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Case history

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Image not available. Mrs LM was diagnosed with ductal carcinoma in situ (DCIS) at the age of 27, following presentation with a left breast lump. She was treated with a wide local excision and radiotherapy. Three years later, she was found to have new microcalcifications in the contralateral breast on screening mammogram and was diagnosed with a grade 3 oestrogen receptor-negative invasive breast cancer. She had a mastectomy and adjuvant chemotherapy. During the treatment, LM noticed that her 13-month-old daughter (BM) had poor growth, acne and was noticeably overweight. Elevated serum androgens were found. BM was diagnosed with an adrenocortical tumour and underwent an adrenalectomy. At this time it was noted that there was an extensive family history of cancer and LM was referred to a geneticist. LM's sister had died of a brain tumour, her father had lung cancer, her paternal uncle had a melanoma, her mother had lymphoma and a maternal cousin had breast cancer (Figure 9.1).

The geneticist was suspicious that LM might have a mutation of the TP53 gene and requested whole gene sequencing of TP53 in germline DNA extracted from blood. This revealed a truncating mutation in exon 4 of the gene.

Unfortunately, LM subsequently developed a stage IV glioblastoma multiforme, which was treated with radiotherapy and had an excellent response. She then developed an anterior right-sided non-small-cell lung carcinoma (NSCLC), which was treated with four cycles of palliative carboplatin and vinorelbine chemotherapy.

BM was diagnosed with a second adrenocortical tumour at the age of 3 and had a contralateral adrenalectomy. She subsequently developed pancytopenia and had a bone marrow transplant for myelodysplastic syndrome. Unfortunately, this transformed into an acute myeloid leukaemia within a short interval and she died aged 4 years.

Six months after completion of first line palliative chemotherapy, LM developed rapidly progressive lung metastases and had no response to docetaxel chemotherapy. She died aged 37.

She was survived by two children, now aged 18 and 24; both have undergone testing for the TP53 mutation identified in their mother and both are carriers. The older daughter has regular breast MRIs as a screening measure.

Is the above story typical of Li-Fraumeni syndrome (LFS)?

What is the pattern of inheritance and penetrance of the syndrome?

Should the oncologist have been alerted to the possibility of LFS based on the family history?

Should cancers in LFS patients be treated differently from their sporadic counterparts?

How should the patient's surviving children be managed?

Are there any screening investigations that could have been done to prevent the patient's subsequent cancers or achieve an early diagnosis?

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Figure 9.1

Family pedigree of the patient LM (proband, P). Current age/age at diagnoses given in years (y) or months (m). AML, acute myeloid leukaemia; ca, cancer; d, age at diagnosis; MDS, myelodysplastic syndrome; SCC, squamous cell carcinoma.

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Is the above story typical of LFS?

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