Hereditary Breast Cancer
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A nonsense mutation in BLM , initially been observed in few BS patients, has been associated with breast cancer in Slavic populations, and the presently available evidence for BS mutations indicates an approximately 2—5 fold increase in breast cancer risk for heterozygotes [ 45 , 46 , 91 ]. Heterozygous carriers have been reported with a 2—3 fold increase in breast cancer risk, with rare homozygotes being found at a much higher risk [ 55 , 56 ]. In Eastern Europe, two further truncating mutations have been associated with at least similarly high breast cancer risks, whereas a missense mutation, p.
IT, has a lower penetrance [ 41 , 57 , 58 ]. There has also been some evidence for an association of CHEK2 mutations with ovarian cancer and for additional malignancies suggesting a more general role in cancer predisposition [ 89 , 93 ]. It is interesting to note that, although CHEK2 interacts with BRCA1 in the same pathway, its mutations are significantly associated with estrogen receptor positive breast tumours, indicating an impact on tumour etiology that is different from BRCA1.
By contrast with the other genes discussed above, all of the identified PPM1D mutations were mosaic in lymphocyte DNA and, where tested, were not observed in breast or ovarian tissue, suggesting a late origin in the germ-line.
Genetics and Hereditary Breast Cancer Clinic
Their mechanism of action in breast or ovarian cancer development is presently unknown. Somatic mosaicism has previously been observed for TP53 mutations outside of Li-Fraumeni families [ 89 ] suggesting that, in addition to classical heritable genetic factors, mosaic mutations may also contribute to the genetic predisposition to breast and ovarian cancer.
These observations, if confirmed, could have important consequences for mutational screening as well as counselling. Certainly, the origin and frequency of mosaic mutations need to be studied in more detail before final conclusions can be derived.
Risk Factors for Hereditary Breast Cancer
Beyond the genes with relatively rare mutations discussed above, common polymorphisms have been predicted to significantly impact on risk and prevention if breast cancer were regarded as a polygenic disease [ 94 ]. This has been mainly achieved through genome-wide association studies GWAS of single nucleotide polymorphism by large consortia during the past six years.
The published GWAS efforts have uncovered over 70 genomic loci for breast cancer at a genome-wide significance level [ 72 , 95 — ]. As these loci still explain only a small part of the heritable fraction, it is likely that the numbers will increase rapidly. But evidence suggests that several hundreds of low-penetrance breast cancer loci might exist, meaning that even with the numbers reached so far, studies have merely grazed the surface of the iceberg [ 72 ].
Many of the identified GWAS loci appear to be specific for breast carcinomas. For example, the gene for fibroblast growth factor receptor 2, FGFR2 , harbours variants associated with breast but not ovarian cancer [ 95 , 96 ] and breast cancer-associated variants in this gene appear to regulate the transcriptional activation of FGFR2 in an estrogen-dependent manner [ ].
A minor group of common susceptibility loci has turned out to be relevant for other common cancers as well, perhaps due to their general relevance for genome integrity [ ]. A closer inspection of the TERT locus, encoding a component of telomerase, has uncovered three independent regions of strong association with breast or ovarian cancer that only partially overlap and appear to act through different mechanisms of transcriptional regulation or splicing, respectively [ ].
Similarly, a closer inspection of the 8q24 locus upstream of MYC has indicated that the associations with different cancers were caused by independent variants at the same locus, possibly explained by tissue-specific regulation of gene expression through long-distance effects of enhancer regions [ ].
These findings illustrate that, in several instances, low-penetrance breast cancer susceptibility alleles may exert regulatory roles in the fine-tuning of gene expression in the respective tissue, and the patterns of regulation can be complex. As a caveat, a GWAS roughly localises but usually does not yet identify the causal variant. In several cases there is more than one candidate gene in the region spanned by the associated LD block, and there can be even more candidate genes under putative regulatory control of the identified locus.
For example at the 5q In some instances, available microarray data supported an association of the identified SNP with gene expression [ 72 , ]. In other instances, identified loci have independently been correlated with previously known risk factors for breast cancer, such as FTO for obesity, INHBB for breast size or ZNF for mammographic density, strongly suggesting that the risk for breast cancer could be mediated via these physiological traits [ — ].
