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Genetic Mutation Types

As science continues to evolve so does our understanding of genetic mutations that can increase an individuals risk of developing breast and ovarian cancers.

Beyond the most commonly known BRCA, there are several other mutations which have varying lifetime risk. All of these mutations can be inherited through both parents – male or female.

 

BRCA1 & BRCA2

The two most common genetic mutations associated with hereditary breast and ovarian cancers are BRCA1 and BRCA2. Inherited from either your mother, or your father, an individual who carries either a BRCA1 or BRCA2 mutation has an increased risk of ovarian cancer in women, prostate cancer in men, and breast, melanoma and pancreatic cancer in both sexes. Carriers also have a 50:50 (or 1 in 2) risk of handing it on to his or her children, male or female.

Breast Cancer

Women who inherit the BRCA1 or BRCA2 mutation but have never had a diagnosis of cancer have an increased risk of breast cancer. Whilst every individuals risk is unique, the estimated lifetime risk ranges from 55-80%.

Differing research indicates that the risk can vary between mutations, for instance, a woman with BRCA1 mutation has up to a 65% risk of developing breast cancer by age of 70 and a 45% risk for individuals carrying the BRCA2 mutation. Comparatively, another study indicated that the lifestyle risk for a woman with BRCA1 was 64% versus 56% for women with a BRCA2 mutation. This study utilised “meta-analysis” to determine the lifetime risk.

Ovarian Cancer

Similar to breast cancer studies, various ovarian cancer risk studies in diverse populations have revealed differences in risk estimates. One study, which combined results from a number of smaller research studies indicated the average risk for a woman with BRCA1 to be a 55% lifetime risk, compared to a 31% lifetime risk for BRCA2 carriers.

Another study looking at BRCA1 and 2 mutations common in Ashkenazi Jewish populations suggests the risk could be 54% for BRCA1 carriers and as low as 23% for BRCA2 mutations, whilst another study that looked more broadly and not just at families with a Jewish heritage found the risk comparatively lower, with a 39%  risk for BRCA1 carriers, compared to 11% of BRCA2 carriers by the age of 70.

Despite variations in the estimated risk of a BRCA1/2 mutation, all studies indicate that the risk of ovarian cancer in all BRCA carriers begins after the age of 30, whilst the greatest risk occurs after 40 for BRCA1 mutation carriers, and age 50 for BRCA2 mutation carriers.

Breast Cancer In Men

Male BRCA mutation carriers also carry an increased risk of breast cancer compared to the general male population, however this risk still remains fairly low. Several studies indicate the lifetime risk to be at about 2% with BRCA1, and 8% for men who carry a BRCA2 mutation.

The average male who does not carry a hereditary gene fault has a 0.1% risk of developing breast cancer or a 1 in 1000 risk.

Prostate cancer

Males who carry the BRCA gene mutation have a 15-25% risk of developing prostate cancer in their lifetime, much higher than the average population.

Males who carry the BRCA gene mutation generally contract the disease at a younger age, and the cancer may be more aggressive and therefore life threatening than prostate cancer in men who do not carry a gene fault.

Pancreatic Cancer

The risk for BRCA mutation carriers to develop pancreatic cancer is considered to be a lifetime risk of 5% compared to 1.5% in the general population. The risk of developing pancreatic cancer is increased for BRCA2 carriers, compared to those who have BRCA1.

 

Treatment Options

If you do have a BRCA mutation, your doctor should recommend bilateral risk-reducing mastectomy, followed by self-surveillance of the breast area, if there is a strong family history of breast cancer in women diagnosed under 50 years of age.

High risk surveillance by yearly breast MRI plus mammogram +/- breast ultrasound is recommended from age 30 – 50, with yearly mammogram +/- breast ultrasound + clinical breast examination after age 50 years.

The age to begin surveillance should be individualised depending on the family history of breast cancer in close relatives. The aim of high-risk screening is to ensure that breast cancers are detected at an earlier stage and therefore have a better prognosis and are easier to treat.

Medication such as Tamoxifen may also be an option to reduce the risk of developing breast cancer in women who carry a mutation in the BRCA gene, but careful assessment of the risks and benefits for an individual woman by an experienced doctor is important when considering the use of such medication.

For more information on risk reducing options, you can read more here.

If you think your family may be a carrier of the BRCA1 or BRCA2 gene, please connect with our genetic counsellor service here. If you’re unfamiliar with the role of a genetic counsellor, you can learn more here.

