MB3 – Familial Cancer Syndromes

Medical Biology
Mustafa Çavuşoğlu
mustafacavusoglu@gau.edu.tr
 Introduction

• Familial Cancer Syndrome

• A type of inherited disorder in which there is a higher-than-normal risk of certain types of

cancer.

• FCS are caused by mutations (changes) in certain genes passed from parents to children.

• In a familial cancer syndrome, certain patterns of cancer may be seen within families. These
patterns include having several close family members (such as a mother, daughter, and sister)
with the same type of cancer, developing cancer at an early age, or having two or more types
of cancer develop in the same person.

• Sporadic Cancer; Cancer that occurs in people who do not have a family history of that cancer or an
inherited change in their DNA that would increase their risk for that cancer.
 Introduction

• Is cancer inherited?

• It's important to understand that not every cancer that seems to run in a family is caused by a
family cancer syndrome.

• About 1 in 3 people in the United States will develop cancer during their lifetime, so it’s not
uncommon to have many cancers in a family.

• Sometimes, cancer might be more common in certain families because family members share
certain behaviours or exposures that increase cancer risk, such as smoking or obesity.

• But cancer can sometimes be caused by an abnormal gene that is passed from generation to
generation. Although these cancers are often referred to as inherited cancers, what is actually
inherited is the abnormal gene that can lead to cancer, not the cancer itself.
 Introduction

• Though we have not identified genetic causes for all types of cancer, we do know several gene
changes, or mutations, that can be passed down from parent to child and increase a person's risk of
developing the disease.

• These changes are known as hereditary cancer syndromes.

• Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

• Lynch Syndrome (hereditary non-polyposis colorectal cancer)

• Familial Adenomatous Polyposis (FAP)

• Li-Fraumeni Syndrome
 Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

• Families with hereditary breast and ovarian cancer syndrome (HBOC)

have family members who have developed breast cancer and/or
ovarian cancer.
• HBOC is caused by mutations in the BRCA1 and BRCA2 genes.
• A woman with an inherited mutation in the BRCA genes has a higher
chance of developing breast and ovarian cancer in her lifetime than a
woman who does not carry a mutation.
• A man with an inherited mutation in the BRCA genes has a higher
chance to develop breast and prostate cancer in his lifetime.
 Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

• What are BRCA1 and BRCA2?

• BRCA1 (BReast CAncer gene 1) and BRCA2 (BReast CAncer gene 2) are genes that produce proteins that help
repair damaged DNA.

• Two copies of each of these genes—one copy inherited from each parent. BRCA1 and BRCA2 are called tumour
suppressor genes, when they have certain changes, called harmful (mutations), cancer can develop.
• A harmful variant in BRCA1 or BRCA2 can be inherited from either parent. Each child of a parent who carries any
mutation in one of these genes has a 50% chance of inheriting the mutation. Inherited mutations—also
called germline mutations or variants—are present from birth in all cells in the body.

• About 13% of women in the general population will develop breast cancer sometime during their lives, 55%–72%
of women who inherit a harmful BRCA1 variant and 45%–69% of women who inherit a harmful BRCA2 variant will
develop breast cancer by 70–80 years of age.
• About 1.2% of women in the general population will develop ovarian cancer sometime during their lives. By
contrast, 39%–44% of women who inherit a harmful BRCA1 variant and 11%–17% of women who inherit a
harmful BRCA2 variant will develop ovarian cancer by 70–80 years of age.
 Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

• Women with a strong family history of breast cancer and/or ovarian

cancer may choose to get genetic counselling to help estimate their
risk for having a mutation in one of the BRCA genes.

• The genetics professional can estimate the risk based on a person’s

history of cancer, the history of cancer in their family, and other
factors.

• If they have a high risk, they might choose to be tested

for BRCA mutations

• If a BRCA mutation is present, the woman has a high risk of

developing breast cancer and ovarian cancer

• Having a BRCA mutation can also affect a man’s risk of some other
cancers, such as prostate and pancreatic cancer.
 Lynch Syndrome (hereditary non-polyposis colorectal
cancer)

• HNPCC/Lynch syndrome is a genetic disease of autosomal dominant inheritance.

• It is caused by a mutation in one of four genes of the DNA mismatch repair system and confers a
markedly increased risk.

• People with this syndrome are at high risk of developing colorectal cancer. These cancers are more likely
to develop at earlier ages, often before the age of 50.

• Its prevalence in the general population is about 1 in 500, and it causes about 2% to 3% of all colorectal
cancers.

• Lynch syndrome also leads to a high risk of endometrial cancer (cancer in the lining of the uterus), as well
as cancers of the ovary, stomach, small
intestine, pancreas, kidney, brain, skin, breast, prostate, ureters(tubes that carry urine from the kidneys to
the bladder), and bile duct.
 Lynch Syndrome (hereditary non-polyposis colorectal
cancer)

• Lynch syndrome is diagnosed in two steps:

• If it is suspected, (because a patient develops cancer at an unusually young age or because of

familial clustering), the tumour tissue is analysed for evidence of deficient mismatch repair
(microsatellite instability, loss of mismatch repair protein expression).

• If such evidence is found, a genetic mutation is sought. The identification of a pathogenic

mutation confirms the diagnosis in the patient and enables predictive testing of other family
members.

• Doctors and genetics professionals can check if you are likely to have Lynch syndrome, based on
your personal and family cancer history using certain criteria known as the Amsterdam criteria and
the revised Bethesda guidelines.
 Lynch Syndrome (hereditary non-polyposis colorectal
cancer)

• Lynch syndrome is due to inherited changes (mutations) in genes that affect DNA mismatch repair,
a process that fixes mistakes made when DNA is copied.

