A proposed explanation for female predominance in ASPS

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Article first published online: 3 FEB 2005

DOI: 10.1002/cncr.20899



Abstract

BACKGROUND


Alveolar soft-part sarcoma (ASPS) is a rare malignant soft tissue tumor with both clinically and morphologically distinct features. It often involves the extremities of adolescents and young adults and shows a predilection for females. Recently, ASPS was found to have a nonreciprocal der(17)t(X;17) translocation with the corresponding fusion gene located in chromosome 17. Because females have an extra X-chromosome, their likelihood of developing an X;autosome translocation is theoretically double that of males, and thus, this extra X-chromosome is a likely explanation for female predominance of ASPS.

METHODS

The authors used data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry program, which included 87 ASPS cases (33 males and 54 females), and published ASPS cases, which included 317 cases (121 males and 196 females), to test our hypothesis. The authors compared the observed proportion of female cases with that expected under the two X-chromosomes–double-risk hypothesis including the consideration of X-inactivation status.


RESULTS


The hypothesis that the fusion gene is not subject to X-inactivation is supported by data (P = 0.6, 0.24, and 0.20 for SEER cases, published cases, and their combination, respectively). In contrast, the competing hypothesis that the fusion gene is subject to X-inactivation is rejected (P = 0.007, < 0.00001, and < 0.00001 for SEER cases, published cases, and their combination, respectively).


CONCLUSIONS


Therefore, the authors found a statistical association between the female predominance observed in ASPS and female possession of an extra X-chromosome/noninactivation of the ASPS X;autosome translocation fusion gene. Cancer 2005. © 2005 American Cancer Society.


DISCUSSION


Based on the biology of X-inactivation, autosomal location of the ASPL-TFE3 fusion gene, and female predominance seen in ASPS, the authors hypothesized that the increased risk of ASPS in females is due to their possession of an extra X-chromosome and the ASPL-TFE3 fusion gene being not subject to X-inactivation. The authors tested this hypothesis and found that both SEER registry data and published cases are consistent with this hypothesis. The SEER cases are population based, whereas cases from literature compilation are not, and thus the latter may be subject to bias. Nevertheless, the observed proportion of female cases in both data sets was similar. The 2 data sets together have more than 400 ASPS cases, which is the largest compilation of cases to date. The combination of these two complementary data sets likely represents a true picture of ASPS in terms of the sex-specific proportion of cases. Similar results were obtained from analyzing both data sets separately and in combination, thus providing further support for this argument. In the current study, the authors were unable to examine results by race and geographic region because of limited numbers of cases and/or incomplete information.


ASPS and synovial sarcoma (SS) share many similarities. They both are malignant soft-tissue sarcomas with unique morphology and unknown histogenesis, and both ASPS and SS show a characteristic X;autosome translocation, ASPS at t(X;17) and the others at t(X;18). However, some key differences between the two tumors exist. In contrast to ASPS, SS does not show a female predominance, and its SYT-SXX fusion gene is located in the derivative X-chromosome, and, thus, it is subject to X-inactivation. Based on the model in the current study, the X-inactivation is probably a key factor in determining the fate of an oncogenic X;autosome translocation fusion gene. Further, using SEER data on SS, the authors previously provided population-based evidence to support our hypothesis that no increased risk of SS in females is due to t(X;18) fusion gene being subject to X-inactivation.134


Interestingly, a balanced t(X;17)(p11.2; q11) has been reported in a subset of young patients with renal cell carcinoma.6, 136, 137 The same fusion transcript ASPL-TFE3 as that of ASPS was identified in these patients. Unlike in ASPS, a balanced or reciprocal translocation is present in all cases tested by fluorescence in situ hybridization.6 A reciprocal fusion product, TFE3-ASPL, was found in all three males, but only in two out of five females, by reverse transcriptase-polymerase chain reaction (RT-PCR). The existence of female patients with identifiable ASPL-TFE3 fusion product but no TFE3-ASPL fusion product appears initially confusing but, actually, is consistent with and supportive of our model. According to our model, the TFE3-ASPL fusion gene at the der(X) is subject to X-inactivation; thus a fusion transcript can only be identified in those females with activated der(X) but not in those females with inactivated der(X). In contrast, ASPL-TFE3 fusion gene on the der(17) is not subject to X-inactivation, and, therefore, is functional.


The results of the present study should be interpreted with caution because what the authors found is just a statistical association or population-based evidence awaiting future molecular evaluation. There are many tumors that have unequal sex ratios but no known genetic involvement of X-inactivation. Our model is only applicable to very few tumors with a defined X;autosome translocation under a certain precondition. In addition, our model is also limited because other alternate non–X chromosome related hypotheses, such as hormonal, occupational, or social factors, can theoretically explain the female predominance in ASPS.


In summary, using two complementary data sets, the authors have shown a statistical association between the increased risks of ASPS in females, i.e., female predominance and their possession of an extra X-chromosome and ASPS t(X;17) translocation fusion gene being not subject to X-inactivation. However, evaluation of this hypothesis at the molecular level is warranted and may explain how a chromosomal translocation can modify the gender distribution of a sarcoma.




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