But for the majority of loci, fine-mapping approaches in different ethnic populations as well as gene expression and chromatin configuration studies are presently being used to further trace down the true predisposing variants. A combination of such approaches has recently identified regulatory mechanisms that underlie the association of independent variants at 11q13 with breast cancer and act in concert to orchestrate cyclin D1 expression [ ]. Copy number variants CNVs have also been investigated at a genome-wide level. Additional recent studies also showed a consistent increase in the frequency of rare CNVs in breast cancer cases when compared to controls [ , ], with a particular enrichment of CNVs in genes involved in estrogen signalling and DNA double strand break repair in one study [ ].
If confirmed, this mirrors some results from genome-wide SNP analyses, although there has been no overlap of the identified loci thus far. Hereditary breast cancer represents a challenge in terms of genetic counselling as well as preventive and therapeutic decisions.
The identification of mutations in individuals from multiple-case families with breast cancer makes it possible to predict the age-dependent risk for different cancers, including recurrence risks in the already affected, and to counsel patient and blood relatives more appropriately. Risk prediction may lead to an increased surveillance or targeted prevention including magnetic resonance imaging, medication such as tamoxifen or preventive surgery such as prophylactic oophorectomy. Although the female carriers for those mutations could also benefit from increased surveillance, large studies on the efficacy of such measures are lacking.
No further counselling is provided for patients carrying common risk alleles at polymorphic loci, as these risks are too small individually to be clinically meaningful. This situation may change, however, if one considers cumulative effects for several of those variants that can reach substantial risk modifications already at the present stage of knowledge. With the identification of many more low-risk loci it may become possible to calculate combinatorial risks that could be useful in a stratified approach of cancer prevention in the future [ — ].
Population diversity needs to be taken into account for breast cancer susceptibility at all levels of penetrance. Due to founder effects, single mutations can contribute significantly to the breast cancer burden in founder populations and intermediate-risk alleles in some genes have almost exclusively been found in certain population groups, such as for FAMA and RAD50 in the Finnish population or NBN in Slavic populations [ 28 , 41 — 44 ].
In fact, much of the present knowledge about those genes relies on particular founder mutations, and in regard of allelic heterogeneity one must be cautious to extrapolate and generalise these observations to other less common alleles. Gene-based strategies for an improved risk prediction will therefore need to be elaborated in a population-specific way.
In addition to risk prediction, identifying the genetic basis of breast cancer in the individual patient might have further prognostic and therapeutic implications. These tumour characteristics are partly determined by germ-line mutations, as exemplified by BRCA1 mutations which are frequently associated with triple-negative breast cancers, but breast cancer pathology also seems to be influenced by low-penetrance variants like those in FGFR2 that are strongly correlated with estrogen-receptor positive disease [ 95 , 96 , ].
Further studies are presently underway to investigate whether SNP profiling could be of prognostic value [ ]. The identification of breast cancer susceptibility alleles may also guide the development of new drugs that target additional breast cancer pathways, such as oncogenic signalling mediated by FGF receptors [ ] or mutation accumulation mediated through ABOBEC3B. Such new drugs are particularly needed in the treatment of otherwise poorly targetable breast carcinomas such as triple-negative tumours [ ] and the identification of risk alleles in genes like BABAM1 or MDM4 in this particular subgroup may offer promising avenues for new therapeutic regimens.
Tremendous progress has been made during the past few years in deciphering the polygenic susceptibility to breast cancer. The results suggest that key pathways are targeted by different sources of genetic variation influencing the hereditary risk.
Orphanet: Hereditary breast and ovarian cancer syndrome
With many more genes being identified, a deeper understanding of breast cancer development and progression together with the ability of gene-based stratification should ultimately lead to improved prevention and an individually tailored therapy to the benefit of each patient. Genetic aspects. CMA Journal , 29— Warthin AS: Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, — Arch Intern Med , — Malkin D: Li-Fraumeni syndrome.
