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==[[BRCA1]]/[[BRCA2]] ==
==[[BRCA1]]/[[BRCA2]] ==
Genetic markers, if present, suggest an 80% likelihood of breast cancer occurrence.
Genetic markers, if present, suggest an increased likelihood of breast cancer occurrence.
 
BRCA1
 
Certain variations of the ''BRCA1'' gene lead to an increased risk for [[breast cancer]] as part of a hereditary breast-ovarian cancer syndrome. Researchers have identified hundreds of [[Mutation|mutations]] in the ''BRCA1'' gene, many of which are associated with an increased risk of cancer. Females with an abnormal BRCA1 or BRCA2 gene have up to an 80% risk of developing breast cancer by age 90; increased risk of developing ovarian cancer is about 55% for females with BRCA1 mutations and about 25% for females with BRCA2 mutations.
 
These mutations can be changes in one or a small number of DNA [[Base pair|base pairs]] (the building-blocks of DNA), and can be identified with PCR and DNA sequencing.<sup>[''citation needed'']</sup>
 
In some cases, large segments of DNA are rearranged. Those large segments, also called large rearrangements, can be a deletion or a duplication of one or several exons in the gene. Classical methods for mutation detection (sequencing) are unable to reveal these types of mutation. Other methods have been proposed: traditional [[quantitative PCR]], [[Multiplex Ligation-dependent Probe Amplification]] (MLPA), and Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF). Newer methods have also been recently proposed: heteroduplex analysis (HDA) by multi-capillary electrophoresis or also dedicated oligonucleotides array based on [[comparative genomic hybridization]] (array-CGH).
 
Some results suggest that [[Methylation|hypermethylation]] of the BRCA1 promoter, which has been reported in some cancers, could be considered as an inactivating mechanism for BRCA1 expression.
 
A mutated ''BRCA1'' gene usually makes a [[protein]] that does not function properly. Researchers believe that the defective BRCA1 protein is unable to help fix DNA damage leading to mutations in other genes. These mutations can accumulate and may allow cells to grow and divide uncontrollably to form a tumor. Thus, BRCA1 inactivating mutations lead to a predisposition for cancer.<sup>[''citation needed'']</sup>
 
BRCA1 mRNA [[Three prime untranslated region|3' UTR]] can be bound by an miRNA, [[Mir-17 microRNA precursor family|Mir-17 microRNA]]. It has been suggested that variations in this miRNA along with [[Mir-30 microRNA precursor|Mir-30 microRNA]] could confer susceptibility to breast cancer.
 
In addition to breast cancer, mutations in the ''BRCA1'' gene also increase the risk of [[Ovarian cancer|ovarian]] and [[Prostate cancer|prostate cancers]]. Moreover, precancerous lesions ([[dysplasia]]) within the [[Fallopian tube]] have been linked to ''BRCA1'' gene mutations. Pathogenic mutations anywhere in a model pathway containing BRCA1 and BRCA2 greatly increase risks for a subset of leukemias and lymphomas.
 
Females who have inherited a defective BRCA1 or BRCA2 gene are at a greatly elevated risk to develop breast and ovarian cancer. Their risk of developing breast and/or ovarian cancer is so high, and so specific to those cancers, that many mutation carriers choose to have prophylactic surgery. There has been much conjecture to explain such apparently striking tissue specificity. Major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen. The target tissue may have receptors for the pathogen, may become selectively exposed to an inflammatory process or to a carcinogen. An innate genomic deficit in a tumor suppressor gene impairs normal responses and exacerbates the susceptibility to disease in organ targets. This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.
 
BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers. It has long been noted that loss of BRCA1 activity, either by germ-line mutations or by down-regulation of gene expression, leads to tumor formation in specific target tissues. In particular, decreased BRCA1 expression contributes to both sporadic and inherited breast tumor progression. Reduced expression of BRCA1 is tumorigenic because it plays an important role in the repair of DNA damages, especially double-strand breaks, by the potentially error-free pathway of homologous recombination. Since cells that lack the BRCA1 protein tend to repair DNA damages by alternative more error-prone mechanisms, the reduction or silencing of this protein generates mutations and gross chromosomal rearrangements that can lead to progression to breast cancer.
 
