Future Directions

Despite the lack of success so far, it seems likely that the next 5 to 10 years will see rapid developments in our understanding of the polygenic basis of breast cancer. The reasons for this optimism lie in the potential of empirical, GWA studies, which, until recently have not been feasible. A new era of GWA association has been made possible by two major advances. Firstly our knowledge of human genomic architecture has been advanced dramatically by projects such as the International Hap Map...

References

The new genetics in clinical practice. Br Med J 1998 316 618-620. 2. Beaudet AL. 1998 ASHG presidential address. Making genomic medicine a reality. Am J Hum Genet 1999 64 1-13. 3. Friend SH. Breast cancer susceptibility testing realities in the post-genomic era news comment . Nat Genet 1996 13 16-17. 4. Holtzman NA, Marteau TM. Will genetics revolutionize medicine N Engl J Med 2000 343 141-144. 5. Vineis P, Schulte P, McMichael AJ. Misconceptions about the use of genetic tests in...

Hormone Replacement Therapy

It is well established that women who use hormone replacement therapy (HRT) are at a slightly increased risk of breast cancer and that risk increases with duration of use (by 2-3 per year of use), but decreases when use is ceased (38). Rebbeck et al. have reported that use of HRT in mutation carriers who had undergone a bilateral prophylactic oophorectomy (BPO) did not significantly alter the reduction in breast cancer risk associated with BPO. These data suggest that short-term HRT does not...

Reactions of Women and Men with Breast Cancer Who Have an Indeterminate Negative Result

Patients who are members of families in which no mutation has been identified can be frustrated by a negative result. If they were expecting that the genetic test would provide a reason for the development of cancer, especially if it occurred at an early age, anger at the continued uncertainty can manifest in a variety of ways. However, others may be pleased because they presume that a negative result means that the cancer in the family does not have an inherited component, which is often not...

Risk Modifiers

The diversity of tumor types and ages within LFS families has been noted since the original report and confirmed with mutation testing (1,14,58), suggesting that additional factors influence tumor development. Early studies of p53 heterozygous knockout mice demonstrated that the tumor types observed were in part dependent on the genetic background of the mice (77). More recently Wu et al. (59) provided statistical evidence for the presence of risk modifiers in p53 mutation kindreds, with a...

Ovarian Cancer

What may perhaps be the more deadly tumor in BRCA mutation carriers, ovarian cancer, must be reckoned with. The clinical issue boils down to How do we screen for this disease (unfortunately, the answer is very poorly). The next bombshell for the patient to consider is the issue of do or don't with respect to the preventive option of prophylactic oophorectomy, once her family is completed. This important subject is discussed by Lu and Skates. Similar options exist with respect to breast...

Clinical Description Of Cs

CS, named after Rachel Cowden, the first reported patient with the disorder (10), is characterized by multiple hamartomas which can affect any organ from all three germ cell layers, including the characteristic mucocutaneous manifestations and benign and malignant neoplasms of the breast, thyroid, and endometrium (7). Underscoring the fulminant nature of the malignancies, Rachel Cowden died at the age of 31 of metastatic breast cancer (11). Published estimates of CS incidence are 1 200,000...

Summary

In summary, evidence to date suggests that the effects of environmental exposures on breast cancer risk may not be the same for mutation carriers as for the general population, and, furthermore, may differ between BRCA1 versus BRCA2 mutation carriers (Table 1). Having many children may be associated with increased risk for carriers under the age of 40 years, particularly in carriers of mutations in BRCA2. Exposure to chest X rays may also increase risk. Breastfeeding appears to offer protection...

Breastfeeding

A collaborative reanalysis of data from 47 epidemiological studies has established that, in the general population, women who breastfeed are at a slightly lower risk of breast cancer, and that each cumulative year of breastfeeding reduces risk by 4.3 (20). This association is independent of parity. Three published studies have investigated this association among BRCA1 and BRCA2 mutation carriers. Based on analyses of 1930 carriers of both mutations from a subset of collaborators in the...

