Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers

Abstract

Biallelic, truncating mutations of the hSNF5/INI1 gene have recently been documented in malignant rhabdoid tumor (MRT), one of the most aggressive human cancers. This finding suggests that hSNF5/INI1 is a new tumor-suppressor gene for which germline mutations might predispose to cancer. We now report the presence of loss-of-function mutations of this gene in the constitutional DNA from affected members but not from healthy relatives in cancer-prone families. Furthermore, a constitutional mutation is documented in a patient with two successive primary cancers. In agreement with the two-hit model, the wild-type hSNF5/INI1 allele is deleted in the tumor DNA from mutation carriers. In all tested cases, DNA from parents demonstrated normal hSNF5/INI1 sequences, therefore indicating the de novo occurrence of the mutation, which was shown to involve the maternal allele in one case and the paternal allele in two other cases. These data indicate that constitutional mutation of the hSNF5/INI1 gene defines a new hereditary syndrome predisposing to renal or extrarenal MRT and to a variety of tumors of the CNS, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumor. This condition, which we propose to term "rhabdoid predisposition syndrome," may account for previous observations of familial and multifocal cases of the aforementioned tumor types. It could also provide the molecular basis for cases of Li-Fraumeni syndrome without p53 germline mutations.

Figure 1

Schematic representation of four pedigrees with mutations of hSNF5/INI1. The results of the molecular analysis are shown below each family member. Normal and italic characters indicate the results of the analysis of constitutional DNA and tumor DNA, respectively. N = normal sequence; a virgule (/) indicates that DNA was not available for analysis. Mb = medulloblastoma; other abbreviations are as defined in the text. The age (in years) of the healthy sibs is indicated. In pedigree 4, the results of the DNA analysis of the two tumors (T1 and T2) are given.

Figure 2

Loss of the wild-type hSNF5/INI1 allele in tumors. The results for the male child in pedigree 3 who had ATTR (II.6) and for the patient in pedigree 4 who had bifocal tumors (II.1) are depicted. The normal sequences (N) are shown at the top; the constitutional sequences (C) that demonstrate heterozygosity between wild-type and mutated alleles are shown below them. a, Case II.6 from pedigree 3. The sequence of the ATTR DNA (T) shows the mutated 591delG allele with complete disappearance of the wild-type allele. b, Case II.1 from pedigree 4. DNA from the two successive tumors (T1 [renal MRT] and T2 [central PNET]) demonstrates the presence of the 601T mutated allele and the loss of the wild-type 601C allele. Therefore, in these three tumors, no functional allele of hSNF5/INI1 was retained.

Figure 3

Parental origin of the mutated allele. Haplotypes around the hSNF5/INI1 gene on chromosome 22 are displayed for pedigrees 2–4. Paternal and maternal haplotypes are indicated on the left and right, respectively. The seven microsatellite markers shown on the left are included within a 3-cM region (Dib et al. 1996). “C” and “T” denote constitutional DNA and tumor DNA, respectively. The point mutations of hSNF5/INI1 are depicted by red crosses. In pedigree 3, the mutation is carried by the maternal allele, whereas in pedigrees 2 and 4 it involves the paternal allele.