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.