PALB2

Whilst BRCA1 and 2 are the most common of the genetic mutations that can raise the risk of breast and/or ovarian cancer, PALB2 is yet another mutation that can also result in an increased risk of breast cancer.

The PALB2 gene normally protects us from breast cancer. It contains instructions to make a protein that works with the Breast Cancer 1 and 2 (BRCA1 and BRCA2) genes to repair changes in the DNA code and prevent tumour growth.

A gene is a piece of the DNA code that we inherit from our parents and could come from either our mother or our father. We have over 20,000 genes in all and we inherit two copies of each gene, one from our mother and one from our father. Each gene contains a specific set of instructions to help all the cells in our bodies to develop and function normally.

When a gene like PALB2 is inherited and mutated, it may lead to the faulty cell growth and/or function, so someone with a gene alteration has a higher chance of developing certain types of cancer over their lifetime.

Someone who inherits the mutated copy of PALB2 gene has a 33% - 55% chance of developing a breast cancer by the age of 70 years depending on their family history, and a 50:50 (or 1 in 2) risk of handing it on to his or her children, male or female.

In addition, there may be a small increased risk of developing pancreatic cancer and possibly breast cancer in males. It remains unclear if the PALB2 gene mutation also increases the risk for ovarian cancer.

If you do have a PALB2 mutation, your doctor should recommend bilateral risk-reducing mastectomy, followed by self-surveillance of the breast area, if there is a strong family history of breast cancer in women diagnosed under 50 years of age. High risk surveillance by yearly breast MRI plus mammogram +/- breast ultrasound is recommended from age 30 – 50, with yearly mammogram +/- breast ultrasound + clinical breast examination after age 50 years.

The age to begin surveillance should be individualised depending on the family history of breast cancer in close relatives. The aim of high-risk screening is to ensure that breast cancers are detected at an earlier stage and therefore have a better prognosis and are easier to treat.

Medication such as Tamoxifen may also be an option to reduce the risk of developing breast cancer in women who carry a mutation in the PALB2 gene, but careful assessment of the risks and benefits for an individual woman by an experienced doctor is important when considering the use of such medication.

If you think your family may be a carrier of the PALB2 gene, please connect with our genetic counsellor service here. If you’re unfamiliar with the role of a genetic counsellor, you can learn more here.

ATM

The ATM Genetic Mutation is another gene mutation that can be detected via genetic testing, with inherited mutations in the ATM (Ataxia-Telangiectasia mutated) gene associated with an increased risk of certain cancers.

Individuals who inherit a mutated copy of ATM from either parent, are at an increased risk of female breast cancer (up to 52% lifetime risk) as well as at an increased risk of pancreatic, prostate and other cancers.

Like other genetic mutations, people with this mutation can opt for either high-risk screening or even consider risk-reducing mastectomy based on their personal and family history of cancer.

In the unlikely event that an individual was to inherit a mutated copy of the ATM gene from both parents, it can cause a rare childhood disease called Ataxia-Telangiescatasia (AT). Children with AT have progressive neurodegeneration, difficulty fighting infections and have an increased risk of cancer.

If you are concerned that you may be at risk of carrying the ATM mutation, we recommend consulting with our genetics expert who can assess your personal and family history of cancer and help you to determine the best personalised approach to manage your health.

If you’re unfamiliar with the role of a genetic councillor, you can learn more here.

CDH1 (Hereditary Diffuse Gastric Cancer Syndrome)

Genetic testing can reveal a mutation known as CDH1. This mutation is associated with hereditary diffuse gastric cancer syndrome, which is known to increase the risk of stomach cancer (by up to 80% in a lifetime) along with lobular breast cancer in women (up to 52% in a lifetime).

Carriers of the CDH1 mutation tend to develop cancer at a younger age than those with an average cancer risk. Whilst there continues to be research into the risks and best management for carriers of the CDH1 genetic mutation, it is recommended that individuals speak to their doctors to best understand their personalised treatment plan options, which may include but not be limited to high risk screening from age 30 years (annual breast MRI +/- +/- ultrasound +/- mammogram + clinical breast examination at a high-risk breast clinic) and risk reducing mastectomy. Preventative gastrectomy (an operation to remove the stomach) is recommended after the age of 20, or earlier depending on family history, as there is no evidence for the long-term benefit of surveillance for gastric cancer.

