Hereditary breast cancer the implications of

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Hereditary breast cancer the implications of

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 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 Hereditary breast cancer the implications 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. 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.

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.

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.

Being a woman

The intrinsic subtypes are found to be highly conserved across different microarray platforms and across tumors from distinct ethnic populations. 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 familythree 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.

Genetics: Breast Cancer Risk Factors

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.

Genomic aberration in hereditary breast cancer With the implementation of microarray-based comparative genomic hybridization array-CGHhigh resolution analysis of chromosomal aberrations in tumor samples became easy accessible.

Hereditary breast cancer the implications of

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.

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 gain5q loss6p gain12p13 gain12q lossand 13q gain. Chromosomal aberrations specific for BRCA2-mutated tumors were loss of 13q and 14q and gain of 17q.

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. 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 lncRNANGS, as well as epigenetic studies will undoubtedly add important details to the description of the complex genetic architecture underlying hereditary breast cancer.

What causes cancer?

Footnotes Author Contributions Wrote the first draft of the manuscript: Contributed to the writing of the manuscript: Agree with manuscript results and conclusions:Prepare for your BRCA gene test by learning how genetic testing for breast cancer and ovarian cancer may affect you and your family members.

The psychological, emotional and social implications of genetic testing also are worth considering, both for yourself and for members of your family. Breast cancers in women with a harmful BRCA1 mutation tend to be "triple-negative cancers" (that is, the breast cancer cells do not have estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein), which generally have poorer prognosis than other breast cancers.

Breast cancer is a disease in which certain cells in the breast become abnormal and multiply uncontrollably to form a tumor. Although breast cancer is much more common in women, this form of cancer can also develop in men. In both women and men, the most common form of breast cancer begins in cells lining the milk ducts (ductal cancer).

In women, cancer can also develop in the glands . Abstract. NCCN guidelines recommend genetic testing for all triple-negative breast cancer (TNBC) patients aged ≤60 years. However, due to the lack of prospective information in unselected patients, these guidelines are not uniformly adopted by clinicians and insurance carriers.

Prepare for your BRCA gene test by learning how genetic testing for breast cancer and ovarian cancer may affect you and your family members.

The psychological, emotional and social implications of genetic testing also are worth considering, both for yourself and for members of your family.

BRCA1 and BRCA2: The most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 or BRCA2 gene. In normal cells, these genes help make proteins that repair damaged DNA. In normal cells, these genes help make proteins that repair damaged DNA.

Breast Cancer Risk Factors You Cannot Change