Welcome to GG Hospital Fertility and Women's Speciality Centre.

Short background on breast cancer

Most women who get breast cancer do not have any family history of breast cancer. Just because a family member had breast cancer does not always mean that you will get breast cancer.

We do know that there are some genes associated with a known increased risk of breast cancer. These are BRCA 1 (breast cancer 1, early onset human tumor suppressor gene) and BRCA 2 (breast cancer type 2, susceptibility protein). Only 10 percent of women with breast cancer have these inherited genes. These women usually get breast cancer at a young age and have multiple family members with breast or ovarian cancer.

Fewer than 3 out of every 100 breast cancers (3%) are caused by an inherited faulty gene. There are a group of genes that increase the risk of breast cancer and can be tested for, a few enlisted below are –

  • BRCA1 and BRCA2
  • TP53 and PTEN

If you are known to have a gene that increases breast cancer risk, your specialist may suggest that you have regular screening.

BRCA1 and BRCA2 genes

Between 45 and 90 women out of 100 (45 to 90%) with a faulty BRCA1 or BRCA2 gene develop breast cancer during their lifetime. Faulty BRCA1 and 2 genes are rare. But they can also increase the risk of other cancers such as ovarian cancer, pancreatic and prostate cancer.

TP53 and PTEN

Faults in TP53 and PTEN mutations are rarer than BRCA1 and BRCA2 mutations.

The TP53 gene normally controls when a cell divides. It is a type of tumor suppressor gene. It causes breast cancer as part of a rare cancer syndrome called Li Fraumeni syndrome. It causes less than 1 in 100 (1%) of all breast cancers diagnosed.

PTEN is the gene fault in a rare condition called Cowden syndrome. It increases your risk of breast cancer.

Advances in molecular genetics have led to the identification of numerous genes associated with inherited susceptibility to breast and/or ovarian cancer. Approximately 5-10% of all cases of breast cancer and ~25% of all cases of ovarian cancer are associated with a cancer predisposition gene.

BRCA1 and BRCA2 function

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function, although some missense mutations cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on one copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome.

In most breast and ovarian cancers that have been studied from mutation carriers, deletion of the normal allele results in loss of all function, leading to the classification of BRCA1 and BRCA2 as tumor suppressor genes. In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in myriad functions within cells, including homologous DNA repair, genomic stability, transcriptional regulation, protein ubiquitination, chromatin remodeling, and cell cycle control.

Venkataraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108 (2): 171- 82, 2002.

Narod SA, Foulkes WD: BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4 (9): 665-76, 2004.

WHY

  • Development of a treatment plan that is likely to reduce cancer risk in individuals who test positive. This may include facilitating difficult medical decisions, like whether or not to have prophylactic mastectomy or oophorectomy.
  • The opportunity to design a personalized cancer screening program, tailored to individual risk
  • Understanding the source of cancer risk in the family, and following the latest research on possible interventions.
  • Making information available for adult children, and children as they become adults.
  • Improved ability to cope with cancer risk, since the risk could be better defined and understood through genetic testing. Some individuals with a known mutation in their family will learn they did not inherit a gene mutation and are not at high risk in spite of their strong family history of cancer. Some individuals will learn they did inherit a gene mutation and will then have more information to alter their cancer risk management

WHEN

BRCA1/2 testing maybe considered for individuals with a personal or family history of any of the following:

  • Early-onset breast cancer (<45 years-of-age) or bilateral breast cancer
  • Two primary breast cancers or clustering of breast and ovarian cancer
  • Presence of male breast cancer
  • Ovarian cancer at any age

TAGLINE: Establishing a molecular diagnosis can help guide preventative measures, direct surgical options and estimate personal and familial cancer risk!!!

WHO ALL SHOULD BE TESTED

The following individuals have an increased risk for hereditary breast and ovarian cancer and are appropriate candidates for BRCA1/2 testing

  1. An individual diagnosed with breast cancer, with one or more of the following:
    • Diagnosed ≤age 45
    • Two primary breast cancers with the first diagnosed ≤age 50
    • Diagnosed ≤ age 50 with ≥1 close* relative with breast cancer at any age or limited family history
    • Diagnosed ≤age 60 with triple negative disease
    • Diagnosed at any age with ≥1 close* relative with breast cancer ≤ age 50
    • Diagnosed at any age and ≥2 close* relatives with breast cancer at any age
    • Diagnosed at any age with ≥1 close* relative with epithelial ovarian, fallopian tube or primary peritoneal cancer
    • Diagnosed at any age and ≥2 close* relatives with pancreatic cancer or aggressive prostate cancer at any age
    • Close* male relative with breast cancer diagnosed at any age
    • Diagnosed at any age and of Ashkenazi Jewish ancestry, OR
  2. Any woman diagnosed with epithelial ovarian, fallopian tube or primary peritoneal cancer at any age, OR
  3. Male with breast cancer at any age, OR
  4. An individual with a personal history of pancreatic cancer or aggressive prostate cancer and ≥2 close* relatives with breast and/or ovarian, fallopian tube or primary peritoneal cancer and/or pancreatic or aggressive prostate cancer, OR
  5. An individual without a personal history of BRCA1/2-related cancer with a close* relative meeting the above criteria.

In some cases, limited family history may not allow for evaluation of these criteria. Limited family history is typically defined as <2 first- or second-degree female relatives living beyond 45 years on the same side of the family.*Close blood relatives include first, second and third-degree relatives on the same side of the family

Explain that once a mutation is detected and confirmed, testing in relatives is relatively cheap.

If a mutation is detected and confirmed, then testing his/her relatives will be relatively cheap since the mutation is already known, hence focusing on the mutation confirmed. Cost of running the test with a known mutation is cheaper.

What does a negative BRCA1 or BRCA2 test result mean?

A negative test result can be more difficult to understand than a positive result because what the result means depends in part on an individual’s family history of cancer.
If a close (first- or second-degree) relative of the tested person is known to carry a harmfulBRCA1 or BRCA2 mutation, a negative test result is clear: it means that person does not carry the harmful mutation and cannot pass it on to their children. Such a test result is called a “true negative.” A person with such a test result has the same risk of cancer as someone in the general population.

If the tested person has a family history that suggests the possibility of having a harmful mutation in BRCA1 or BRCA2 but no such mutation has been identified in the family, a negative result is less clear. The likelihood that genetic testing will miss a known harmful BRCA1 orBRCA2 mutation is very low, but it could happen.

It is also possible for people to have a mutation in a gene other than BRCA1 or BRCA2 that increases their cancer risk but is not detectable by the test used. In this case, we would suggest to do a Germ line Cancer panel which will help in confirming the negative test result.

Germ line Cancer Panel

A saliva-based DNA test to detect cancer predisposition.

The Germline Test is a 86 gene panel that identifies genomic markers implicated in cancer predisposition on proven next-generation sequencing technology.

It targets the coding region of significant genes such as BRCA1, BRCA2, TP53 and many other genes associated with common (e.g., breast, colorectal) and rare cancers. A small amount of saliva is sufficient to perform the Germline Test.

Courtesy: Supratech

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