Risks of Other Cancers in BRCA1BRCA2 Carriers

In addition to the marked excess of breast and ovarian cancer in BRCA1 and BRCA2 carriers, there is also evidence of more moderate risks of other cancer types. The largest study of cancer risks in BRCA1 carriers, based on 699 carrier families, found an overall cancer risk in male carriers very close to that in the general population, but the risk of cancers other than breast or ovarian in female carriers was increased by approximately twofold (44). Specifically, significant excesses were seen...

Epidemiological Studies Of Familial Breast Cancer

Much of the impetus for breast cancer genetics has come from observations of families with extraordinary numbers of cases of the disease (5). These families have often been critical to the identification of the high-risk susceptibility genes. They are, however, less useful for evaluating the risks associated with a family history of breast cancer or with any particular gene, because they are not collected in a systematic fashion. To provide useful information for genetic counseling, risk...

Treatment Implications Ionizing Radiation

Exposure to ionizing radiation (IR) results in DNA damage, most significantly DSBs. In normal cells, DNA damage induces cell cycle arrest to prevent the spread of deleterious cells and activates repair pathways to correct genomic defects. IR as the basis of radiotherapy is a standard treatment used against cancer and is indicated for approximately 60 of cancer patients (41). Yet, even though it is an important cancer therapy, improving outcomes after radiation therapy remains an important...

Breast Cancer Risk In Males

Familial clustering of female breast cancer was demonstrated as early as 1926 (81), and epidemiological studies have shown that although both men and women with breast cancer are more likely to have family histories in first-degree relatives than unaffected individuals, men with breast cancer were even more likely to have a first-degree relative with ovarian cancer than affected women (82,83). It is noteworthy that initial linkage studies of BRCA1 did not reveal an association with male breast...

Gel Electrophoresis Based Sequencing Methods

During the period of the BRCA1 and BRCA2 positional cloning projects, the most efficient sequencing based mutation-screening strategy was in fact dideoxy cycle sequencing of PCR products using 32P labeled nucleotides to label the sequencing products. Mutation screening by radioactive cycle sequencing required four lanes of a slab sequencing gel, corresponding to the A, C, G, and T sequence reactions, for each sample. However, instead of running the four lanes representing each sample adjacently...

Control Proband Series

Control proband series are limited by the relative rarity of BRCA mutations, as well as the complexity and cost of genotyping thousands of control individuals to identify a handful of BRCA mutation-carrying kindreds. A crucial factor in the feasibility of this type of study design was the discovery of founder mutations among a genetic isolate amenable to research participation. The discovery of three Ashkenazi mutations, two in BRCA1 and one in BRCA2, is detailed elsewhere in this volume. The...

Component Malignancies

Component malignancies in CS include breast, thyroid (16), and endometrial carcinomas (Table 2) (17). The most common malignancy seen in CS is adenocarcinoma of the breast, with lifetime risks in female CS patients estimated to be 25 to 50 compared with the lifetime risk of 12 to 13 in the general population (18,19). As commonly described in other hereditary breast cancer predisposition syndromes, the average age of breast cancer diagnosis is lower in patients with CS compared with that in...

Counseling Highrisk Individuals For Genetic Testing

Cancer genetic testing programs are typically staffed by a multidisciplinary team of providers. These providers can include an oncology provider (physician or nurse practitioner), a genetics provider (a genetic counselor, geneticist, or genetics nurse), and support staff (clinical coordinator, phlebotomist). Typically such programs have a mental-heath provider such as a psychologist or social worker and other physician specialists such as a surgeon, gynecologic oncologist, or radiologist...

Models Of Breast Cancer Susceptibility

Several models have been developed to derive estimates of risk to women with a family history of breast cancer or to estimate the probability of carrying a mutation in the BRCA1 or BRCA2 gene. These models can be broadly categorized as empirical models and genetic models. Empirical models are based summarily on measures of family history, such as the number of affected relatives and other risk factors. Perhaps the most widely used model of this kind is the Gail model, which incorporates a...

