HC5: Hereditary aspects of cancer

Risk of developing cancer

The chance of getting cancer increases with age:

• 8% by the age of 65
• 25% by the age of 80
• 32% by the age of 100

If someone has a sibling with breast cancer and is 40-50 years old, the chance of developing breast cancer is 2x as high as usual. In case of colon cancer, the cancer is 3x as high. Among monozygotic twins, the risk is higher → genetic factors play an important role in the risk of developing cancer.

Breast cancer

Genetic factors:

There are 14.000 new diagnoses of breast cancer per year in the Netherlands, of which 3.500 die every year. 13% have a first degree relative.

Genetic factors play a role in whether or not someone develops breast cancer:

• High/medium penetrant genes
• Low penetrant genes/loci/SNPs

There are 200 SNPs (single nucleotide polymorphisms) that increase the risk of breast cancer → per SNP, the increase is 0,1%, but multiple SNPs can be present at the same time.

Genetic counseling:

Genetic counseling is useful to:

• Recognize patients and their families with inheritable cancer
• Improve morbidity and mortality by early recognition and treatment
• Psychosocial guidance and advice

Cancer syndromes:

Many cancer-causing genes have been discovered. Examples are:

• RB gene
• APC gene
• Mismatch repair genes
• BRCA1 and BRCA2
• CDKN2A
• MUTYH
• BAP1

Criteria for genetic testing:

1 of the following situations has to be present to test for genetic breast cancer (BRC):

• BRC occurs at <40 years
• Bilateral BRC or multiple tumors in 1 breast with 1 tumor <50 years
• First grade male with BRC
• BRC <50 years and prostate cancer <60 years in the same branch of family
• BRC <50 years and 1 or more first degree with BRC <50 years
• BRC and 2 or more first and/or second degrees with BRC, of which at least 1 <50 years
• Ovarian cancer irrespective of age
  • Have a 10% risk of a germline BRCA1 or BRCA2 mutation

BRCA1 and BRCA2:

BRCA1 and BRCA2 mutations are associated with inheritable breast cancer. They are DNA-repair genes. Chances of developing cancer if 1 of these mutated genes is present are high:

• Breast cancer
  • BRCA1: 60-80%
  • BRCA2: 60-80%
• Ovarian cancer
  • BRCA1: 30-60%
  • BRCA2: 5-20%

BRCA mutation carriers undergo different types of surveillance, starting at early age:

• Breast surveillance
  • 25-60 years: yearly MRI
  • 25-60 years: clinical breast examination
  • 30-60 years: yearly mammography
  • 60-75 years: population screening
• Ovaries
  • 35-40 years: prophylactic adnex extirpation
    • Ovaries and fallopian tubes are removed

For males with a BRCA2 gen, the risk of developing prostate cancer is 2-4x as high.

They undergo a blood test for PSA at the GP, every 2 years starting at the age of 45.

Li Fraumeni syndrome:

In case of Li Fraumeni syndrome (LFS), there is a mutation of the TP53 gen. LFS is characterized by:

• Tumors at childhood
  • Sarcomas
  • Gliomas
  • Adrenal cortical carcinoma
• Breast cancer at young age
  • 30% are mutation carriers of breast cancer <30 years

CHEK2 pathogenic variants:

The CHEK2 del 1100C mutation is a common hereditary mutation increasing the risk of breast cancer. It is a moderate penetrance gene, which doesn’t always cause cancer.

With CHEK2 in the family, the lifetime risk for breast cancer varies between 20-55%. Between 35-60 years, a yearly mammography is made.

Other familial cancer syndromes:

Other familial cancer syndromes with high incidence of breast cancer are:

• CDH1
  • Stomach cancer
• PTEN/Cowden syndrome
  • Big head circumference
  • Skin inspection
• STK11 Peutz Jeghers syndrome
  • Lip and mouth pigmentations
• Neurofibromatose 1 (NF1)
  • Pigmentations on the skin

These syndromes all are very rare.

Knudsons two hit theory

Vogelstein model:

The Vogelstein model describes the development of cancer, for instance of colon cancer:

1. A single cell is infected → develops mutations in genes
   • Mostly APC genes
   • Usually tumor suppressor genes → both genes need to be mutated for something to happen
2. The cell starts dividing → polyps
3. Polyps acquire other mutations in other cells and genes

Retinoblastoma:

An individual with the RB gene is predisposed for retinoblastoma. Retinoblastoma is characterized by non-reflecting eyes. A retinoblastoma can be familiar or sporadic. In familial cases, the retinoblastoma is:

• Usually bilateral
• Associated with multiple tumors
• Diagnosed at an earlier age

The genetic defect consists of germline mutations in the RB1 gene. RB1 negatively regulates genes required for cell division. It is a tumor suppressor gene. If RB1 is being phosphorylated or isn’t present due to mutation, the cell starts dividing even though it shouldn’t → tumor development. If a second hit occurs in the same gene, the tumor can start developing → Knudson’s 2 hit theory.

