Mutation in BRCA Gene substantially Increases the Risk of Breast Cancer in both Female and Male

An article published in Mail Online about the story of a young lady, who in spite of regular screening for breast cancer, preferring for prophylactic mastectomy before the age of 31, discovered that she is already harboring a 6 cm tumor in her breast. The article can be accessed here.

Emma Cunliffe has mutated BRCA (BReast CAncer) gene that dramatically increases the risk of cancers; breast and ovarian cancer in particular.

Her mother and grandmother both had been diagnosed in their early 30s for breast cancer. Now, she plans to have her ovaries removed after having a family.

Role of BRCA genes:

Faults or breaks develop in the DNAs (Deoxyribonucleic Acid) that house several genes, may be following repeated divisions or other environmental factors like radiation. The primary responsibility of the BRCA gene is to signal for a protein that can repair the defects in the genes in association with some other proteins. Both BRCA 1 and BRCA 2 protein interact with the protein produced by the RAD51 and PALB 2 gene to mend breaks in DNAs.

BRCA 1 gene encodes a nuclear phosphoprotein that acts as a tumour suppressor. The encoded protein combines with other tumour suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination.

Mutated forms of the genes produce a protein that is not perfect; hence, cannot do the repair work. This leaves the cells multiply uncontrollably, without check.

Apart from breast cancer, mutations in the BRCA1 gene also increase the risk of ovarian cancer, prostate cancer, and colon cancer. The BRCA1 gene is located on chromosome 17q21 -- the long (q) arm of chromosome 17 at position 21.

BRCA 2 gene is located on the chromosome 13q12.3; on the long (q) arm of chromosome 13 at position 12.3.

Heredity - autosomal dominant (AD) (Photo credit: Wikipedia)

Risk to Women having mutated BRCA 1 & 2 genes:

A woman’s lifetime risk of developing breast and/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2.

·         Breast cancer: About 12 percent of women in the general population will develop breast cancer sometime during their lives. By contrast, 55 to 65 percent of women who inherit a harmful BRCA1 mutation and around 45 percent of women who inherit a harmful BRCA2 mutation will develop breast cancer by age 70 years.

These genes also increase breast cancer risk in men. 

·         Ovarian cancer: About 1.4 percent of women in the general population will develop ovarian cancer sometime during their lives. By contrast, 39 percent of women who inherit a harmful BRCA1 mutation and 11 to 17 percent of women who inherit a harmful BRCA2 mutation will develop ovarian cancer by age 70 years.

Types of faulty genes:

The first breast cancer gene faults to be found were BRCA1 and BRCA2.  There are other genes that significantly increase a woman's risk of breast cancer. They are called TP53 and PTEN. Tests are available for the following genes;

·     BRCA1

·     BRCA2

·     TP53

·     PTEN genes

Researchers have found other common genes that can slightly increase a woman's risk of developing breast cancer. No tests are available for these genes yet but they include

·     CASP8

·     FGFR2

·     TNRCP

·     MAP3K1

·     rs4973768

·     LSP1

Rare genes that can also increase breast cancer risk slightly include

·     CHEK2

·     ATM (ataxia telangiectasia mutated)

·     BRIP1

·     PALB2

No individual tests are available for these genes yet.

Who all need to be screened for defective genes?

·         Breast cancer diagnosed before age 50 years

·         Ovarian cancer

·         Cancer in both breasts

·         Both breast and ovarian cancers

·         Multiple breast cancers

·         Two or more primary types of BRCA1- or BRCA2-related cancers in a single family member

·         Cases of male breast cancer

·         Ashkenazi Jewish ethnicity

·         Triple-negative (estrogen receptor negative, progesterone receptor negative, and HER2/neu negative) breast cancer

·         Pancreatic cancer with breast or ovarian cancer in the same individual or on the same side of the family

·         Two or more relatives with breast cancer, one under age 50

·         Three or more relatives with breast cancer at any age

·         A previously identified BRCA1 or BRCA2 mutation in the family

In the instant case, MRI could not detect it as it was of a cotton-wool consistency; it was reported.

Recommendation:

In these high risk women;

1.     Breast Self Examination (BSE) should start as age of 20

2.     Clinical Breast Examination (CBE) by a heath care person at the same age

3.      Contrast MRI and Mammogram, both, not anyone, should start from 25 years or 10 years before the age at which the breast cancer in family member is detected; but not before the age of 15.

Contrast MRI and Mammogram both act as complimentary, as MRI is more sensitive, but less specific, gives more unnecessary warnings; Mammography, can even detect some tumors which MRI cannot.

This information is not at all a substitute for the opinion of your consultant.

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