What Is Hereditary Breast Cancer

It is worth stating at the outset that the term hereditary breast cancer, while in widespread usage, is somewhat problematic. Hereditary implies that the propensity to disease in that individual has been inherited. Thus, the implication is that breast cancer can be dichotomized into those cases where susceptibility is inherited and those where it is not. This concept arose from consideration of cancers with a simpler genetic basis such as retinoblastoma and Wilm's tumor, which can be usefully...

Genotype Phenotype Correlation in CS

Approximately two-thirds of germline PTEN mutations are found in exons 5, 7, and 8, and approximately 40 of all CS mutations are located in exon 5, although this exon represents only 20 of the coding sequence (1,14). This reflects the biological significance of this domain, which encodes the phosphatase core motif. There is a correlation between the presence of germline PTEN mutations and breast carcinoma in probands meeting operational criteria for CS (14). In other words, the risk of breast...

PTEN and Cowden Syndrome Prevention Of Breast Cancer In Cs

Some women with CS consider prophylactic mastectomy, especially if breast tissue is dense, making surveillance difficult, or if repeated breast biopsies have been necessary. Prophylactic mastectomy reduces the risk of breast cancer by 90 in women at high risk (63), although no studies have specifically addressed this intervention in patients with CS. There is no direct evidence to support the routine use of agents such as tamoxifen or raloxifene in individuals with CS to reduce the risk of...

Family Communication Issues And The Duty To Warn

The desire to obtain risk information for relatives often motivates individuals to obtain genetic testing (55). Indeed, one of the distinguishing features of genetic tests compared with other medical tests is that the results may have implications for biological relatives. However, rates of disclosure to at-risk relatives are surprisingly variable. Recent surveys of genetic counselors and medical geneticists, most of whom practiced in prenatal and pediatric settings, revealed that patients...

Nonmodifiable Factors

Additional established risk factors for breast cancer in the general population that have been studied in carriers of mutations in BRCA1 and BRCA2, but which are not modifiable, are later age, early age at menarche, and increasing mammographic density (19,55,56). The magnitude of age-specific RRs of breast cancer for mutation carriers versus noncarriers appears to differ by gene. An analysis of pooled data from 22 population-based studies of families of unselected mutation carriers found that...

Central Nervous System Manifestations

Macrocephaly, often quite pronounced, is common, with head circumference > 2 SD above the mean in greater than 40 of patients (26). More specifically, the increased head circumference is due to megalencephaly, an increase in brain volume. In addition, the head is often dolichocephalic even when head circumference is normal. Developmental delay is described but is less common in CS than in BRRS. Adult onset Lhermitte-Duclos disease (LDD) has recently been moved to the pathognomonic criteria...

Contribution Of Known Genes To Breast Cancer Incidence

The frequency of BRCA1 and BRCA2 mutations in breast cancer cases has been estimated by a number of studies. By pooling data from a number of population-based studies, Thompson and Easton (78) estimated that the prevalences of BRCA1 and BRCA2 mutations among breast cancer patients diagnosed below their mid-30s were approximately 4.6 and 3.5 , respectively. In contrast, the Anglian Breast Cancer Study (the largest population-based study to date) found the prevalences among cases diagnosed...

Progress Toward Identifying Common Lowpenetrance Alleles

The main alternative to linkage studies for disease gene mapping is the association study, in which the frequency of a genetic variant in diseased individuals (cases) and individuals without the disease (controls) are compared (15,16). Allelic association is present when the distribution of genotypes differs in cases and controls. Such an association provides evidence that the locus under study, or a neighboring locus, is related to disease susceptibility. Association studies for disease genes...