Similarly, BRCA1 expression is low in the majority (55%) of sporadic [[Ovarian cancer#Epithelial carcinoma|epithelial ovarian cancers (EOCs)]] where EOCs are the most common type of ovarian cancer, representing approximately 90% of ovarian cancers. In [[Ovarian cancer#Serous carcinoma|serous ovarian carcinomas]], a sub-category constituting about 2/3 of EOCs, low BRCA1 expression occurs in more than 50% of cases. Bowtell reviewed the literature indicating that deficient homologous recombination repair caused by BRCA1 deficiency is tumorigenic. In particular this deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy. Especially noted was that BRCA1 deficiency could be the cause of tumorigenesis whether due to BRCA1 mutation or any other event that causes a deficiency of BRCA1 expression.
 
=== Mutation of ''BRCA1'' in breast and ovarian cancer[edit | edit source] ===
Only about 3%–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2. Similarly, ''BRCA1'' mutations are only seen in about 18% of ovarian cancers (13% germline mutations and 5% somatic mutations).
 
Thus, while BRCA1 expression is low in the majority of these cancers, ''BRCA1'' mutation is not a major cause of reduced expression.
 
=== ''BRCA1'' promoter hypermethylation in breast and ovarian cancer[edit | edit source] ===
''BRCA1'' [[DNA methylation|promoter hypermethylation]] was present in only 13% of unselected primary breast carcinomas. Similarly, ''BRCA1'' promoter hypermethylation was present in only 5% to 15% of EOC cases.
 
Thus, while BRCA1 expression is low in these cancers, ''BRCA1'' promoter methylation is only a minor cause of reduced expression.
 
=== MicroRNA repression of BRCA1 in breast cancers[edit | edit source] ===
There are a number of specific [[MicroRNA#DNA repair and cancer|microRNAs]], when overexpressed, that directly reduce expression of specific DNA repair proteins (see [[MicroRNA#DNA repair and cancer|MicroRNA section DNA repair and cancer]]) In the case of breast cancer, microRNA-182 (miR-182) specifically targets BRCA1. Breast cancers can be [[Breast cancer classification|classified]] based on receptor status or histology, with triple-negative breast cancer (15%–25% of breast cancers), [[Breast cancer#HER2 and cancer|HER2+]] (15%–30% of breast cancers), [[Estrogen receptor#Cancer|ER+]]/[[Progesterone receptor|PR+]] (about 70% of breast cancers), and Invasive lobular carcinoma (about 5%–10% of invasive breast cancer). All four types of breast cancer were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue. In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression. Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182.
 
In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression. These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation. Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.
 
=== MicroRNA repression of BRCA1 in ovarian cancers[edit | edit source] ===
In both [[Ovarian cancer#Pathophysiology|serous tubal intraepithelial carcinoma]] (the precursor lesion to [[Ovarian cancer#Pathophysiology|high grade serous ovarian carcinoma (HG-SOC)]]), and in HG-SOC itself, miR-182 is overexpressed in about 70% of cases. In cells with over-expressed miR-182, BRCA1 remained low, even after exposure to ionizing radiation (which normally raises BRCA1 expression). Thus much of the reduced or absent BRCA1 in HG-SOC may be due to over-expressed miR-182.
 
Another microRNA known to reduce expression of BRCA1 in ovarian cancer cells is miR-9. Among 58 tumors from patients with stage IIIC or stage IV serous ovarian cancers (HG-SOG), an inverse correlation was found between expressions of miR-9 and BRCA1, so that increased miR-9 may also contribute to reduced expression of BRCA1 in these ovarian cancers.
 
=== Deficiency of ''BRCA1'' expression is likely tumorigenic[edit | edit source] ===
DNA damage appears to be the primary underlying cause of cancer, and deficiencies in DNA repair appears to underlie many forms of cancer. If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutational errors during [[DNA replication]] due to error-prone [[DNA repair#Translesion sythesis|translesion synthesis]]. Excess DNA damage may also increase [[Epigenetics|epigenetic]] alterations due to errors during DNA repair. Such mutations and epigenetic alterations may give rise to [[cancer]]. The frequent microRNA-induced deficiency of ''BRCA1'' in breast and ovarian cancers likely contribute to the progression of those cancers.


