Features and Risks of BRCA1 and BRCA2Related Cancers

Compared with the general population, BRCA1/2 mutation carriers have an increased risk of ovarian cancer. The lifetime risk of ovarian cancer in the general population

Figure 3-3. Factors affecting penetrance. (From ASCO Curriculum: Cancer Genetics and Cancer Predisposition Testing, 2nd ed, 2004, Slide 1-36.)

BRCA2 by exon

Original OCCR

Breast Ovarian

12 13 15

Breast Ovarian

1719

Breast Ovarian

Based on data from 164 families, mutations in this region (versus non-OCCR mutations) are associated with

• Significantly lower risk of breast cancer (RR = 0.63)

• Somewhat lower risk of prostate cancer (RR = 0.52)

21 22

Û Proportion of breast cancer cases

Proportion of epithelial ovarian cancer cases

HI Possible range of boundary on optimal OCCR

1000 bp

Figure 3-4. BRCA2: the ovarian cancer cluster region (OCCR) and genotype-phenotype correlations. (From Thompson D, Easton D, and the Breast Cancer Linkage Consortium: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68: 410-419, 2001. Reprinted with permission from the University of Chicago Press.)

is approximately 1.3%, whereas the lifetime risk of BRCA mutation carriers is estimated at 10% to 65%.

BRCA1 mutations confer a higher risk of ovarian and primary peritoneal cancer compared with BRCA2 mutations, and they are associated with earlier age of onset. Fallopian tube cancers, though much rarer than ovarian cancer, are also higher in carriers than in noncarriers21; again this risk is increased more in BRCA1 carriers than in BRCA2 carriers. BRCA1 -associated and BRCA2-associated ovarian cancers are pathologically and histologically indistinguishable from one another. However, they are generally of serous histology, with endometrioid being the next most common. Mucinous tumors are unlikely to be associated with BRCA1 or BRCA2 mutations, whereas rarer forms such as clear cell tumors are not common enough for an association (or lack thereof) to be determined to date. In addition, borderline and low malignant potential tumors of the ovary are not believed to be associated with BRCA1 or BRCA2 mutations.20

Compared with the general population, BRCA1 and BRCA2 mutation carriers also have an increased risk of developing breast cancer. The lifetime risk of invasive breast cancer conferred by a BRCA1 or BRCA2 mutation is estimated to be between 36% and 85%. BRCA1 and BRCA2--associated breast cancers are diagnosed at a younger age, often premenopausally.22 This is particularly true for BRCA1 carriers, approximately 20% of whom develop breast cancer before age 40 and 50% develop breast cancer by age 50.23 A recent retrospective cohort study indicated that ductal carcinoma in situ (DCIS), with or without invasive cancer, is just as prevalent in mutation carriers (37%) as in high-risk noncarriers (34%), but that it may develop at an earlier age.24 A population-based case-control study looked at the prevalence of BRCA1 and BRCA2 mutations in women diagnosed with DCIS. It was found that mutation prevalence rates in this group were similar to those found for invasive breast cancer, suggesting that the criteria used to assess eligibility for screening and risk for positive mutation-carrier status should include diagnoses of DCIS.25 In another cohort study of mutation carriers with stage I or II breast cancer, it was found that the risk of a second primary breast cancer in the contralateral breast was approximately 30% over 10 years and was even higher in women who did not use chemoprevention or undergo oophorectomy.26

In addition to conferring the risk of lower age of onset of breast cancer, BRCA1-related breast cancers typically have features associated with a poorer prognosis, including numerous mitoses and substantial pleomorphism.27 Compared with sporadic and BRCA2-related cancers, BRCA1 -type breast cancers typically exhibit higher frequency of grade 3 tumors, lower frequency of both estrogen receptors (ER) and progesterone receptors (PR), and are rarely HER2/neu--positive.28 Approximately 75% of BRCA2--associated breast cancers are hormone receptor-positive, whereas a similar proportion of BRCA1 -associated breast cancers are not.28

The lack of estrogen receptor, progesterone receptors, and HER2 receptor expression comprises the "triple-negative" or basal phenotype, which has been identified as having a poorer prognosis than other tumors because of the limited number of therapies that can specifically target these cells.

Men with BRCA1 and BRCA2 mutations are also at increased risk for cancer. Although the risk for male breast cancer is known to be increased with BRCA1 mutations, it is higher with BRCA2 mutations, with a lifetime risk estimate of 5% to 6% compared with 0.1% in men who are noncarriers. The lifetime risk of prostate cancer is also increased, but has not been reliably quantified. Although there is a trend toward younger-onset prostate cancer, it is not strikingly young, as is often seen with breast cancer in women.

