# 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.