Correspondence

Multiple Tumors in a Child with Germ-Line Mutations in TP53 and PTEN

N Engl J Med 2008; 359:537-539July 31, 2008

Article

To the Editor:

TP53, a tumor-suppressor gene, is frequently inactivated by somatic mutations in cancer. Inheritance of a heterozygous TP53 mutation results in the Li–Fraumeni syndrome of a hereditary predisposition to cancer.1 A germ-line mutation of the PTEN gene is associated with Cowden's syndrome of familial susceptibility to multiple hamartomas and to cancers of the breast, thyroid, and central nervous system.2 We describe a child who inherited mutations of both TP53 and PTEN.

A 7-month-old girl received concurrent diagnoses of an abdominal-wall lipoma and stage 3 differentiating neuroblastoma; at 16 months of age, a localized, anaplastic juvenile granulosa-cell tumor of the ovary was detected. She also had macrocephaly and hemangiomas. At 3 years of age, a temporal-lobe xanthoastrocytoma developed, and at 4 years of age, she was found to have a pelvic pleomorphic liposarcoma that was metastatic to lung and bone and that was unresponsive to therapy. Histologic analysis of the four tumors revealed extreme pleomorphism and bizarre mitoses with abnormal karyotypes (Figure 1Figure 1Histologic Specimens from Tumors of the Proband.).

At 7 years of age, the proband's sister received a diagnosis of synchronous anaplastic medulloblastoma and abdominal ganglioneuroma. The father had benign thyroid disease and macrocephaly, and his family history included early-onset breast cancer in two aunts. The patient's mother had a cerebellar astrocytoma, two vaginal tumors, and a malignant nevus (Figure 2AFigure 2Pedigree of the Proband's Family, RNA Analysis of PTEN, and Analysis of Loss of Heterozygosity in a Tumor Specimen.).

The germ-line PTEN genes of the child and her father had a base change, c.334C→G. Although this change putatively encodes an L112V missense mutation, PTEN messenger RNA (mRNA) analysis instead revealed activation of a cryptic splice site (Figure 2B). The germ-line TP53 gene in the proband, her sister, and her mother contained an R282W deleterious missense mutation. Thus, the proband had inherited deleterious mutations in both TP53 and PTEN.

In tumors from patients with the Li–Fraumeni syndrome or Cowden's syndrome, there is often somatic mutation or silencing of the second copy of the tumor-suppressor gene.3 The granulosa-cell tumor, xanthoastrocytoma, and multiple liposarcoma samples from our proband revealed no somatic mutations in TP53 or PTEN. Loss of heterozygosity was not detected in TP53, but it was detected in PTEN in the granulosa-cell tumor and the liposarcoma specimen after chemotherapy (but not in specimens from the initial resection and lung metastasis) (Figure 2C). The finding that several of the patient's tumors did not have loss of heterozygosity or somatic mutations was also reported for tumors from a mouse model that was doubly heterozygous for p53 and Pten mutations.4

The types and numbers of tumors that developed in the proband by 4 years of age are not typical of the Li–Fraumeni syndrome or Cowden's syndrome, and four malignant conditions are expected to develop in only 2% of patients with the Li–Fraumeni syndrome.1,5 This tumor spectrum may reflect the intricate coregulation of the TP53 and PTEN proteins.4 Clinically, it may be useful to sequence in parallel multiple cancer-associated genes of patients with unusual cancer phenotypes.

Sharon E. Plon, M.D., Ph.D.
Michael L. Pirics, B.Sc.
Jed Nuchtern, M.D.
John Hicks, M.D., Ph.D.
Heidi Russell, M.D.
Baylor College of Medicine, Houston, TX 77030
splon@bcm.edu

Shipra Agrawal, Ph.D.
Kevin Zbuk, M.D.
Charis Eng, M.D., Ph.D.
Cleveland Clinic Foundation, Cleveland, OH 44195

Madhuri Hegde, Ph.D.
Ephrem Lip-Hon Chin, B.Sc.
Emory University School of Medicine, Atlanta, GA 30322

5 References

1. 1

   Birch JM, Alston RD, McNally RJ, et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 2001;20:4621-4628
   CrossRef | Web of Science | Medline

2. 2

   Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004;22:2954-2963
   CrossRef | Web of Science | Medline

3. 3

   Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001;1:157-162
   CrossRef | Web of Science | Medline

4. 4

   Freeman DJ, Li AG, Wei G, et al. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 2003;3:117-130
   CrossRef | Web of Science | Medline

5. 5

   Hisada M, Garber JE, Fung CY, Fraumeni JF Jr, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 1998;90:606-611
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Franck Bourdeaut, Bertrand Isidor, Sandrine Ferrand, Caroline Thomas, Anne Moreau, Marc-David Leclair, Albert David, Gaelle Pierron, Cedric Le Caignec, Olivier Delattre. (2011) Homozygous PTEN deletion in neuroblastoma arising in a child with Cowden syndrome. American Journal of Medical Genetics Part A 155:7, 1763-1766
   CrossRef

2. 2

   Matthew J. Schniederjan, Bahig Shehata, Daniel J. Brat, Natia Esiashvili, Anna J. Janss. (2009) De novo germline TP53 mutation presenting with synchronous malignancies of the central nervous system. Pediatric Blood & Cancer 53:7, 1352-1354
   CrossRef