2010P - Mutational profile and tumour mutational burden in Li-Fraumeni Syndrome associated cancer

Background

Li-Fraumeni syndrome (LFS) is associated with germline mutations in the TP53 gene, which is essential in maintaining genomic integrity. Cells in patients with LFS fail to arrest secondary to DNA damage and are suggested to exhibit a ‘mutator’ phenotype, susceptible to multiple genomic mutations. Next generation sequencing (NGS) techniques allow us to explore the molecular landscape of cancers. The aim of our study was to delineate the mutational profile and tumour mutational burden (TMB) in LFS associated cancers with NGS.

Methods

Patients with a pathogenic germline TP53 mutation and a cancer diagnosis were identified from the Cancer Genetics Database in St. James’s Hospital. Those with a TP53 mutation deemed a variant of uncertain significance were excluded. Patient demographics were collected from electronic patient records. NGS was performed on formalin fixed paraffin embedded tumour blocks with the Foundation One® CDx test. This reports on mutations in a panel of 324 genes and genomic signatures, including TMB.

Results

Nine patients have consented to participate with a total of twelve tumour specimens available for testing (3 patients with 2 separate primaries, denoted A and B where relevant below). Five patients have results to date. The remainder of the results will be included at the time of meeting presentation. Patient demographics are outlined in the table below. Table: 2010P

Patient	Age at diagnosis	Sex	Primary site	Gene mutations	TMB Muts/Mb
1.	43	F	Breast, invasive ductal carcinoma (IDC)	ERBB2 (amplification) AURKA (amplification) GATA3 (p409fs*99) GNAS (amplification) SMAD4 (R361H) TP53 (R337H)	0
2. A	39	M	Soft tissue sarcoma	SDHB (R46Q) TP53 (R342*)	Undetermined
2. B	40	M	Thyroid, papillary	BRAF (V600E) SDHB (R46Q) TP53 (R342*)	0
3	31	F	Breast, IDC	BRCA1 (Duplication exons 20-23) MYC (Amplification) TP53 (R273H)	3
4	44	F	Breast, IDC	MUTYH (G382D) PRKAR1A (rearrangement intron 4) TP53 (R257W)	Undetermined
5	42	M	Rectal adenocarcinoma	ATM K2756* APC Q1378* TP53 C229fs*10	0

TMB was found to be low in all specimens (testing failed in 2). One or more actionable mutations were identified in half of the tumour specimens. A similar mutational profile was identified in the patient with 2 separate primary cancers.

Conclusions

NGS provides an insight into the molecular pathogenesis of LFS associated cancer. Our study does not demonstrate evidence of high tumour mutational burden in these patients, despite the loss of a functioning TP53 protein.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Bobby Bastow Cancer Genetics Foundation.

Disclosure

All authors have declared no conflicts of interest.