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Genetic counseling: Osteosarcoma and Li-Fraumeni Syndrome

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Osteosarcoma and Li-Fraumeni Syndrome


  • 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 BackgroundEdit

  • 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 OverviewEdit

  • 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 EtiologyEdit

  • 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 FeaturesEdit

  • 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


  • 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


  • 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 DiagnosisEdit

  • 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


  • 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.
  • 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.
  • Schneider, Katherine. Counseling about Cancer: Strategies for Genetic Counseling (2002).


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

This material has been imported fom the wikibook "Genetic counseling"[] under the GNU Free Documentation License.

Heckert GNU white Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.2 or any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy of the license is included in the section entitled "GNU Free Documentation License."

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