==HER2==
==HER2==

Revision as of 14:10, 19 April 2019


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2] Mirdula Sharma, MBBS [3]l; Ammu Susheela, M.D. [4]

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Overview

Laboratory studies play a crucial role in prevention, diagnosis, staging, treatment planning, management, determining prognosis and follow up of patients with breast cancer. Among them are single gene studies (i. e. BRCA1and 2, HER2), multiple gene panels (i.e. Oncotype DX), tumor markers (Ki67), and metastatic markers such as serum alkaline phosphatase as a marker of bone metastasis. A variety of other blood chemistry tests are also used in the management process of patients with breast cancer, among them are liver function tests (alanine aminotransferase (ALT), aspartate transaminase (AST) , bilirubin, alkaline phosphatase) and markers of kidney function (BUN, creatinine).

Blood chemistry

Blood chemistry tests measure certain chemicals in the blood. They show how well certain organs are functioning and can also be used to detect abnormalities. They are used to stage breast cancer. [1]

  • Increased levels could indicate that cancer has spread to the liver.
  • Increased levels could indicate that cancer has spread to the bone.
  • Tumor markers such as Ki67

BRCA1/BRCA2

Genetic markers, if present, suggest an increased likelihood of breast cancer occurrence.

BRCA1

Certain variations of the BRCA1 gene lead to an increased risk for breast cancer as part of a hereditary breast-ovarian cancer syndrome. Researchers have identified hundreds of mutations in the BRCA1 gene, many of which are associated with an increased risk of cancer. Females with an abnormal BRCA1 or BRCA2 gene have up to an 80% risk of developing breast cancer by age 90; increased risk of developing ovarian cancer is about 55% for females with BRCA1 mutations and about 25% for females with BRCA2 mutations.

These mutations can be changes in one or a small number of DNA base pairs (the building-blocks of DNA), and can be identified with PCR and DNA sequencing.[citation needed]

In some cases, large segments of DNA are rearranged. Those large segments, also called large rearrangements, can be a deletion or a duplication of one or several exons in the gene. Classical methods for mutation detection (sequencing) are unable to reveal these types of mutation. Other methods have been proposed: traditional quantitative PCR, Multiplex Ligation-dependent Probe Amplification (MLPA), and Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF). Newer methods have also been recently proposed: heteroduplex analysis (HDA) by multi-capillary electrophoresis or also dedicated oligonucleotides array based on comparative genomic hybridization (array-CGH).

Some results suggest that hypermethylation of the BRCA1 promoter, which has been reported in some cancers, could be considered as an inactivating mechanism for BRCA1 expression.

A mutated BRCA1 gene usually makes a protein that does not function properly. Researchers believe that the defective BRCA1 protein is unable to help fix DNA damage leading to mutations in other genes. These mutations can accumulate and may allow cells to grow and divide uncontrollably to form a tumor. Thus, BRCA1 inactivating mutations lead to a predisposition for cancer.[citation needed]

BRCA1 mRNA 3' UTR can be bound by an miRNA, Mir-17 microRNA. It has been suggested that variations in this miRNA along with Mir-30 microRNA could confer susceptibility to breast cancer.

In addition to breast cancer, mutations in the BRCA1 gene also increase the risk of ovarian and prostate cancers. Moreover, precancerous lesions (dysplasia) within the Fallopian tube have been linked to BRCA1 gene mutations. Pathogenic mutations anywhere in a model pathway containing BRCA1 and BRCA2 greatly increase risks for a subset of leukemias and lymphomas.

Females who have inherited a defective BRCA1 or BRCA2 gene are at a greatly elevated risk to develop breast and ovarian cancer. Their risk of developing breast and/or ovarian cancer is so high, and so specific to those cancers, that many mutation carriers choose to have prophylactic surgery. There has been much conjecture to explain such apparently striking tissue specificity. Major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen. The target tissue may have receptors for the pathogen, may become selectively exposed to an inflammatory process or to a carcinogen. An innate genomic deficit in a tumor suppressor gene impairs normal responses and exacerbates the susceptibility to disease in organ targets. This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.

BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers. It has long been noted that loss of BRCA1 activity, either by germ-line mutations or by down-regulation of gene expression, leads to tumor formation in specific target tissues. In particular, decreased BRCA1 expression contributes to both sporadic and inherited breast tumor progression. Reduced expression of BRCA1 is tumorigenic because it plays an important role in the repair of DNA damages, especially double-strand breaks, by the potentially error-free pathway of homologous recombination. Since cells that lack the BRCA1 protein tend to repair DNA damages by alternative more error-prone mechanisms, the reduction or silencing of this protein generates mutations and gross chromosomal rearrangements that can lead to progression to breast cancer.

Similarly, BRCA1 expression is low in the majority (55%) of sporadic epithelial ovarian cancers (EOCs) where EOCs are the most common type of ovarian cancer, representing approximately 90% of ovarian cancers. In serous ovarian carcinomas, a sub-category constituting about 2/3 of EOCs, low BRCA1 expression occurs in more than 50% of cases. Bowtell reviewed the literature indicating that deficient homologous recombination repair caused by BRCA1 deficiency is tumorigenic. In particular this deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy. Especially noted was that BRCA1 deficiency could be the cause of tumorigenesis whether due to BRCA1 mutation or any other event that causes a deficiency of BRCA1 expression.

Mutation of BRCA1 in breast and ovarian cancer[edit | edit source]

Only about 3%–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2. Similarly, BRCA1 mutations are only seen in about 18% of ovarian cancers (13% germline mutations and 5% somatic mutations).

Thus, while BRCA1 expression is low in the majority of these cancers, BRCA1 mutation is not a major cause of reduced expression.

BRCA1 promoter hypermethylation in breast and ovarian cancer[edit | edit source]

BRCA1 promoter hypermethylation was present in only 13% of unselected primary breast carcinomas. Similarly, BRCA1 promoter hypermethylation was present in only 5% to 15% of EOC cases.

Thus, while BRCA1 expression is low in these cancers, BRCA1 promoter methylation is only a minor cause of reduced expression.

MicroRNA repression of BRCA1 in breast cancers[edit | edit source]

There are a number of specific microRNAs, when overexpressed, that directly reduce expression of specific DNA repair proteins (see MicroRNA section DNA repair and cancer) In the case of breast cancer, microRNA-182 (miR-182) specifically targets BRCA1. Breast cancers can be classified based on receptor status or histology, with triple-negative breast cancer (15%–25% of breast cancers), HER2+ (15%–30% of breast cancers), ER+/PR+ (about 70% of breast cancers), and Invasive lobular carcinoma (about 5%–10% of invasive breast cancer). All four types of breast cancer were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue. In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression. Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182.

In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression. These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation. Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.

MicroRNA repression of BRCA1 in ovarian cancers[edit | edit source]

In both serous tubal intraepithelial carcinoma (the precursor lesion to high grade serous ovarian carcinoma (HG-SOC)), and in HG-SOC itself, miR-182 is overexpressed in about 70% of cases. In cells with over-expressed miR-182, BRCA1 remained low, even after exposure to ionizing radiation (which normally raises BRCA1 expression). Thus much of the reduced or absent BRCA1 in HG-SOC may be due to over-expressed miR-182.

Another microRNA known to reduce expression of BRCA1 in ovarian cancer cells is miR-9. Among 58 tumors from patients with stage IIIC or stage IV serous ovarian cancers (HG-SOG), an inverse correlation was found between expressions of miR-9 and BRCA1, so that increased miR-9 may also contribute to reduced expression of BRCA1 in these ovarian cancers.

Deficiency of BRCA1 expression is likely tumorigenic[edit | edit source]

DNA damage appears to be the primary underlying cause of cancer, and deficiencies in DNA repair appears to underlie many forms of cancer. If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations may give rise to cancer. The frequent microRNA-induced deficiency of BRCA1 in breast and ovarian cancers likely contribute to the progression of those cancers.

HER2

  • ERBB2 is a gene that has changed (mutated) so it helps a tumor grow oncogene. It is more commonly known as HER2 (or HER2/neu). HER2 stands for human epidermal growth factor receptor 2.[1]
  • HER2 status testing is done to find out the amount of HER2 produced by a breast tumor.

Multiple gene panels

  • Oncotype DX®
  • MammaPrint®

References

  1. 1.0 1.1 Breast cancer. Canadian Cancer Society (2015) http://www.cancer.ca/en/cancer-information/cancer-type/breast/signs-and-symptoms/?region=on#ixzz3xScycfqv Accessed on January 16, 2016

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