A genetics expert can look at your personal and family medical history and see if it is consistent with hereditary diffuse gastric cancer syndrome and order testing if appropriate. Individuals with hereditary diffuse gastric cancer need multidisciplinary care and should be looked after by an experienced centre.

CHEK2 (Checkpoint Kinase 2)

CHEK2 is a genetic mutation which can be linked to an increased risk of cancer. Women with certain mutations in the CHEK2 gene have an increased lifetime risk of breast cancer. This risk is correlated with family history, increasing when carriers have close relatives who have had breast cancer, and may be as high as 44%. Men who carry the mutation may be at increased risk for breast and prostate cancers.

Both men and women with a CHEK2 mutation may also be at increased risk of colon cancer and other cancers, however research into the precise risks of developing these cancers in individuals with CHEK2 mutations is ongoing.

A genetics expert can look at your personal and family medical history and see if it is consistent with a CHEK2 mutation and order testing if appropriate. If you’re unfamiliar with the role of a genetic counsellor, you can learn more here.

NBN

A number of studies have shown that people who inherit a mutated copy of NBN from one parent are at an increased risk of female breast or male prostate cancer. Ongoing research is still being done to better understand the associated cancer risks and subsequent treatment options for patients.

Patients who carry an NBN mutation should work directly with their doctor to determine the best personalised treatment plan for them. We also recommend that potential NBN carriers consult with a genetics expert who can assess your personal and family history of cancer and can help you to determine the best risk-management plan.

Inheriting a mutated copy of the NBN gene from both parents could result in a rare childhood disease called Nijmegen Breakage Syndrome (NBS). Children with NBS experience slow growth, have difficulty fighting infections and are at an increased risk of other childhood cancers.

NF1

Genetic testing can find mutations in a gene called Neurofibromatosis type 1 (NF1), which is linked to an increased risk of tumours of the nervous system and rare tumours of the gastrointestinal system known as gastrointestinal stromal tumours (GIST).

Women who are known carriers of the NF1 mutation are also at an increased risk of breast cancer with a lifetime risk of 18%. In families with a history of breast cancer under age 35 years individualised screening may be recommended, but generally high-risk screening is recommended from age 35 years by annual breast MRI +/- mammogram +/- ultrasound until age 50 years, and 2 yearly mammogram +/- ultrasound after age 50 years. Mammography should not be performed during pregnancy.

Because NF1 can be associated with other types of tumours, people who test positive for a NF1 mutation should consult with a genetics specialist for advice about how best to manage their health and reduce their cancer risk.

PTEN (Cowden Syndrome)

Carriers of the PTEN genetic mutation are associated with a cluster of diseases known collectively as PTEN hamartoma tumour syndrome. One of these, Cowden Syndrome is known to greatly increase the risk of certain cancers including:

• Female breast cancer (uncertain but greater than 30% lifetime risk)

• Uterine cancer (increased, may be greater than 10% lifetime risk)

• Thyroid cancer (increased, may be greater than 10% lifetime risk)

• Kidney cancer (increased, may be greater than 10% lifetime risk)

Cowden syndrome is also associated with benign (noncancerous) tumours in the thyroid, uterus (fibroids), and gastrointestinal tract (polyps).  There can also be an excess of autism and autism-like features in PTEN families.

Preventative health measures a PTEN individual can take can include, but not be limited to:

• High risk breast screening using MRI and/or MRI and/or ultrasound and/or mammogram every 12 months beginning at age 30 or earlier based on family history

• Risk-reducing mastectomy (removal of breast tissue) followed by self-surveillance of breast area

• Hysterectomy after completion of childbearing. There is no evidence for surveillance by trans-vaginal ultrasound and/or endometrial biopsy

• Thyroid: annual clinical examination starting at age 5 years. Imaging is not recommended unless nodules are present on examination.

• Kidney: consider renal ultrasound every 2 years from age 40 years

• Bowel polyps: consider baseline colonoscopy at age 35-40 years and then every 5 years after that, or more frequently if polyps are found

A genetics expert can look at your personal and family medical history to see if it is consistent with Cowden syndrome and order testing if appropriate.

SKT11

Inherited mutations in the SKT11 gene are associated with Peutz-Jeghers syndrome (PJS), a rare disorder that leads to an increased risk of noncancerous growths and increased risk of certain cancers.

