No abstract

Ongoing modernization in India has elevated the prevalence of many complex genetic diseases associated with a western lifestyle and diet to near-epidemic proportions. However, although India comprises more than one sixth of the world's human population, it has largely been omitted from genomic surveys that provide the backdrop for association studies of genetic disease. Here, by genotyping India-born individuals sampled in the United States, we carry out an extensive study of Indian genetic variation. We analyze 1,200 genome-wide polymorphisms in 432 individuals from 15 Indian populations. We find that populations from India, and populations from South Asia more generally, constitute one of the major human subgroups with increased similarity of genetic ancestry. However, only a relatively small amount of genetic differentiation exists among the Indian populations. Although caution is warranted due to the fact that United States–sampled Indian populations do not represent a random sample from India, these results suggest that the frequencies of many genetic variants are distinctive in India compared to other parts of the world and that the effects of population heterogeneity on the production of false positives in association studies may be smaller in Indians (and particularly in Indian-Americans) than might be expected for such a geographically and linguistically diverse subset of the human population.

We recently identified a frame-shift mutation in the PAX9 gene as the underlying cause for hypodontia involving permanent molar teeth segregating in an autosomal dominant pattern in a single large family (Stockton et al. 2000). Here we report a small nuclear family in which a father and his daughter are affected with severe hypodontia, involving agenesis of all primary and permanent molars, evidently caused by deletion of the entire PAX9 gene. Hemizygosity at the PAX9 locus in the two affected individuals was initially discovered when an informative single nucleotide polymorphism, identified while sequencing the gene for mutations, appeared to demonstrate non-Mendelian inheritance. Fluorescence in situ hybridization (FISH) analysis with a cosmid containing the PAX9 gene yielded a signal on only one chromosome 14 homologue and confirmed the presence of a deletion encompassing the PAX9 locus. Analysis of microsatellite loci in the vicinity of PAX9 delineated one breakpoint of the deletion. These data, in concert with FISH analysis with cosmids encompassing a 199 kb region, indicated that the deletion is between approximately 44 kb and 100 kb. PAX9 is one of two genes, and the only odontogenic gene within the deletion interval, thus supporting the model of haploinsufficiency for PAX9 as the underlying basis for hypodontia.

We describe the molecular analysis of three families with hypodontia involving primarily molar teeth and report two novel mutational mechanisms. Linkage analysis of two large families revealed that the hypodontia was linked to the PAX9 locus. These two families revealed missense mutations consisting of a glutamic acid substitution for lysine and a proline substitution for leucine within the paired domain of PAX9. A pair of identical twins affected with hypodontia in a third family demonstrated a 288-bp insertion within exon 2 that resulted in a putative frameshift mutation and a premature stop codon. The insertion was associated with the loss of 7-bp from exon 2. A block of 256-bp of sequence within the insertion was completely identical to downstream sequence from the second intron of the PAX9 gene. These studies extend the spectrum of mutations in PAX9 associated with hypodontia to include heretofore undescribed categories, including missense mutations.

Purpose:We examined a cohort of patients with alveolar soft part sarcoma (ASPS) treated at our institution and showed the characteristic ASPSCR1-TFE3 fusion transcript in their tumors. Investigation of potential angiogenesis-modulating molecular determinants provided mechanistic and potentially therapeutically relevant insight into the enhanced vascularity characteristic of this unusual tumor. Experimental Design: Medical records of 71patients with ASPS presenting at the University of Texas M.D. Anderson Cancer Center (1986-2005 were reviewed to isolate 33 patients with formalin-fixed paraffin-embedded material available for study. RNA extracted from available fresh-frozen and formalin-fixed paraffin-embedded human ASPS tumors were analyzed for ASPSCR1-TFE3 fusion transcript expression using reverse transcription-PCR and by angiogenesis oligomicroarrays with immunohistochemical confirmation. Results: Similar to previous studies, actuarial 5-and 10-year survival rates were 74% and 51%, respectively, despite frequent metastasis. ASPSCR1-TFE3 fusion transcripts were identified in 16 of 18 ASPS samples. In the three frozen samples subjected to an angiogenesis oligoarray, 18 angiogenesis-related genes were up-regulated in tumor over adjacent normal tissue. Immunohistochemistry for jag-1, midkine, and angiogenin in 33 human ASPS samples confirmed these results. Comparison with other sarcomas indicates that the ASPS angiogenic signature is unique. Conclusion: ASPS is a highly vascular and metastatic tumor with a surprisingly favorable outcome; therapeutically resistant metastases drive mortality. Future molecular therapies targeting overexpressed angiogenesis-promoting proteins (such as those identified here) could benefit patients with ASPS. Alveolar soft part sarcoma (ASPS) is a malignancy of uncertain histogenesis, first described in 1952 (1). A rare soft tissue sarcoma (STS) subtype, it has a uniquely indolent growth pattern combined with unexpectedly high metastatic (particularly pulmonary) activity. Unlike other STS, ASPS also metastasizes to the brain (2 -7). Interestingly, whereas the metastatic rates in this disease are high, prior large series indicate prolonged survival with metastatic disease. Surgery is the therapeutic mainstay for localized and metastatic disease; chemoresistance frequently precludes meaningful systemic intervention. A characteristic translocation in ASPS results in a novel fusion of the ASPSCR1 (previously designated ASPL) and TFE3 genes (chromosomes 17q25 and Xp11.2, respectively), resulting in a functional transcription factor with altered target gene activation (8). This creates a novel ASPSCR1-TFE3 fusion protein that seems to acts as an aberrant transcription factor that induces unregulated transcription of TFE3-regulated genes.Histologically, ASPS has a distinctive appearance, usually consisting of nests of epithelioid to polygonal cells arranged in nests or bundles, sometimes with a central lack of cohesion that is reminiscent of pulmonary alveolar structures. Intracellul...