Li Fraumeni

Syndrome
1/4/23
Overview
• What is it
• Diagnosis
• Types of Ca
• Investigation/Management/Surveillance
Overview
• What is it
• Diagnosis
• Types of Ca
• Investigation/Management/Surveillance
What is it
• Familial cancer SYNDROME
• Often associated with 1 mutant TP53 gene
• Chromosome 17p13.1
• In 80 % of cases, the mutation occurs in exons 5-8
• Germline TP53 mutations are identified in 75% of patients with classic LFS
• Major role in managing fate of cells with damaged DNA delays cell cycle progression, allows DNA repair initiation, or
triggers apoptosis
• Autosomal dominant
• Very high penetrance
• Mean age of first tumour is 25 years
• Lifetime likelihood of a TP53 mutation carrier developing cancer approaches 75% in males and almost 100% in
females
• Higher in females due to breast cancer
Diagnosis
• Do not have phenotypic alterations to help with diagnosis
• Rely on:
• FAMILY HISTORY
• TYPE OF TUMOUR
The TP53 mutation is present in:
• 70 % of patients who meet the classic criteria
• 22 % of those who meet Birch criteria
• 20 % of those who meet Chompret criteria
Cancers - SBBA
• Sarcomas
• Breast
• Brain
• Adrenocortical carcinoma
Breast cancer
• Most common
• 25-30% incidence
• Mean age onset 33 years old
• Exclusively in women
• The risk of contralateral breast cancer in TP53 carriers diagnosed at less than 35 years of age is
approximately 4 to 7 percent annually, around twice that in BRCA carriers 
• More likely HER2 positive
• Different treatment to rest of population
• Mastectomy, rather than lumpectomy, + radiation therapy
• Due to risk of second breast primary or radiation-induced second cancer
Sarcomas
• 25% of all cancers
• Most commonly rhabdomyosarcomas in children, with onset mainly age <5
• Osteosarcomas at any age
• NOT in LFS: Ewing sarcoma, GIST, angiosarcomas
CNS tumours
• 9-16% all patients
• Most common types:
• Astrocytoma
• Glioblastoma
• Medulloblastoma
• Choroid plexus carcinomas
• CPCs also most strongly associated with a TP53 germline mutation, even without FHx Ca

• Mean age onset 16 y.o.

Adrenocorticoid carcinoma
• 6-13% patients
• Bimodal age distribution (<5 y.o., 40-50 y.o.)
• Very frequently associated with germline pathogenic variants in TP53
Others
• Make up remaining 30%
• Leukaemia (ALL, AML), MDS, GIT, urogenital, lung, neuroblastoma…
Differentials
• BRCA1 & BRCA2 pathogenic variants
• Increased risk premenopausal breast & ovarian cancer, but also pancreatic cancer, melanoma &
prostate cancer
• Mismatch repair cancer (Lynch) syndrome
• Risk of leukaemia, brain tumours, intestinal cancer
Issues
• Lifetime cancer risk
• Risk of multiple different cancers
• Risk of radiation-associated cancers
Management
• Test for pathogenic variants in TP53 gene
• Management of individual cancers
• Same as rest of population, aside from breast cancer
• Surveillance
• Testing in family members
• Genetic counselling
Surveillance
• https://www1.racgp.org.au/ajgp/2021/august/risk-management-for-young-people-with-inherited-ca
• Biannual clinical review for children
• Annual whole-body MRI for sarcoma
• Annual brain MRI for brain Ca
• 4-monthly abdo USS from birth to age 10 for adrenocortical carcinoma
• Breast awareness & annual breast MRI from age 20
• Risk-reducing bilateral mastectomy at age 25, consider risk-reducing medications
• Colonoscopy every 1-2 years or 2–5 years from the age of 20 years
Genetic counselling
• Test family members
• Autosomal dominant – 50% risk passed on to children
• Preimplantation genetic diagnosis (PGD) in the setting of in vitro fertilisation (IVF) it is
possible to prevent the familial TP53 mutation being passed on to future generations
FLASH QUIZ / ANKIs
To which cancers does Li Fraumeni
syndrome primarily predispose?
To which cancers does Li Fraumeni
syndrome primarily predispose?
SBBA
• Sarcoma 25%; often rhabdomyosarcoma
• Breast 30%
• Brain 10-15%; choroid plexus carcinoma, astrocytoma, glioblastoma, medulloblatoma
• Adrenocortical carcinoma 5-15%
What is Li Fraumeni syndrome?
What is Li Fraumeni syndrome?
• Familial cancer syndrome
• Suspect if young age of onset of cancer, pathognomonic cancers sarcoma, breast, brain,
adrenocorticoid, and family history
• Often associated pathogenic TP53 gene mutation 75% of those with Li Fraumeni
Management of Li Fraumeni syndrome
Management of Li Fraumeni syndrome
• Test for pathogenic variants in TP53 gene
• Management of individual cancers. Breast cancer managed slightly differently, with bilateral
mastectomy & radiation recommended, rather than lumpectomy
• Surveillance annual full-body MRIs, 1-2-yearly colonoscopies, double mastectomies, abdo USS,
biannual reviews
• Testing in family members & genetic counselling recommend IVF with preimplantation genetic
diagnosis (PGD)