Normal versus inheritable cancer

There are several differences between normal and inheritable cancer:

• Sporadic cancer
  • Mainly occurs at older age
• Inherited cancer
  • Young age of diagnosis
  • Same cancer occurs twice or more in a family
  • Multiple cancers in 1 patient

Many genes are involved in sporadic cancer. There are over 200 known tumor syndromes involved in inherited cancer, most of which are very rare. Mutations in oncogenes are much more rare than mutations in tumor suppressor genes.

Modes of inheritance

• Autosomal dominant
  • Children have a ½ chance of inheriting a mutation
  • Mutation will come to expression during life
• Autosomal recessive
  • Both parents need to carry the gene → interfamilial reproduction
  • Carriers have a slightly increased risk of developing cancer

Colorectal cancer

It is quite common to develop an adenoma at an older age → screening isn’t directly necessary. Colon cancer is usually preceded by adenomas. If blood is found in stool, patients can be sent in for colonoscopy.

Most cases of colon cancer are sporadic. 1/3 are familial, of which a small part has a highly penetrant predisposition for colon cancer:

• Lynch syndrome
• FAP (APC)
• MAP (MUTYH)
• Other forms

Lynch syndrome is associated with only a few polyps, while other forms have many more polyps.

Lynch syndrome:

Lynch syndrome was previously known as HNPCC. There is a germline variant in a mismatch repair (MMR) gene:

• MLH1
• MSH2 (and Epcam)
• MSH6
• PMS2

These proteins usually form a mismatch repair complex. If 1 protein isn’t present or is mutated, mismatch repair cannot occur. This mainly causes colon cancer. The risk of developing colon cancer depends on which gene is affected → the risk is highest if MLH1 and MSH2 are affected.

APC mutation:

In case there are many colon polyps, the germline variant of the APC gene may be mutated. This is the case in most adenomas and sporadic cases colon polyps

Usually APC binds to a complex with β-catenin. If the WNT pathway is activated the complex gets loose and the β-catenin enters the nucleus → stimulates cell proliferation. In case the APC isn’t produced anymore, the cell will continuously have β-catenin in the nucleus and cannot stop dividing.

Most APC mutations are autosomal dominant, but de novo APC-mutations are also possible. Usually this already occurs in the fertilized egg → older cells also have the mutation. However, the mutation can also occur later in life → only the colon cells are affected. These cases usually are milder. This mutation usually isn’t present in germline DNA → children do not receive the mutation.

MUTYH:

Mutations in MUTYH genes cause polyps. Carriership is 1/100. The MUTYH gene is a DNA repair gene which is involved in mutations which occur due to oxidative stress:

1. Oxidative stress can oxidize guanine
2. The OGG1 protein can remove this guanine, but this doesn’t always happen
3. If oxidized guanine isn’t removed, it binds with adenine → this usually is solved by the MUTYH protein
4. If this doesn’t happen, a G-C to G-A mutation occurs.

NTHL 1:

The NTHL 1 gene is also a DNA repair gene. Mutations in NTHL 1 cause adomatous polyposis and colorectal cancer. The carriership is 1:300.

Familial colorectal cancer:

Families who do not have Lynch syndrome can still have a high risk for colon cancer. If these families fit certain criteria, they are called familial colorectal cancer families (FCC families). These families all get an advice for screening. If someone has a sibling under 50 with colorectal cancer, the chance of developing cancer is 3x as high → screening every 5 years is necessary.

More rare tumor syndromes:

More rare tumor syndromes associated with polyps are:

• Peutz-Jeghers syndrome (STK11)
• Juvenile polyposis (SMAD4)
• PTEN hamarotoma syndrome

These syndromes can easily be recognized by pathologists.

Melanoma

Screening:

Familial melanoma needs to be tested if:

• Melanoma is diagnosed in 2 first degree relatives, of which 1 is <40 years
• Melanoma in 3 or more relatives

Other reasons for DNA testing are:

• Individual with more than 3 melanomas
• Individual with a melanoma <18 years
• Melanoma and pancreatic cancer in 1 family

Genes:

Most melanoma cases are sporadic, but 10% of cases are familial. A number of genes are associated with familial melanomas:

• CDKN2A gene
  • 40% of cases
• Polygenic
  • 20% of cases
• Other genes

CDKN2A:

The CDKN2A gene is expressed in many cells. It codes for 2 proteins which both act as tumor suppressors by regulating the cell cycle:

• p14
  • Activates the p52 tumor suppressor protein → blocks apoptosis
• p16
  • Inhibits CDK4/6 and CDK2 → blocks the G1 to S-phase

The lifetime risk for someone with a mutation in CDKN2A is quite high:

• 70% for melanoma
• 20% for pancreatic cancer

Surveillance consists of:

• Skin: 2x per year from the age of 12 years
• Pancreas screening: from the age of 50 years