People with PJS are at a greatly increased risk of:

• Breast cancer in women (up to 45% by age 70 years)

• Colon cancer (up to 39% by age 70 years)

• Pancreatic cancer (up to 26% by age 70 years)

• Stomach cancer (up to 29% by age 65 years)

• Gynaecological cancers (up to 18% by age 70 years)

• Small intestine cancer (up to 13% by age 65 years)

People with PJS also tend to develop noncancerous polyps in the stomach and intestine. Children with this syndrome often have dark spots in or near the mouth, eyes, nostrils and/or fingers.

Personalised treatment for those with the inherited STK11 mutations could include but not be limited to:

• Heightened screening for breast cancer in women as described for PALB2 and NF1 above

• Gastroduodenoscopy and colonoscopy every 3 years, and either video capsule endoscopy, magnetic resonance endoscopy or barium follow through every 3 years, starting at age 30 years

• Referral to a gynaecological oncologist or gynaecologist for a yearly pelvic examination and endocervical smear test from the age of 18 years

A genetics expert can look at your personal and family medical history and see if it is consistent with PJS and order testing if appropriate. If you’re unfamiliar with the role of a genetic counsellor, you can learn more here.

TP53 (Li-Fraumeni Syndrome)

Li-Fraumeni syndrome is a rare hereditary cancer syndrome associated with inherited mutations in the TP53 gene, sometimes referred to as P53.

Li-Fraumeni syndrome is associated with a number of different young-onset cancers.  Individuals with traditional Li-Fraumeni syndrome have up to a 90% risk of developing cancer by age 60 and are also at risk for developing various different cancers over their lifetimes.

Increased cancer risk associated with Li-Fraumeni syndrome include:

• Pre-menopausal breast cancer

• Connective tissue cancer (sarcoma)

• Bone cancer

• Adrenal cancer

• Pancreatic cancer

• Colon cancer

• Liver cancer

• Childhood cancers

• Brain tumours

• Leukemia

Preventative health options to manage TP53 can include, but not be limited to:

• Avoidance of radiation whenever possible

• Preventative bilateral mastectomy before age 50 years followed by self-surveillance of the breast area.

• High-risk screening for breast cancer by annual breast MRI and breast exam in women beginning at age 20 or earlier based on family history

• Discussing the option of risk-reducing mastectomy

• Annual physical, skin, and neurologic exams

• Annual brain MRI

• Annual whole-body MRI

• Colonoscopy every 2 to 5 years from age 20 years or younger depending on family history

• Gastroscopy every 2 to 5 years from age 25 years or younger if there is a family history of gastric cancer

• Annual review and physical examination by a clinician with appropriate expertise

• Alerting paediatricians to the risk of childhood cancers in the family

A genetics expert can look at your personal and family medical history and see if it is consistent with Li-Fraumeni syndrome and order testing if appropriate. If you’re unfamiliar with the role of a genetic counsellor, you can learn more here.

Lynch syndrome (MLH1, MSH2, MSH6, PMS2, or EPCAM)

Lynch syndrome (also sometimes called hereditary nonpolyposis colorectal cancer, or HNPCC) is hereditary and affects 1 in 500-1,000 people.

Inherited mutations in the MLH1, MSH2, MSH6, PMS2 genes, or certain mutations in the EPCAM gene, are associated with Lynch syndrome.

Increased cancer risks are associated with Lynch syndrome and can include:

• Colon (38% to age 70 years)

• Uterine (33% to age 70 years)

• Ovarian cancers (up to 15%to age 70 years)

• Gastric cancers (6% to age 70 years)

• Urinary tract cancer (<3% to age 70 years)

• Small bowel cancer (<3% to age 70 years)

The exact increase in risk for each cancer varies depending on the specific Lynch syndrome gene mutation, and recommendations for surveillance and risk reduction should be tailored to the gene involved in consultation with your doctor and health care team.

There is currently no definite evidence that Lynch syndrome mutations are associated with an increased risk of breast cancer and research in this area is ongoing. Hormone replacement therapy (HRT) after surgical removal of the ovaries to reduce ovarian cancer risk in women is therefore not contraindicated.

Management options for individuals carrying the Lynch Syndrome is dependent upon the specific inherited mutation that is associated with Lynch syndrome. We recommend consulting with a genetics expert to understand your exact risk and risk management options. If you’re unfamiliar with the role of a genetic counsellor, you can learn more here.