  • Most, but not all, women who carry deleterious mutations in BRCA1 or BRCA2 will develop breast or ovarian cancer. The risk of cancer among mutation carriers varies between families and countries. Several study designs can be used to estimate disease penetrance and modifiers of penetrance.

  • Reasons for variation include different mutations in the same gene (allelic variation) and the effect of modifying genes.

  • Genetic modifiers of breast cancer risk include the androgen receptor, the steroid-hormone receptor coactivator NCOA3 and possibly the DNA-repair gene RAD51.

  • Genetic modifiers of ovarian cancer risk include the HRAS1 oncogene and, possibly, the androgen receptor.

  • Preventive oophorectomy, a non-genetic modifier, reduces the risk of ovarian cancer and of breast cancer in BRCA1-mutation carriers.

  • Non-genetic modifiers of breast cancer risk include tamoxifen and reproductive history (such as parity and breastfeeding).

  • Non-genetic modifiers of ovarian cancer risk include oral contraceptives and (in BRCA1-mutation carriers) tubal ligation.

Abstract

Hereditary breast and ovarian cancer is among the most commonly encountered adult genetic disease, and it is increasingly important that geneticists, oncologists, surgeons and gynaecologists are aware of the issues regarding risk assessment, prevention and management of women with inherited susceptibility to cancer. Genetic risk can be modified by external factors, but what are these factors, and how might our knowledge of them help us to better define the risks for individual women and to develop strategies for cancer prevention?

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Figure 1: Possible reasons for penetrance differences with different mutations in a given gene.
Figure 2: Factors that modify risk of breast or ovarian cancer.

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Author information

Authors and Affiliations

  1. The Centre for Research on Women's Health, Women's College Hospital, 790 Bay Street, Room 750

    Steven A. Narod

  2. University of Toronto, Toronto, M5G 1N8, Canada

    Steven A. Narod

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  1. Steven A. Narod
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DATABASES

CancerNet:

breast cancer

colon cancer

thyroid cancer

melanoma

ovarian cancer

pancreatic

pheochromocytoma

prostate cancer

retinoblastoma

testicular cancer

 LocusLink:

androgen receptor

BARD1

BRCA1

BRCA2

CYP3A4

HRAS

NCOA3

oestrogen receptor-α

p53

RAD51

RB

 Medscape DrugInfo:

raloxifene

tamoxifen

FURTHER INFORMATION

BIC (BRCA Information Core)

Glossary

FOUNDER EFFECT

The occurrence of many individuals in a population with the same mutation of a particular gene, owing to its inheritance, over many generations, from a common ancestor (founder).

MAJOR GENE

A gene for which there are one or more alleles that confer a high lifetime risk of cancer (or other disease). Refers to the high risk of disease, not the frequency of mutations.

GENETIC MODIFIER

A gene for which there are one or more alleles that confer a modest, but significant, altered risk of cancer (or other disease). Usually refers to a gene that modifies the risk of the disease in carriers of a mutation in a major gene, but might also modify risk of disease in the general public.

HAZARD RATIO

The risk of cancer (or other disease) in the exposed group, divided by the risk in the unexposed group. Derived from a cohort study.

ODDS RATIO

The odds of developing cancer (or other disease) in the exposed group divided by the odds of developing it in an unexposed group. Usually derived from a case–control study.

PROBAND

The family member who was initially ascertained (that is, came to the attention of the researcher) in a study of familial aggregation of cancer (or other disease).

GENE LINKAGE

Two genes, or genetic sequence variants, that are situated closely on the same chromosome and that tend to co-segregate in meiotic cell divisions.

CO-SEGREGATE

The co-inheritance of linked sequence variants (for example, a marker and a disease gene) through two or more generations in a family.

TAMOXIFEN

One of a group of anti-oestrogenic drugs. Acts by blocking oestrogen signalling by binding to the oestrogen receptor.

CONTRALATERAL BREAST CANCER

After the initial diagnosis of breast cancer, the occurrence of a second, independent primary breast cancer in the other breast.

CHEMOPREVENTION

The strategy of reducing the risk of cancer by using drugs (tamoxifen or oral contraceptives), vitamins or other agents.

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Narod, S. Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2, 113–123 (2002). https://doi.org/10.1038/nrc726

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