Germline PTEN mutation Cowden syndrome: an underappreciated form of hereditary kidney cancer

Abstract

Purpose: Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma.

Materials and methods: Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity.

Results: Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies.

Conclusions: Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.

Keywords: BHD; Birt-Hogg-Dube; CS; CS associated renal cell carcinoma; CS-RCC; Cowden syndrome; HPRC; LOH; RCC; VHL; Von Hippel-Lindau; carcinoma; genetic diseases; hamartoma syndrome; hereditary papillary renal cell carcinoma; inborn; loss of heterozygosity; multiple; renal cell; renal cell carcinoma.

Figure 1. Cowden/PTEN Syndrome Family Pedigrees

Cowden/PTEN Syndrome families (patients 1-4) are shown with blue segments representing the occurrence of any Cowden Syndrome diagnostic features (described with age of diagnosis) and red segments highlighting the occurrence of Renal Cell Carcinoma (RCC). Ca. – cancer; Pap. – papillary.

Figure 2. CT Imaging of Cowden/PTEN Syndrome Associated RCC (CS-RCC)

A) A contrast-enhanced CT scan of Patient 3 demonstrating a left-sided T1a clear cell RCC. B) & C) Contrast-enhanced CT scans of Patient 4 demonstrated bilateral, multifocal chromophobe RCC, a left-sided T2 and a right-sided T1b respectively.

Figure 3. Histology of Cowden/PTEN Syndrome Associated RCC (CS-RCC)

Patients 1 (A) and 2 (B) had papillary type 1 RCC, Patient 3 had clear cell RCC (C) and patient 4 had chromophobe RCC (D).

Figure 4. Clinical Manifestations (Head Circumference and Dermatologic Lesions) that may be seen on Physical Exam of Cowden/PTEN Syndrome Patients

A) Measurement of occipito-frontal head circumferences demonstrated that all four patients had macrocephaly (>97% by height). Macrocephaly is considered major criteria for the diagnosis of Cowden Syndrome. (Adapted from Bushby, KM, et al., Arch. Dis. Child. 1992, 67:1286-1287). A variety of dermatologic manifestations are pathopneumonic for Cowden Syndrome present in Patient #1 B) Oromucosal papillomatous papules creating a cobblestone appearance on the dorsal aspect of the patients tongue C) Cutaneous verroucous papule (white arrow) located at its characteristic distribution, over the central portion of the face.

Figure 5. PTEN mutation map for CS-RCC and Evidence of PTEN loss of heterozygosity (LOH)

A) A schematic of the PTEN demonstrates the 9 coding exons (fat blue boxes) and the 5′ and 3′ UTRs (thin blue boxes) with the known functions domains shown below linked to their relevant coding exons (P60484 – http://www.uniprot.org/). The mutations from this report (red arrows) were combined with the recent series reported by Mester and colleagues (white arrows) and mapped to the PTEN gene with annotation of the reviewed pathology. Pap I – Papillary Type 1, Pap II – Papillary Type 2, Chrom – Chromophobe, Clear – Clear Cell. B) The loss of heterozygosity (LOH) was assessed in all tumors and two examples are shown here. The left panel demonstrates normal control sequence followed by heterozygous deletion of a T in the blood DNA of Patient 1, creating a frameshift, and LOH of the frameshift in the tumor DNA. The right panel demonstrates normal control sequence followed by heterozygous substitution of a C for a T in the blood DNA of Patient 4 and LOH of this mutation in the DNA of both the assessed tumors.

Figure 6. The Kidney Cancer Gene Pathways

Kidney cancer is not a single disease; it is made up of a number of different types of cancer with different histologies, having different clinical courses, responding differently to therapy and caused by different genes (e.g., VHL, MET, FLCN, FH, SDHB/C/D, TFE3, TFEB, MITF, TSC1, TSC2 and PTEN).^, The PTEN gene, which is frequently found to be mutated in the germline of patients affected with Cowden Syndrome, encodes for a plasma membrane lipid phosphatase that inhibits the PI3K signaling pathway. Loss of PTEN leads to accumulation of phosphatidlyinositol 3,4,5 triphosphate (PIP₃), which activates AKT. Activation of AKT affects the TSC1/2 pathway, resulting in activation of the mTOR pathway. (Adapted from Linehan.)