Genes Cancer , 2: — Science , — Nature , — Science , 66— Clin Cancer Res , — J Med Genet , — Br J Cancer , — Am J Gastroenterol , — Breast Cancer Res , R The first cancers. Cancer Genet Cytogenet , — The first microarray-based study of hereditary breast cancers was published by Hedenfalk et al in The authors identified 51 genes whose variation in expression best differentiated the three groups of cancers.
Further investigations revealed hypermethylation of the BRCA1 promoter in the single misclassified tumors. The study served as a proof-of-concept study; however, concerns have been raised because of the small sample size and a lack of appropriate matching according to clinical parameters such as ER-status, known to have profound impact on the gene-expression pattern. Based on absolute correlation coefficients they identified optimal marker genes for use in a leave-out one cross validation LOOCV classification algorithm.
Again, promoter hypermethylation was demonstrated in a sporadic tumor classified as BRCA1 -like. The main concern has been that the genes used for classification were identified using all samples, including also the left-out ones, wherefore the classification performance may be biased because of possible information leakage. Sixty genes were found to be differentially expressed between the two subgroups.
- Being born female.
- Hereditary breast cancer.
Of these, ribosomal-related genes were overrepresented. Notably, all families in which multiple family members were examined remained intact when divided into subgroups. The authors noted that these subgroupings could reflect different underlying genetic predispositions; however, they never validated their observation. A pioneering study in by Perou and colleagues was the first to show that breast cancers can be divided into subtypes distinguished by differences in their gene-expression profiles.
These subtypes correspond broadly to histopathological characteristics and correlate to clinical outcome. Cancers of the luminal subtypes are ER-positive. In addition, lumA is low-grade and PR-positive tumor, while lumB is often high-grade cancer and to some extent PR-negative. The intrinsic subtypes are found to be highly conserved across different microarray platforms and across tumors from distinct ethnic populations.
The first study to investigate molecular breast cancer subtypes in association with hereditary breast cancers was conducted by Waddell et al in These subgroups showed some association with the BRCA1 mutation type protein truncating versus missense. These numbers were highly concordant with the previous studies. Surprisingly, we found that members of the same family shared the same tumor subtype in 8 of the 11 families.
Three of the families were characterized by lumA tumors only including the three-case family , three families had lumB tumors, one had HER2-enriched tumors, and one had only basal-like tumors. To confirm our observations, we subtyped the samples of Hedenfalk et al 98 consisting of tumors from a total of five high-risk families. The patterns of aggregation of molecular subtypes within families were confirmed in four of the families.
These findings could indicate an underlying common genetic basis in these families. The family members may carry an inherited susceptibility not just to breast cancer but to a particular subtype of breast cancer. In light of these findings, future genetic analysis may benefit from subgrouping families into molecularly homogeneous subtypes in order to search for new high-penetrance susceptibility genes.
Our results support the hypothesis that BRCA1 -associated tumors represent a distinct biological subgroup among basal-like tumors, which has been a topic of debate. With the implementation of microarray-based comparative genomic hybridization array-CGH , high resolution analysis of chromosomal aberrations in tumor samples became easy accessible.
BRCA2 classification resulted in 9 of 12 samples correctly classified and 4 misclassified. In addition, they identified 4p, 4q, and 5q as frequently lost in BRCA1 tumors relative to sporadic tumors.
Family history and hereditary breast cancer
The study observed highest frequencies of copy number alternations in BRCA1 tumors. On this background, it was suggested that ER-status should be considered in future study designs. The genomic subtypes were highly concordant to the intrinsic subtypes determined by gene-expression. Luminal-complex BRCA2 tumors were characterized by losses on 3p The most abundant genomic abbreviations that differed between BRCA1 and sporadic tumors were 3q gain , 5q loss , 6p gain , 12p13 gain , 12q loss , and 13q gain. Chromosomal aberrations specific for BRCA2 -mutated tumors were loss of 13q and 14q and gain of 17q.
The results from the last decade of pathological and molecular characterization of hereditary breast cancer have unquestionably contributed with important insights into the biological mechanism underlying hereditary breast cancers. It is now well established that tumors of hereditary breast cancers are not phenotypically distinct groups of cancers, instead they are associated with the intrinsic molecular subtypes. The described studies also stress the importance of careful study design.