Other Breast Cancer Genes High Risk Breast Cancer Genes

Breast cancer is involved in two other hereditary syndromes, for which causative genes have been identified. The Li-Fraumeni syndrome is characterized by childhood sarcoma and early-onset breast cancer, brain tumors, and a variety of other cancers. Most families with Li-Fraumeni syndrome appear to be due to germline mutations in the TP53 gene. TP53 mutations confer a very high risk of breast cancer (approaching 100 by age 50) but are much rarer than BRCA1 or BRCA2 mutations (45,46). Cowden's...

Identification Of Hereditary Cancer Risk

Eliciting an accurate family history is a core activity when assessing risk for cancer and remains the single most cost-effective approach to identifying individuals for genetic counseling and testing and for implementation of cancer risk management strategies (4). Clinicians sometimes rely on answers to the inquiry, tell me, who in the family has had cancer, as the sole method for obtaining this type of information. Unfortunately, this approach may or may not reveal enough information to...

BRCA2 and Fanconi Anemia

The notion that BRCA2 is solely involved in breast and ovarian cancer was challenged recently. Investigators working on a rare inherited disorder, Fanconi Anemia (FA), discovered that mutations in BRCA2 cause certain subtypes of FA (34). FA is characterized by developmental defects, bone marrow failure, and susceptibility to certain types of cancer, most notably, acute myelogenous leukemia. Cells from FA patients exhibit chromosome fragility and are hypersensitive to DNA-damaging agents. FA is...

Breast Cancer As A First Or Subsequent Cancer In

Not only is breast cancer the most common cancer observed in LFS, it plays a major role in subsequent cancers. In the Hisada et al. (71) series, 200 LFS patients had at least one cancer, including 104 females and 96 males among 30 patients who developed one or more additional cancers, 19 (63 ) were in females. The 19 females who had multiple primary tumors experienced a total of 46 cancers (original plus subsequent), with breast cancer accounting for 26. Forty-five of the original tumors were...

Other Genes

There are several other genes for which there has been a single report evaluating their role as genetic modifiers of BRCA1 and BRCA2, but without any subsequent validation. Phelan et al. (88) examined a variable number of tandem repeats (VNTR) polymorphism downstream of the HRAS1 gene in a panel of 307 BRCA1 carriers from 79 different families, of whom 173 were affected with breast cancer, 42 with ovarian cancer, and 20 with both cancers. Carrier status for 41 of these carriers was inferred on...

Radiation And Chemotherapy Risks

Most series of LFS families, as well as case reports, have noted not only the high risk of multiple primary tumors but the frequent occurrence of new cancers in radiation-treated sites (48,53,58,60,71-73). Hisada et al. (71) observed only one of 14 subsequent breast cancers arising in a previously irradiated area however most of the subsequent sarcomas arose in previously irradiated areas, and studies of childhood cancer survivors, especially young soft tissue patients (67,74), have noted a...

Types Of Cancer Associated With Brca12 Mutations Ovarian Cancer

The most significant cancer, other than breast cancer, in individuals with BRCA1 2 mutations is ovarian cancer, as reflected in the nomenclature, hereditary breast ovarian cancer (HBOC) syndrome. As with breast cancer, early linkage studies probably overestimated the penetrance of ovarian cancer for BRCA1 2 mutation carriers with estimates by the age of 70 years of 44 for BRCA1 carriers (51) and 27 for BRCA2 carriers (97). In contrast, later studies, utilizing nonlinkage-based ascertainments,...

Penetrance For Breast Cancer In P53 Mutation Carriers

Overall data from the IARC TP53 Database (14) confirm findings of smaller series that breast cancer is the most common cancer in LFS, accounting for about 25 to 30 of all cancers. For p53 mutation carriers the median age of breast cancer onset is 33 years, significantly earlier than for non-p53 LFS at 42.5 years. To date no genotype-phenotype correlation, that is, no association of specific p53 mutations by structural or functional domain, or by mutation type, has been observed for breast...

Penetrance Estimates From Series Based On Direct Brca Genotyping

Following the identification of BRCA1 and BRCA2, it became possible to directly genotype individuals and to derive penetrance by examining the family structure of these probands. These series, in which the index case or proband was selected on the basis of having breast cancer and then being genotyped, have been referred to as case proband studies or genotyped affected proband series (1,53). In case proband series, there may be significant bias, depending on how the cases were ascertained. In...