• MLH1

• MSH2

• MSH6

• PMS2

• Unlike familial adenomatous polyposis (FAP), HNPCC syndrome usually involves only single
colorectal adenomas or carcinomas that cannot be clinically distinguished from sporadic tumours.
 Familial Adenomatous Polyposis (FAP)

• Familial adenomatous polyposis (FAP) is a rare, inherited condition caused by a

defect in the adenomatous polyposis coli (APC) gene.

• Most people inherit the gene from a parent.

• FAP causes extra tissue (polyps) to form in your large intestine (colon) and rectum.
Polyps can also occur in the upper gastrointestinal tract, especially the upper part of
your small intestine (duodenum). If untreated, the polyps in the colon and rectum
are likely to become cancerous around 40s.

• Most people with familial adenomatous polyposis eventually need surgery to

remove the large intestine to prevent cancer.
 Familial Adenomatous Polyposis (FAP)

• A polyp is a projecting growth of tissue from a surface in the body, usually a mucous membrane.
Polyps can develop in the: colon and rectum.

• The clinical presentation of familial adenomatous polyposis will vary based on family history.

• Patients with a known family history of FAP should begin screening at a young age with an annual
endoscopy evaluation.
 Familial Adenomatous Polyposis (FAP)

• Adenomatous polyposis coli (APC) is a protein that in humans is encoded by the APC gene which is classified as a
tumour suppressor gene.

• The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which
are involved in cell adhesion.

• The APC protein helps control how often a cell divides, how it attaches to other cells within a tissue, how the cell
polarizes and the morphogenesis of the 3D structures, or whether a cell moves within or away from tissue

• This protein also helps ensure that the chromosome number in cells produced through cell division is correct. The
APC protein accomplishes these tasks mainly through association with other proteins, especially those that are
involved in cell attachment and signalling.

• Mutations in the APC gene may result in colorectal cancer. Most of these mutations cause the production of an APC
protein that is abnormally short and presumably non-functional. This short protein cannot suppress the cellular
overgrowth that leads to the formation of polyps, which can become cancerous. The most common mutation in familial
adenomatous polyposis is a deletion of five bases in the APC gene.
 Li-Fraumeni Syndrome

• Li-Fraumeni Syndrome (LFS) is a rare genetic condition characterized by an increased risk of

developing multiple types of cancer.

• The cancers that occur in LFS can be diagnosed during childhood, adolescence or adulthood.

• Most individuals with LFS are found to have mutations in the TP53 gene.
 Li-Fraumeni Syndrome

• The most common types of cancer associated with LFS include:

• Soft tissue sarcomas (tumour in fat, muscle, nerve, joint, blood vessel, bone or deep skin)

• Breast cancer

• Leukaemia

• Lung cancer

• Brain tumours

• Adrenal gland cancer

• People with Li-Fraumeni syndrome can develop more than one cancer in their lifetime. They also
seem to have a higher risk of getting cancer from radiation exposure, so doctors treating these
patients might try to avoid giving them radiation therapy when possible.
 Li-Fraumeni Syndrome

• This syndrome is most often caused by inherited mutations in the TP53 gene, which is a tumour
suppressor gene.

• A normal TP53 gene makes a protein that helps stop abnormal cells from growing, provides instructions
for making a protein called tumour protein p53 (or p53), so it regulates cell division by keeping cells from
growing and dividing (proliferating) too fast or in an uncontrolled way.

• When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or ultraviolet
(UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired,
or the damaged cell will self-destruct (undergo apoptosis).

• If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired,
this protein prevents the cell from dividing and signals it to undergo apoptosis.

• By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of
tumours.

• Therefore, it has been nicknamed the "guardian of the genome."

 Genetic Testing

• What is genetic testing?

• Genetic testing looks for specific inherited changes (variants) in a person’s genes. Genetic variants can have harmful,
beneficial, neutral (no effect), or unknown or uncertain effects on the risk of developing diseases.

• Who should consider genetic testing for cancer risk?

• People who are concerned about whether their family history puts them at risk for cancer should consult with a genetic
counsellor.

• Cancer was diagnosed at an unusually young age

• Several different types of cancer occurred in the same person

• Cancer in both organs in a set of paired organs, such as both kidneys or both breasts

• Several first-degree relatives (the parents, siblings, or children of an individual) have the same type of cancer (for example,
a mother, daughter, and sisters with breast cancer); family members with breast or ovarian cancer; family members with
colon cancer and endometrial cancer
 Genetic Testing

• How is genetic testing done?

• Genetic tests are usually requested by a person’s genetic counsellor, doctor, or other health
care provider who has reviewed the individual’s person and family history.

• Testing is done on a small sample of bodily fluid or tissue—usually blood, but

sometimes saliva, cells from inside the cheek, or skin cells.
• Types of genetic testing;

• Full Gene sequencing

• When a single gene is suspected, but exact mutation is not known (first testing in a family)
• Techniques: Sanger Sequencing

• Single mutation analysis

• A known mutation in a family or founder mutation in an ethnicity
• Techniques: PCR amplification, allele specific oligonucleotides

• Copy number variation

• When a whole exon of a gene is deleted, and sequencing will read the other normal copy
• Techniques: Multiplex-ligation probe ligation assay, array CGH

• Triplet repeat expansion

• Mutation is a repeat-type expansion not easily amplified by DNA polymerase
• Techniques: Southern blot, quantitative PCR

• Imprinted genes
• Gene is affected by methylation of the bases, not the sequence change
• Techniques: Methylation-specific enzyme digestion