The association of other cancers with BRCA1 and BRCA2 mutations has been studied in a number of cohorts. In particular, BRCA2 mutations are associated with an increased risk of pancreatic cancer and melanoma.10,29 Unfortunately, the lifetime risk for these malignancies has not been reliably quantified. A kin-cohort study of unselected patients newly diagnosed with ovarian cancer looked at cancer incidence in first-degree relatives of confirmed BRCA1 and BRCA2 mutation carriers. A higher risk ratio was associated with ovarian, female breast, and testicular cancer in BRCA1 carriers, with higher risk for ovarian, female and male breast, and pancreatic cancers associated with BRCA2 carriers.30

The precise factors that determine which mutation-positive women will and which will not develop cancer are unknown. Variation in penetrance of BRCA1 and BRCA2 has resulted in the identification of possible cancer risk modifiers in carriers. Both hormonal and genetic influences have been examined. The use of oral contraceptives, for example, has been reported to protect against ovarian cancer in noncarriers.31 Studies in carriers present differential risk in regard to breast or ovarian cancer, showing a protective effect of oral contraceptive use against ovarian cancer,32 or no reduction in risk.33 However, a clinical dilemma is presented by data suggesting that the use of oral contraceptives in BRCA1 carriers may also significantly increase breast cancer risk.18 At present, oral contraceptives are not actively recommended for ovarian cancer prevention, but short-term use for contraceptive needs is not contraindicated.

The relation of endogenous hormonal factors to breast and ovarian cancer risk has also been assessed in BRCA1 and BRCA2 carriers. In a study of the reproductive histories of BRCA1 carriers, the risk of breast cancer was increased in those who experienced menarche before age 12, and in those with parity of less than 3.32 It is interesting to note that the risk of ovarian cancer in BRCA1 carriers has been found to be lower with greater parity, in contrast to BRCA2 carriers, in whom parity was associated with a significant increase in ovarian cancer risk.34

Modifier genes may also play a role in the expression and penetrance of BRCA1 and BRCA2 genes. For instance, in one study, BRCA1 carriers with certain rare alleles of the HRAS1 variable number of tandem repeats (VNTR) polymorphism had a twofold greater risk of ovarian cancer than carriers with the more common HRAS1 alleles.35

Further studies to address gene-environment and gene-gene interactions are ongoing. These studies are needed to potentially make it possible to provide more personalized risk estimates to an individual woman.

Genetic Testing for Hereditary Breast and Ovarian Cancer

Family history features suggestive of a BRCA1 or BRCA2 mutation include premeno-pausal breast cancer, ovarian cancer, and male breast cancer. A referral for genetic counseling is indicated if the medical or family history is consistent with hereditary breast and ovarian cancer (Box 3-1).

Because of autosomal dominant inheritance, it is most informative to begin genetic testing in a family member who has had the cancer of concern. This is because one goal of genetic testing is to first identify the mutation in a relative with cancer in the family and to then determine which other relatives did, and did not, inherit it. Those who did inherit the mutation have an increased risk for specific malignancies, whereas the risk of cancer for those who did not inherit the mutation is much lower and based on other cancer-specific risk factors, such as age at menarche, age at menopause, body mass index (BMI), hormone replacement therapy (HRT), and other factors.

Box 3-1. Features Indicating a Need for Referral for Cancer Genetic Counseling

Breast cancer diagnosed before menopause (typically before age 50 years) Member of a family with a known BRCA1 or BRCA2 mutation

Two breast primaries in a single individual, particularly if one was diagnosed premenopausally Breast and ovarian cancer in a single individual Personal or family history of male breast cancer

Two breast cancers or ovarian cancers in close relative(s) from the same side of family (maternal or paternal)

Breast or ovarian cancer in a member of a high-risk population (i.e., Ashkenazi Jewish) Ovarian and colorectal cancer in the same person or in close relative(s) from the same side of the family (maternal or paternal)

Synchronous ovarian and endometrial cancers, particularly with close relative(s) with colorectal cancer

Data from Daly MB, Axilbund JE, Bryant E, et al: Genetic/farnilial high-risk assessment: breast and ovarian. J Natl Compr Cancer Netw 4(2):156-176, 2006; and Levin B, Barthel JS, Burt RW, et al: Colorectal Cancer Screening Clinical Practice Guidelines. J Natl Compr Cancer Netw 4(4):384-420, 2006.

Figure 3-5. In this family, Mary is concerned about her risk for ovarian cancer because her mother, Susan, and her maternal aunt, Jane, both had ovarian cancer. Genetic testing is most informative if it begins with Susan.