Breast Cancer Prognosis In

Many studies have indicated that a p53 somatic mutation is an independent poor prognostic indicator for breast cancer (86), with some data suggesting that the prognosis may be influenced by the nature of the mutation (87). Miller et al. (30) have shown that an expression signature for p53 functional status in breast cancer is more predictive of outcome than p53 sequence analysis, and suggest that p53 may be functionally attenuated in the absence of DNA sequence variants. From those data one...

Conclusions

Although the major risks associated with inherited mutations of BRCA1 and BRCA2 are now well described, there remains debate about the precise magnitude and spectrum of risks due to syndromic cancers. The ranges of risks reported to date may reflect the inherent biases in the ascertainment methodologies employed, and more recent studies may provide more stable estimates of these risks (128). In addition, environmental and other genetic modifying factors impact on kindreds, segregating BRCA...

The Evidence For Lowpenetrance Genes

Breast cancer, like other common cancers, exhibit some degree of familial clustering, with disease being approximately two-fold more common in first-degree relatives of cases (6,7). The higher rate of most cancers in the monozygotic twins of cases than in dizygotic twins or siblings suggests that most of the familial clustering is the result of genetic variation rather than lifestyle or environmental factors (8,9). Further evidence for the relative importance of genetic factors comes from the...

High Resolution Melt Curve Analysis

High-resolution melt curve analysis (HRM or MCA) has been recently introduced as a promising technique for high throughput genotyping (69) and mutation scanning (70). The method rests on three biophysical principles and is elegant in its simplicity. First, certain dyes bind to double-strand DNA, fluoresce under ultraviolet light when bound, and are compatible with PCR at saturating concentrations. This makes possible highresolution fluorescence versus temperature, or melting curve, analysis of...

Nonmalignant Solid Organ Involvement

At least 50 of patients with CS exhibit benign breast disease (26). In a series of specimens from CS patients who had undergone breast biopsies or resections, 98 had 76 of affected females 30-50 of affected females 30-40 50-67 evidence of benign breast lesions (20). The spectrum of lesions includes ductal hyperplasia, intraductal papillomas, sclerosing adenosis, lobular atrophy and fibroade-nomas, dense stromal fibrosis, and fibrocystic changes (20,26). These benign manifestations, in addition...

Ethics Framework For Clinicians

In their seminal textbook, Beauchamp and Childress propose a useful, overarching framework known as principlism that can be applied to the examination of many ethical issues in the biomedical field (2). The four main principles they espouse are respect for persons, beneficence, nonmaleficence, and justice (Table 1). Respect for persons, or autonomy, entails respect for a person's right to make decisions based on his or her own values, beliefs, and preferences (2). To make fully autonomous...

Introduction

Major advances in the understanding of the molecular basis of cancer have made it possible to identify families where breast cancer risk has a strong inherited basis. Individuals who perceive themselves to be at high cancer risk are increasingly seeking out clinical genetics services that assess their cancer risk and provide management recommendations. Physicians are also increasingly referring patients for genetic testing, since identification of genetic risk may influence certain patient...

Breast Cancer Susceptibility And Other Risk Factors

An important and largely unresolved question is the relationship between genetic and lifestyle risk factors for breast cancer. The combined analysis by the Collaborative Group examined the effect of several important risk factors on the familial risk of breast cancer, including parity, age at first full-term pregnancy, and ages at menarche and menopause. In each case, they found that the relative risks conferred by these risk factors were similar in women with and without a family history (1)....

Cancer Surveillance And Prevention

Recently the American Cancer Society issued new guidelines for breast screening based on level of risk (89). These recommendations include annual screening with MRI as an adjunct to mammography for women with a 20 to 25 lifetime breast cancer risk, based on evidence accumulated from prospective trials of BRCA mutation carriers, and Expert Consensus Opinion for LFS. The BRCA studies indicated an increased sensitivity, but reduced specificity, for MRI as compared with mammography. Importantly,...

