Handbook of Genetic Counseling/Osteosarcoma and Li-Fraumeni Syndrome

Osteosarcoma and Li-Fraumeni Syndrome

Contracting

What concerns do you have for yourself or for your family?
What questions do you have?
Overview of agenda
- Elicit medical history
- Review family history
- Discuss genetics, testing, treatment and management

Osteosarcoma Background

Most common type of bone cancer
- Arises in osteoid tissue in bones
- Most common in knees, upper legs, and upper arms
- Commonly affects people from ages 10-25
  - Accounts for about 5% of childhood tumors
  - 50% form in bones around knee
  - Only about 30% of patients with localized tumors survive free of relapse
Symptoms of bone cancer
- Pain is most common symptom
- Other symptoms depend on location and size of tumor
  - Tumors in or near joints may cause swelling or tenderness
  - Can interfere with normal ability to move
- May weaken bones and make fractures more likely
- General symptoms include fatigue, fever, weight loss, and anemia
Diagnosis
- Alkaline phosphatase assay
  - Blood test to determine enzyme levels
  - Large amounts of alkaline phosphatase found in blood when cells of bone tissue are active
    - During childhood growth
    - During mending of broken bone
    - When tumor causes production of abnormal bone tissue
- X-rays show location, size, and shape of tumor
- Bone scan, CT, MRI, or angiogram may be recommended if X-ray suggests that a tumor is cancerous
- Biopsy needed to determine for sure if tumor is cancer
  - Needle biopsy - make small hole in bone and remove tissue sample from tumor with needle-like instrument
  - Incisional biopsy - cut into tumor and remove sample of tissue
- No staging system for osteosarcoma so use general terms
  - Localized
  - Metastatic - most often to lungs or other bones (20% of patients)
  - Recurrence - most often in the lungs (5 year survival is 20-40% following surgery)
Treatment
- Depends on type, size, location, and stage of cancer
- Surgery
  - Amputation of limb necessary in some cases
  - Pre or post-operative chemotherapy has improved success of limb-sparing surgery
  - May remove only cancerous section of bone and replace it with prosthesis
- Chemotherapy and radiation may be used alone or together
  - Tumors are generally resistant to radiation
  - Degree of necrosis following chemotherapy predicts prognosis
- Various clinical trials for surgeries, radiation therapies, and chemotherapies
Risk factors for bone cancers
- Radiation or chemotherapy treatment in children or young adults for other conditions
- Adults with Paget's disease are at increased risk for osteosarcoma
- Hereditary factors

Li Fraumeni Syndrome Overview

Cancer predisposition syndrome
- Associated with soft-tissue sarcomas, breast cancer, leukemia, osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal cortex, and brain
- Increases risk for development of cancers
Diagnosis is made clinically and genetic testing is available

Genetic Etiology

Due to mutation in TP53 gene on 17p13 that codes for TP53 protein in more than 50% of cases
- Tumor suppressor gene nicknamed "guardian of the genome"
- Acts as checkpoint control following DNA damage by delaying cell cycle progression until damaged DNA is repaired or cell commits to apoptosis
  - Activates downstream genes to repair DNA
  - Signals molecule to confirm damage and proceed with apoptosis
- Arrests cell cycle by mediating RB pathway
CHEK2 gene at 22q12.1 also associated with Li-Fraumeni syndrome
- Reported in only a few families thus far
- Putative tumor suppressor gene
  - Lies in TP53 pathway
  - One of checkpoint genes activated in response to DNA damage by phorsphorylating p53
- Not known if cancer risks are different than those due to TP53 mutations
- Mutations in this gene appear to be most common in osteosarcomas
Autosomal dominant inheritance
- Offspring of affected individuals have 50% chance of inheriting mutation
- Most individuals diagnosed have an affected parent
- De novo mutation rate unknown
Fewer than 400 families reported worldwide
Association of malignancies with TP53 mutations
- Less than 1% of all breast cancers
- 2-10% of childhood brain tumors
- 50-100% of childhood adrenocortical carcinomas
- 2-3% of osteosarcomas
- 9% of rhabdomyosarcomas
- 7-20% of multiple primaries occurring at young ages
Penetrance
- May be as high as 90%
- About 25% of cancers occur before age 18
- About 50% of individuals have malignancy by age 40
- About 90% of individuals have malignancy by age 70
- Different studies give different numbers - may be genetic heterogeneity

Clinical Features

Predisposes to a number of different types of tumors
- Osteosarcomas (23/151)
- Soft-tissue sarcomas (32/151)
- Pre-menopausal breast cancers (36/151)
- Brain tumors - neuroblastoma commonly (14/151)
- Adrenal cortical tumors (4/151)
- Leukemia - particularly acute leukemia (9/151)
Also associated with excess rates of other cancers
- Melanoma
- Stomach cancer
- Colon cancer
- Pancreatic cancer
- Esophageal cancer
- Gonadal germ cell tumors diagnosed at young ages
- Wilm's tumor
Adult women have higher cancer risk than men because of high frequency of breast cancer
Also increases risk to develop multiple primary cancers
- Up to 50% may develop second cancer
- 4% develop third cancer
- 2% develop four cancers
- Survivors of childhood cancer have greatest risk to develop another primary
- Radiation exposure appears to increase risk of second cancer
Genotype-phenotype correlation
- R337H mutations associate with development of childhood adrenocortical carcinoma as low penetrance allele
- 13964gc mutation in intron 6 in series of patients with breast cancer as low penetrance allele

