Heritable Breast and Ovarian Cancers

Breast and ovarian cancers rank among the leading causes of cancer and cancer-related deaths among women in the United States. More than 200,000 new cases of breast or ovarian cancer are diagnosed annually, and a woman's lifetime risk of breast cancer is 1 in 8.¹ Although most breast and ovarian cancers are sporadic, the familial nature and genetic contribution to disease development can be significant.
About one in five women with breast or ovarian cancer has a family history of the disease. Between 5% and 10% of cases are believed to reflect heritable breast and/or ovarian cancer.² Among unaffected, gravid women aged 35 years or older, 7% to 8% have been found to have at least one family member with breast or ovarian cancer.³

Overall, a woman s lifetime risk of sporadic breast or ovarian cancer is approximately 1 in 10, and approximately 1 in 10 women will develop or is at increased risk of developing a familial or heritable form of these cancers.

In light of the significant genetic contribution to breast and ovarian cancer risk, recent advances in molecular biology are generating great interest and excitement. Both the lay and the scientific press have enthusiastically described the identification of newly discovered genes thought to be linked to these disorders. These reports have brought new hope for a better understanding of the mechanisms responsible for such cancers, as well as heightened expectations for improved diagnostic tools and medical therapies. Although these breakthroughs will likely enhance the management of breast and ovarian cancers, today s clinicians and their patients must be aware of the risks and limitations of this technology, as well as the benefits it promises for the management of a select group of women.

FAMILIAL CANCERS
A family history of breast or ovarian cancer has long been recognized as a significant independent risk factor for either cancer. The relationship of the affected individual(s), the age of disease onset, and the presence of multiple primary lesions are likewise important in estimating recurrence risks. Risk estimates for breast or ovarian cancer have been calculated from epidemiologic data derived from families with limited disease involvement.^4,5 Women with no family history of breast cancer have a 5% to 6% lifetime risk of breast cancer, whereas the lifetime risk of breast cancer increases two- to threefold among women who have a sister with unilateral postmenopausal breast cancer. Women who have a sister with bilateral premenopausal breast cancer have a 30% to 50% risk of breast cancer. Similarly, the risk of ovarian cancer rises from 1.2% to 4.7% among women who have a first-degree relative with ovarian cancer.

Familial breast or ovarian cancer refers to a limited family history of these malignancies. The heritable classification, on the other hand, is reserved for cancers occurring in families with at least three affected individuals from at least two generations, and in which at least one affected individual is a first-degree relative (mother or sister) of the other two.

The mode of inheritance observed in families with heritable breast and/or ovarian cancer is autosomal dominant (i.e., maternal or paternal transmission of the gene, with a 50% risk of transmission from parent to offspring). Family members who inherit the putative gene are reported to have an 85% lifetime risk of breast cancer and a 26% to 85% lifetime risk of ovarian cancer^6,7. Female first-degree relatives of the affected women have a lifetime breast cancer risk of 42% and lifetime ovarian cancer risk reported to range from 13% to 42%.

Research involving families with heritable breast cancer was instrumental in isolating the BRCA1 and BRCA2 genes and continues to shed light on the clinical consequences of various mutations in these genes. Given the significant disparity in risk observed between women with familial versus heritable cancers, this distinction is critical for patient counseling and clinical management.

MOLECULAR GENETICS
The groundwork for our current understanding of heritable cancers was laid by Alfred Knudson in 1971.⁹ Knudson observed that children with bilateral retinoblastoma were younger at the time of first tumor diagnosis than were children whose disease was unilateral. Knudson thus hypothesized that the development of retinoblastoma requires the presence of two distinct mutations, each involving the complementary alleles of the same gene pair i.e., the two-hit hypothesis.

Specifically, Knudson s model proposed that children with bilateral retinoblastoma inherited one mutated germ-line allele that was present in all cells. While the complementary allele remained functional in a given cell, no tumor developed. With time, however, a mutation occurred in the complementary allele and triggered tumor development.

As these children carried the heritable mutation in every cell, they required only one additional hit in any retinal cell to develop additional tumors. Therefore, these children were more likely to develop tumors in both eyes. Furthermore, as they were born with a heritable mutation in every cell, they were one hit closer to developing tumors from the outset and were thus more likely to be younger at disease onset and diagnosis.