Pten Mutations In Cs

The International Cowden Consortium mapped the susceptibility locus for CS to 10q22-q23 (2) and subsequently demonstrated that germline mutations of PTEN cause CS (46). Utilizing strict operational criteria, > 80 of individuals with CS harbor a germline PTEN mutation (14) (Table 3). Initial studies of families meeting strict operational criteria for CS demonstrate no genetic heterogeneity (2). To date, no additional disease susceptibility loci have been confirmed for CS. It is thus believed...

Low Risk Breast Cancer Genes

A growing list of genes is associated with more moderate risks of breast cancer. The first such gene to be identified was ATM. Mutations in this gene cause the recessive condition Ataxia-Telangiectasia (A-T) (62). Studies dating back over 30 years have suggested that relatives of A-T patients were at increased risk of breast (and perhaps other) cancer (63). This was long regarded as controversial because the studies were small. However, more recent national cohort studies, and direct studies of...

Parity

It is well established that parity reduces the risk of female breast cancer in the general population in the longer term, with the degree of protection increasing with the number of births (19). The largest dataset analyzed estimated the risk reduction to be around 7 per additional birth (20). Each full-term pregnancy is associated with a transient increase in risk, so that the protective effect of parity is most apparent in women over the age of 40 years (21). Women who have their first birth...

Management of Malignancy in CS

The treatment of the malignant manifestations of PHTS is generally the same as for their sporadic counterparts. Several caveats deserve mention however. Like other hereditary breast cancer syndromes, the risk of second primaries, not only within the breasts but also in other affected organs, is increased in CS, although no data exists on the frequency of their occurrence. In addition, some women with CS have extensive fibrocystic changes and or fibroadenomas that make surveillance difficult....

Twin Studies and Bilateral Breast Cancer

In principle, the familial aggregation of breast cancer may be due either to genetic factors or to lifestyle or environmental factors that are shared among relatives. The latter possibility is unlikely in that no lifestyle risk factors that are sufficiently strong to materially affect familial aggregation of the disease have been identified. More formal evidence that familial aggregation has a genetic basis comes from twin studies. Based on an analysis of population-based twin registers from...

Genetic Counseling Provider Roles Service Delivery And Informed Consent

One of the primary obligations of healthcare providers is the identification of individuals for whom genetic counseling, and possibly testing, is indicated. Since the cloning of BRCA1 and BRCA2, position statements and other resources have been developed to assist clinicians with the identification and management of high-risk individuals (10-13). In addition, educational materials are widely available to assist clinicians with the recognition and management of hereditary breast cancer syndromes...

Preimplantation And Prenatal Testing For Hereditary Breast Cancer

Another emerging issue concerns the use of preimplantation genetic diagnosis (PGD) (89) and prenatal diagnosis for hereditary cancer syndromes. A recent review of this issue cited 55 reports of testing for these purposes (90). Both technologies have been utilized in families with Li-Fraumeni syndrome, and PGD has been used by parents at risk for having a child with a BRCA1 2 mutation (90). The ethical issues raised by these procedures share some similarities but also have some unique features....

BARD1BRCA1Associated RING Domain

BRCA1 -associated really-interesting-new-gene (RING) domain protein (BARD1) was identified in a yeast two-hybrid screen as a binding partner of BRCA1 (81). Like BRCA1, BARD1 has a RING-finger domain BRCA1 and BARD1 form a functional heterodimer through the interaction of those domains (82). The interaction of BRCA1 and BARD1 serves to stabilize the two proteins. Mutations in BRCA1 in the RING domain abrogate the interaction between BRCA1 and BARD1 and are associated with susceptibility to...