Diagnosis

Clinical diagnostic criteria (LFS)
- Proband with sarcoma diagnosed under 45 years of age
- First-degree relative with any cancer under 45 years of age
- Third family member who is first- or second-degree relative with cancer under 45 or sarcoma at any age
Li-Fraumeni-like syndrome (LFL)
- Share some, but not all features of LFS
- Birch's definition
  - Proband with any childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed under 45 years of age
  - First- or second-degree relative with a typical LFS cancer at any age
  - Additional first- or second-degree relative with any cancer under the age of 60
- Eele's definition
  - Two first- or second-degree relatives with LFS-related malignancies
  - Can occur at any age
Molecular genetic testing
- Identifies mutations in TP53 gene in about 70% of patients with LFS and 8-22% of families with LFL
- DNA sequencing
  - Available clinically
  - Identifies mutations in about 75% of families
  - About 80% of identifiable mutations are in exons 5-8 so testing is often limited to only these exons
  - Full gene sequencing and protein function for novel missense mutations generally only offered on research basis
- Chip-based DNA sequencing
  - Available on research basis only
  - Detects most of common single base pair mutations that have been identified
  - Sensitivity of 90-98% depending on how much of coding region is sequenced
- Can test asymptomatic individuals once mutation is identified in the family
  - Cannot predict age of onset, severity, type of cancer, or rate of preogression
  - Lack of proven surveillance or prevention so not justified for management but may be useful for reproductive, financial, and career planning or peace of mind
  - Testing has been confined to individuals 18 and older since no proven management options
- Prenatal testing is possible if mutation identified in family but requires careful genetic counseling
- Potential risks of testing
  - May not be covered by insurance
  - Possible problems with health, life, and disability insurance coverage
  - Possible employment and educational discrimination
  - Changes in social and family interaction
  - Implications for other at-risk family members
  - Limitations in management options
- Potential benefits of testing
  - Explanation for frequent/rare occurrence of cancer in family
  - Clarification of risk/relief if individual tests negative for known mutation
  - Help make decisions regarding medical management or life decisions
- Clinical molecular testing
  - City of Hope
    - Sequencing of coding exons 2-11 and intron junctions
    - Sensitivity estimated to be greater than 95% for point mutations
    - Requires 6 cc of whole blood in yellow or lavender topped tube
    - Full mutation analysis - $450, known mutation analysis $250
    - Turn-around time is 4 weeks
  - University of Pennsylvania
    - Conformation sensitive gel electrophoresis (CSGE)
    - Shows differences in 2 alleles as small as single base substitution, insertion, deletion
    - Sensitivity estimated to be greater than 95% in coding sequence
    - Turn-around time is 4 weeks
  - Fairview Molecular Diagnostic Laboratory
    - Sequencing analysis
    - Requires 15 ml blood in yellow topped tube
    - Turn-around time is 4-8 weeks

Management

No surveillance except breast cancer screening has been show to reduce morbidity and mortality
At-risk individuals should pay attention to signs and symptoms
- Lingering aches and illnesses
- Headaches, bone pain, abdominal discomfort
Surveillance for at-risk children
- Complete physical exam
- Urinalysis
- Complete blood count
- Abdominal ultrasound examination
- Additional organ-targeted surveillance based on family history
Surveillance for at-risk adults
- Annual complete physical exam including skin, nervous system, rectum, and Pap smear for women
- Consider scans of head and abdomen annually
- Semi-annual clinical breast exam for women
- Annual mammograms, breast ultrasonography, or MRI
  - Mammograms controversial because of increased sensitivity to radiation
  - Should begin screening by age 25-30
- Additional organ-targeted surveillance based on family history

Differential Diagnosis

Hereditary breast/ovarian cancer syndrome
Retinoblastoma - Autosomal dominant
- Due to mutations in RB1 gene at 13q14
- RB1 protein is negative regulator of cell growth
- Approximately 90% of retinoblastomas occur before age 3
- Increases risk to develop osteosarcoma 500-fold
Rothmund-Thomson syndrome - Autosomal recessive
- Due to mutations in RECQL4 gene at 8q24.3 in some families
- Cancer risks increased but not quantified
- Clinical features include:
  - Skin atrophy marbleized pigmentation
  - Telangiectasia
  - Cataracts
  - Osteosarcoma is most commonly reported malignancy
Werner syndrome - Autosomal recessive
- Due to mutations in WRN (RECQL2) gene at 8p12
- Cancer risk is 10% lifetime
- Clinical features include:
  - Multiple complaints of problems associated with aging beginning in 20's and 30's
    - Cataracts, graying hair or balding, decreased muscle mass, arteriosclerosis, scleroderma, endocrine failure, and NIDDM
    - Also may have lack of growth spurt in puberty or dysmorphic features
  - Increased risk for osteosarcoma, soft-tissue sarcoma, melanoma, thyroid cancer, and hematological malignancies

References

Hillmann A, et al. "Familial Occurrence of Osteosarcoma: A Case Report and Review of the Literature." J Cancer
Res Clin Oncol (2000) 126: 497-502.
"Li-Fraumeni Syndrome." GeneReviews. http://www.genereviews.org
Lindor NM, et al. "The Concise Handbook of Family Cancer Syndromes." Journal of the National Cancer Institute (1998) 90(14): 1039-1071.
"Osteosarcoma/Malignant Fibrous Histiocytoma of Bone." National Cancer Institute. http://www.cancer.gov
Schneider, Katherine. Counseling about Cancer: Strategies for Genetic Counseling (2002).
www.lfsassociation.org

Notes

The information in this outline was last updated in Nov 2002.