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