In contrast, individuals with unilateral disease did not carry a germ-line mutation. Such individuals developed a sporadic mutation involving one allele that was limited to a single somatic cell. With time, a second mutation occurred in the complementary allele of that somatic cell, thus resulting in tumor development. As the first hit in these patients was not present in all cells, the odds of a second tumor occurring were equivalent to the odds that two new independent hits would occur in another somatic cell i.e., very low.

The Knudson two-hit hypothesis views the loss of normal gene function as the basis of cancer development. Indeed, since this model was first proposed, tumor suppressor gene mutations have been implicated in heritable human cancer.

Tumor suppressor genes often function as cell-growth regulators, preventing unrestricted cell growth and division. Mutations of tumor suppressor genes can result in unrestricted cell growth and division. These mutations appear to act in an autosomal-recessive manner at the cellular level, so that mutation of a single allele does not result in tumor development unless the complementary allele also mutates (i.e., complete loss of function). According to this model, individuals who have inherited mutated tumor suppressor genes are more likely to have tumors and the tumors are likely to appear at an earlier stage of life than if the individual lacked the mutated tumor suppressor genes.

The Knudson hypothesis also accounts for the observation that multiple primary tumors are more common among individuals with heritable cancers. As the mutations are germ-line in origin, every cell in every tissue would carry these alterations.

It would be expected that tissues whose cellular regulation depends on a specific tumor suppressor gene would undergo neoplastic alteration following the second hit on the complementary tumor suppressor gene. In fact, many heritable cancers are characterized by multiple primary lesions in the same organ, multiple primary tumors affecting multiple organ systems, and/or metachronous primary lesions. Furthermore, as the second hit is sporadic, the tissues in which primary lesions occur may vary greatly among mutation carriers and even among relatives sharing the same germ-line mutation (i.e., variable expressivity).

It may seem paradoxical that mutations of tumor suppressor genes (which behave in an autosomal-recessive fashion at the cellular level) are inherited in an autosomal-dominant fashion. In fact, it is not the cancer itself but the predisposition toward cancer that is transmitted. It is only when the corresponding allele sporadically mutates in somatic tissue that a tumor develops. This explains why some individuals with a heritable predisposition never develop cancer (i.e., incomplete penetrance). However, unlike in other autosomal-recessive conditions, the presence of just one aberrant cell is sufficient to cause disease (i.e., tumor development secondary to clonal expansion).

Thus, the two-hit hypothesis predicts the principal characteristics of heritable cancers: an autosomal-dominant inheritance pattern, the involvement of tumor suppressor genes, early age of onset, incomplete penetrance, variable expressivity, multiple primary lesions, and metachronous lesions. These characteristics are shared by many familial cancer syndromes in contrast to sporadic cancers, which tend to be later in onset and usually associated with only a single primary lesion.

BRCA1 AND BRCA2
Years of extensive study of families with a high incidence of breast cancer resulted in the isolation of two genes, BRCA1 and BRCA2 each of which is thought to be responsible for 45% of heritable breast cancers.^10-12 BRCA1 was localized to chromosomal region 17q21, whereas BRCA2 was mapped to chromosome region 13q12 ¹³.

In addition to their association with breast cancer, both genes share several molecular features. Both genes produce very large proteins whose functions and cellular localization continue to be debated. As with many large genes, more than 85% of mutations are nonsense mutations (i.e., premature stop codons) that result in a truncated protein product.13 It is speculated that these genes may have a nuclear regulatory function or may be involved in DNA repair, but the physiologic role of these genes and their corresponding mutations are yet to be established.

The mutated forms of BRCA (BRCA1 and BRCA2) do not cause cancer directly but rather confer an increased risk of cancer, thus suggesting that these genes function much like tumor suppressor genes. It follows that the clinical characteristics of women with these mutations exhibit a pattern similar to that found with other forms of heritable cancer.

Cancer susceptibility associated with BRCA gene mutations is transmitted in an autosomal-dominant fashion. Therefore, it can be inherited from the maternal or paternal lines. Penetrance is high but incomplete for both genes. The lifetime cumulative risk of breast cancer in women with mutations in either gene is 85%.^6,7,12,14 Age of onset of breast cancer is significantly earlier than that seen in the general population. About half of the women with BRCA mutations exhibit breast cancer by age 50.6 BRCA gene alterations also heightened the risk of bilateral disease as well as the risk of multiple tumors involving other organ systems.

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Originally published in The Female Patient -- May, 1998

© Copyright, 1998 Quadrant Publishing, All Rights Reserved

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