Because of the strong association to the molecular subtypes, proper sample matching is important to avoid bias in order to detect genomic features unique for hereditary breast cancers. Such signatures could also be used as a tool for preselecting patients for mutation screening, as a significant proportion of BRCA1 and BRCA2 germline mutation carriers do not have a family history of breast cancers. Molecular signatures could potentially prove to provide a general method for detecting BRCA- deficient tumors sensitive to new target therapies making it applicable for optimal treatment decisions.
The landscape of hereditary breast cancer is starting to emerge; however, studies of non-coding RNA expression such as microRNA and lncRNA , NGS, as well as epigenetic studies will undoubtedly add important details to the description of the complex genetic architecture underlying hereditary breast cancer. Author Contributions. Wrote the first draft of the manuscript: MJL. All authors reviewed and approved of the final manuscript. Dimri, Editor in Chief. Brogaard og Hustrus Mindefonde. The authors confirm that the funder had no influence over the study design, content of the article, or selection of this journal.
Paper subject to independent expert blind peer review by minimum of two reviewers. All editorial decisions made by independent academic editor. Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties.
National Center for Biotechnology Information , U. Journal List Breast Cancer Auckl v. Breast Cancer Auckl. Published online Oct Find articles by Martin J Larsen. Find articles by Mads Thomassen.
Other inherited gene mutations
Find articles by Anne-Marie Gerdes. Find articles by Torben A Kruse. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Introduction Breast cancer is the most frequent malignant disease and the leading cause of cancer death among women in both economically developed and developing countries. Clinical Implications of Hereditary Breast Cancer Genetic counseling and risk assessment Familial breast cancer cases are today identified by evaluation of a family pedigree showing breast and ovarian cancer cases.
Molecular Profiling of Hereditary Breast Cancer During the last decades, the microarray technology has been used extensively to study breast cancer biology. Table 1 Published microarray RNA profiling studies of hereditary breast cancers. Open in a separate window. Table 2 Published array-CGH studies of hereditary breast cancers.
Gene-expression profiling of hereditary breast cancer The early studies The first microarray-based study of hereditary breast cancers was published by Hedenfalk et al in Molecular subtypes of hereditary breast cancer A pioneering study in by Perou and colleagues was the first to show that breast cancers can be divided into subtypes distinguished by differences in their gene-expression profiles.
Genomic aberration in hereditary breast cancer With the implementation of microarray-based comparative genomic hybridization array-CGH , high resolution analysis of chromosomal aberrations in tumor samples became easy accessible.
Conclusion and Future Perspectives The results from the last decade of pathological and molecular characterization of hereditary breast cancer have unquestionably contributed with important insights into the biological mechanism underlying hereditary breast cancers. Global cancer statistics.
CA Cancer J Clin. Broca P. Paris: Asselin; pp. The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications. Mod Pathol. Clin Genet. The complex genetic landscape of familial breast cancer. Hum Genet. The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. This is different from a recurrence or return of the first cancer.
Although this risk is low overall, it's even higher for younger women with breast cancer. Overall, white women are slightly more likely to develop breast cancer than African-American women, although the gap between them has been closing in recent years. In women under age 45, breast cancer is more common in African-American women.
African-American women are also more likely to die from breast cancer at any age. Asian, Hispanic, and Native American women have a lower risk of developing and dying from breast cancer. Risk in different groups also varies by type of breast cancer. For example, African-American women are more likely to have the less common triple-negative breast cancer. Many studies have found that taller women have a higher risk of breast cancer than shorter women. Breasts are made up of fatty tissue, fibrous tissue, and glandular tissue.
Breasts appear denser on a mammogram when they have more glandular and fibrous tissue and less fatty tissue. Unfortunately, dense breast tissue can also make it harder to see cancers on mammograms. A number of factors can affect breast density, such as age, menopausal status, the use of certain drugs including menopausal hormone therapy , pregnancy, and genetics. To learn more, see our information on breast density and mammograms. Women diagnosed with certain benign non-cancer breast conditions may have a higher risk of breast cancer.
Some of these conditions are more closely linked to breast cancer risk than others. Doctors often divide benign breast conditions into 3 groups, depending on how they affect this risk. They include:.