Many patients who might benefit from a hereditary cancer risk assessment do not
have a personal history of cancer or may be cancer survivors and hence are no
longer under the care of an oncologist. Opportunities to identify and appropriately
refer these women are, therefore, seen most frequently by primary care
providers and general obstetricians and gynecologists, requiring that such
clinicians have familiarity with—and be watchful for—the features of hereditary
cancer syndromes. As previously stated, the presence of multiple family members
affected with breast and/or ovarian cancer symptoms (or other Lynch/HNPCC-linked
cancers), an early age of cancer development, and the presence of multiple and/
or bilateral primary cancers should be viewed as an indicator for the possible
presence of a hereditary cancer syndrome (27–29).

However, specific clinical parameters exist that can be used to guide referrals to providers with
expertise in hereditary cancer risk assessment. These clinical features highlight
the importance of considering both personal and family history in a comprehensive
evaluation, and underscore the significance of age of disease onset,
ethnicity, and presence or absence of multiple and/or bilateral primary cancers in
both the patient and family member. While these specific criteria identify the
majority of individuals that meet thresholds for genetic evaluation, there are
some patients who may not meet the specific criteria, but may still benefit from
genetic risk assessment.

These individuals include members of families with few female relatives, resulting in an underrepresentation of female cancers despite
the presence of a predisposing family mutation (46,47); families in which
multiple members underwent hysterectomy and/or oophorectomy at a young age,
thus potentially masking a hereditary gynecologic cancer predisposition (48);
and families that include adoption within the lineage.

Despite the host of factors, including inheritance, environment, hormones, and
behavior, that have been linked to the development of cancer, a single unifying
theory to explain human carcinogenesis remains elusive. It is clear, however, that
cancer is fundamentally a genetic disease, and as research technology rapidly
evolves, the number of cancers in which distinct genetic defects are identifiable
continues to increase.

The total number of cells present in a tissue is dependent on a critical
balance between cell proliferation, senescence, and apoptosis. Ovarian cancer symptoms
exhibit a high degree of genetic disruption that is manifest at both the chromosomal
and molecular levels, and the genetic alterations that underlie the
malignant transformation of ovarian surface epithelium primarily target genes
involved in the control of these processes (5,6). Thus, development of an ovarian
cancer can result from inactivation of tumor suppressor genes or activation of
oncogenes so that disruption of complex regulatory pathways occurs, with the
net effect being an increased number of cells (7). Mutations that inactivate DNA
repair genes accelerate the accumulation of other cancer-causing mutations.

Tumor suppressor genes encode proteins that normally inhibit proliferation,
and inactivation of these genes plays a role in the development of most
cancers. Most hereditary cancer syndromes are due to transmission of germline
mutations in tumor suppressor genes. Knudson’s “two-hit” model established
the paradigm that both alleles must be inactivated in order to exert a phenotypic
effect on tumorigenesis (8). In the case of hereditary cancer susceptibility,
the initial “hit” is the inheritance of an inactivating (germline) mutation
in one copy of the gene. Later, somatic events (frequently large chromosomal
losses) result in the second hit and complete loss of tumor suppressor function.
In contrast, “sporadic” cancers arise through the accumulation of genetic
changes that are acquired throughout the life of an organism. The mechanism
of inactivation of tumor suppressor genes, whether germline or somatic, may
vary from one cancer to the next. Frequently, mutations in tumor suppressor
genes alter the base sequence resulting in the production of a premature stop
codon (TAG, TAA, or TGA) and truncated protein product. Several types of
mutational events can result in the creation of such premature stop codons,
including nonsense mutations, in which a single-base substitution changes the
nucleotide sequence from one that codes for a specific amino acid to one that
produces in a stop codon.