Modifiers Of Penetrance And Breast Cancer Genes Other Than Brca

Several studies have noted an increased penetrance for BRCA1 2 in more recent birth cohorts. The NYBCS (9) confirmed Narod's earlier observation of a significant increase in breast cancer risk by the age of 50 years in birth cohorts after 1940 (67 after 1940, 24 before 1940) (39). Ovarian cancer risk did not differ by birth cohort. This increase in incidence for BRCA1 2 mutation carriers parallels an increase in breast cancer in the general U.S. population over that period (37). Antoniou et al....

Personal History of Untreated Depression or Anxiety or Prior Suicidal Ideation or Attempt

When cancer genetic counseling was first offered, there were few other adult onset conditions for which predisposition testing was available. One was Huntington's disease (HD), and as part of the testing protocol for HD, most centers involve mental health-care providers. However, suicidal ideation is part of the biology of HD, and studies have demonstrated that learning cancer mutation status can cause anxiety but not to the degree that requires professional referrals (57,58). However, because...

Post Test Counselingreactions To The Results Reactions to a Positive Result

For women who do not have cancer, a positive BRCA1 or BRCA2 test result typically engenders more emotional distress than a negative test result however, the distress tends to be of short duration. Several studies have shown that mean anxiety and distress scores are not dramatically increased post disclosure (55). In fact, one study showed that the individuals with the highest anxiety levels were the ones who decided not to learn their results (56). These findings provide reassurance that...

Reactions During the Counseling Session

During any consultation, genetic counselors will assess the psychological ability of the individual and or family to cope with the information, management, and testing choices being discussed. Within a counseling session, patients may exhibit a range of emotions, including anger, grief, guilt, and fear. Collecting information about the pattern of cancer in the family can evoke memories of relatives who have died and uncover family dysfunction. Discussing cancer risks and genetic testing options...

Tyrercuzick International Breast Cancer Intervention Study

This is the most recently developed of the breast cancer risk assessment models (32). It was developed using published data regarding BRCA1 and BRCA2 mutation carrier frequencies from a study of mother-daughter pairs (33) and penetrance estimates from the Breast Cancer Linkage Consortium (34) rather than one specific dataset. There are two parts to the model's calculations a genetic part and a personal risk factors part. Like the BRCAPRO model, International Breast Cancer Intervention Study...

Genetic Modifiers

As discussed at the start of this chapter, the variation in the risk of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers between different studies, and according to the phenotype of the proband, is consistent with the presence of either environmental or genetic modifiers. Genetic modifiers are probably more likely than shared environment to account for familial clustering of cancer sites in Ashkenazi Jewish mutation carriers, for example, since intrafamilial differences in...

Ataxia Telangiectasia Mutated

Individuals homozygous for germline mutations in ataxia telangiectasia mutated (ATM) have ataxia telangiectasia (AT), an autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasias, radiation hypersensitivity, and an increased incidence of malignancy (29). AT homozygotes have cancer risks 60 to 180 times greater than the general population including non-Hodgkins lymphoma (nearly 100 lifetime risk) and breast and ovarian cancer (30). Heterozygosity for...

Breast And Ovarian Analysis Of Disease Incidence And Carrier Estimation Algorithm Boadicea

BOADICEA is one of the latest of the carrier prediction models to be developed (25). It used a U.K. population-based series of 2200 breast cancer cases, 156 multiple case families, and 429 BRCA1I2 carrier families. All were tested for BRCA1I2 mutations. The complex segregation analysis used resulted in a model that allows for the simultaneous effects of BRCA1 and BRCA2. It also takes into account the effect of many low-penetrance genes that are likely to have multiplicative effects on the...

Methods Relying on Gel Electrophoresis to Resolve Heteroduplexes from Homoduplexes

Two somewhat distinct families of mutation-screening techniques rely on gel electro-phoresis to resolve heteroduplexes from homoduplexes. The first family is based on electrophoresis of samples in a denaturing gradient, and its basic implementation is referred to as denaturing gradient gel electrophoresis (DGGE). The second relies on the gel matrix itself to achieve separation between homoduplexes and heteroduplexes. Its basic implementation is referred to as conformation-sensitive gel...