Susan Jane

Susan Jane

Consider the following scenario, which is illustrated in Figure 3-5. A woman (Mary) is concerned about her risk for developing ovarian cancer, since her mother (Susan) was recently diagnosed with the disease. Her maternal aunt (Jane) is deceased from ovarian cancer, suggesting a hereditary component to the family history. If Mary chooses to undergo genetic testing and no mutations are detected (i.e., a negative result), there are two possible explanations for this result. One, Susan's and Jane's ovarian cancers may be due to a mutation in the gene for which Mary was tested. However, owing to autosomal dominant inheritance, Mary did not inherit the mutation from Susan. Thus, in this scenario, Mary's risk for ovarian cancer is probably closer to that of the general population and is based on her own risk factors, since her family history of ovarian cancer is attributable to a genetic mutation that she herself does not have. However, the second possibility is that Susan's and Jane's cancers are due to a mutation in a gene that has not yet been discovered. Since the gene has not been discovered, it is impossible to determine whether Mary has the same mutation. Therefore, in this scenario Mary remains at increased risk for ovarian cancer based on her genetically unexplained family history. Without genetically testing Susan, it is not possible to distinguish between these two possible explanations.

By contrast, if a genetic test were performed on Susan and a mutation were detected, one could reasonably attribute her ovarian cancer to the identified mutation. Determining whether Mary has this same mutation will then indicate whether she, too, is at increased risk for ovarian cancer. It also determines whether Mary's offspring have an increased risk for developing ovarian cancer.

Genetic analysis of the BRCA1 and BRCA2 genes is clinically available. For most families, full sequencing of both genes is required and is considered the most reliable method of gene analysis. However, an estimated 12% of deleterious mutations are large genomic deletions, duplications, or rearrangements, which are not always detectable with sequencing.36 Therefore, additional technology, such as the BRAC Analysis Rearrangement Test (BART), may be necessary in families with a cancer pattern strongly suggestive of a hereditary component. If a woman with ovarian cancer undergoes full analysis of both genes and a mutation is identified, the mutation likely explains the most significant genetic component of her cancer. It also indicates that she is at increased risk for breast cancer, and, depending on her prognosis, increased screening or consideration of breast cancer risk-reducing options may be indicated. In addition, it is possible to offer predictive genetic testing to other interested family members to identify those who also have an increased risk of developing breast and ovarian cancer.

If no mutations are identified, the woman's ovarian cancer is genetically unexplained. Possible explanations are a BRCA1 or BRCA2 mutation that is not identifiable using current technology, a mutation in an undiscovered gene, or a combination

Chapter 3 Ovarian Cancer Family Syndromes and Genetic Testing

of many genetic and environmental factors. The woman's risk for a future malignancy, and cancer risk to her relatives, is based on her family history.

A third possible result is a variant of uncertain significance, which is a change in the DNA sequence whose role in cancer development is not known. Through research, some variants are ultimately determined to be polymorphisms (normal genetic variation between individuals and populations), whereas others are ultimately classified as deleterious (cancer-causing). Until the significance of the variant is determined, genetic testing is generally not offered to unaffected relatives. Uncertain variants are detected in approximately 5% of samples tested from Caucasian individuals. In non-Caucasian populations, such as African Americans, the chance of an uncertain variant increases owing to less available genetic data in minority ethnicities.

In those of Ashkenazi Jewish descent, genetic testing usually begins with analysis of three founder mutations (Fig. 3-6). The 187delAG and 5385insC mutations in the BRCA1 gene and the 6174delT mutation in the BRCA2 gene account for approximately 90% of BRCA1 and BRCA2 mutations detected in the Ashkenazim. Because of the high detection rate with this three-mutation panel, full sequencing is generally considered only in Ashkenazi Jewish individuals who have a high pretest probability of a deleterious mutation and who are shown to be negative for the three founder mutations. Other populations known to have founder mutations include Icelanders (999del5 in BRCA2), as well as those from Finland, France, Russia, Denmark, Sweden, and Belgium.37

Once a mutation has been identified in a family, other relatives have the option of undergoing testing for that specific mutation. This is due to the rarity of BRCA1 and BRCA2 mutations, such that one seldom sees a family with more than one mutation. However, because these mutations are more common among Ashkenazi Jews and because a significant number of Ashkenazi families have more than one mutation, testing for the entire founder mutation panel is generally recommended even when only one founder mutation has been identified in the family.

Because of patent and licensing constraints, sequencing of BRCA1 and BRCA2 is clinically available only through Myriad Genetic Laboratories, a commercial laboratory in Salt Lake City, Utah. Peripheral blood is the preferred specimen, and turnaround time for the analysis is generally 2 to 3 weeks. Full sequencing costs more than $3000, whereas the Ashkenazi Jewish founder mutation panel is around $550 and mutation-specific testing is approximately $450. Most insurance companies cover a portion, if not all, of the cost for patients whose medical or family history is suggestive of an underlying mutation. Because of the expense, though, the laboratory offers insurance preauthorization services. These costs may change in the future.

Natural Cures For Menopause

Natural Cures For Menopause

Are Menopause Symptoms Playing Havoc With Your Health and Relationships? Are you tired of the mood swings, dryness, hair loss and wrinkles that come with the change of life? Do you want to do something about it but are wary of taking the estrogen or antidepressants usually prescribed for menopause symptoms?

Get My Free Ebook


Post a comment