How Much Breast Cancer is Inherited?

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During meiosis, each germ cell (sperm or egg) generated carries a single copy of each gene, resulting in a 50% chance that any one offspring will inherit a mutant copy from the heterozygous parent. Thus, on average, 50% of the related individuals in a family carry the mutant gene. If the penetrance of the gene is high, the pedigree pattern for an autosomal dominant disease is quite striking, with vertical inheritance and half the children of an affected parent being affected, whereas none of the offspring of a homozygous normal parent are affected.

This pedigree pattern also presupposes a low risk in the general population, which is not the case for breast cancer. As a result, breast cancer in women from families that have a known BRCA1 mutation but who do not themselves carry the mutation is not uncommon. Such women are termed phenocopies- they have the phenotype associated with the gene mutation but are noncarriers.

Tumor-Suppressor Genes

Two fundamental types of genetic damage responsible for the development of the malignant phenotype are found in cancer cells: (a) activation of proto-oncogenes producing a “gain of function” in the affected cell, and (b) inactivation of tumor-suppressor genes producing a “loss of function” in the cell. Some tumor-suppressor genes appear to be important in cell cycle regulation, normally functioning as checks on cell growth;others are critical elements in the cellular response to DNA damage, preventing the propagation of mutations in other critical genes.

Mutated tumor-suppressor genes are thought to lose these regulatory functions, leading to malignant transformation. However, because all individuals are born with two copies of every gene, an explanation was needed for the development of cancer in large numbers of individuals who had only a single inherited mutation in a tumor-suppressor gene. In 1971, Knudson put forth the “two-hit hypothesis,” suggesting that cancer arises as a result of two genetic events occurring in the same cell, inactivating both copies of a given tumor-suppressor gene.

In the case of sporadic, or noninherited, cancer, the likelihood that two events would occur in the same cell is quite low. However, individuals from “cancer families” inherit an inactivating mutation in one allele of the implicated tumor-suppressor gene in all cells (i.e., a germ-line mutation); therefore, only one somatic (noninherited) event is required to inactivate the single remaining copy, making the development of cancer a much more common event than in individuals born without the “first hit.”

Angela DeMichele and Barbara L. Weber

A. DeMichele: Departments of Medicine and Epidemiology, The University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania
B. L. Weber: Departments of Medicine and Genetics, Breast Cancer Program, Population Science and Cancer Control, The University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania

References

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