Mucocutaneous Manifestations

The mucocutaneous manifestations of CS are the most common, yet the most difficult to recognize, with an estimated penetrance of 99 by the end of the third decade (17). The characteristic skin lesions of CS are trichilemmomas and papillomatous papules (25). Trichilemmomas are hamartomas of the infundibulum of the hair follicle and are characteristically found at or near the hairline while papillomatous papules are condyloma-like lesions occurring frequently on the face, hands, feet, or oral...

Shattuckeidens Model

This model was one of many developed by Myriad Genetics, Inc., (Salt Lake City, U.S.A.) to predict the likelihood of a given individual having a mutation in one of the breast cancer predisposing genes BRCA1 or BRCA2. This was one of the earliest such models to be developed (17,18), and it only involved prediction of mutations in BRCA1. The authors used full sequencing data from 798 unrelated individuals, who had been selected for testing because of a family history comprising multiple cases of...

Genetic Testing Complexitieswhere To Start

Careful assessment of the cancer pedigree allows the selection of the most appropriate candidate in whom to initiate testing. If possible, it is preferable to initially test a living affected family member (i.e., has had breast or ovarian cancer or a component tumor associated with the particular suspected syndrome) and select the individual who has the highest chance of having a detectable mutation. If a disease-conferring mutation is found in a family, then the source of cancer risk in the...

Penetrance of BRCA1 and BRCA2 Mutations

The cancer risks associated with BRCA1 and BRCA2 mutations are critical for genetic counseling and have been the subject of considerable controversy. Ultimately, estimates of penetrance based on prospective followup of unaffected carriers should become available, but current estimates are derived from retrospective data. Penetrance estimates have been derived from high-risk families (the so-called maximum logarithm of (LoD score) odds score approach) and from population-based studies based on...

Contribution Of Known Genes To Familial Breast Cancer

An important question is the extent to which the known susceptibility genes can explain the familial aggregation of breast cancer. The simplest assessment of this is the proportion of the familial risk to first-degree relatives of cases that is explicable by each gene. We might term this the familial attributable fraction of each gene. These estimates can then be added over genes, on the assumption that the genes interact either additively or combined on a log scale, if the genes interact...

Claus Model

This was one of the first of the risk prediction models to be developed. It was derived from the Cancer and Steroid Hormone (CASH or Claus) study (16). This was a study of 4700 women with breast cancer, who had their family history taken. A statistical model (Claus model, named after the author of the study) was developed that estimated the chance that a cancer-predisposition gene was present in a family. The model dates from before the BRCA1 and BRCA2 genes were identified. The complex...

Examples Of These Models In

For the examples below, we have decided to use some of the models discussed on three sample pedigrees. The pedigrees are not real pedigrees but are based on real histories given by families seen in our cancer genetics clinics, and the mutation status of each family is known. They have been selected to illustrate the various strengths and weaknesses of the models. We have, in addition to the models themselves, incorporated an assessment by an experienced clinician. This reflects the opinion of a...

Cancers Other Than Breast and Ovarian Cancer

Table 1 groups studies, by type, that have examined the association of cancers other than breast and ovarian FT cancers with BRCA1 2 mutations, or in families with breast and or ovarian cancer. Inclusion in the table was restricted to claims of statistically significant findings. Early linkage studies and family-based studies in which there was no genotyping of colorectal cancer cases observed significant associations between BRCA1 2 mutations Table 1 Genotype Phenotype Correlation Studies,...

Manchester

The Manchester scoring system was developed by Evans et al. in 2004. Its aim was to provide a quick accurate method of assessing whether genetic testing for BRCA1 or BRCA2 is appropriate given a family history of breast and ovarian cancer, and if so, which of the two genes should be tested first. Development of the scoring system used a dataset of 422 non-Jewish families with a history of breast and or ovarian cancer. These were subsequently screened for mutations in BRCA1, and a subset was...