Background
A small cell carcinoma of the ovary of hypercalcemic type (SCCHT) is a rare and highly malignant neoplasm affecting young females. In the largest published group of patients the age of onset ranged from 9 to 43 years (median 24 years). Microscopically, the predominant population is that of small undifferentiated ovoid cells. There are also foci of large cells with eosinophilic cytoplasm, with or without eccentrically displaced nuclei (rhabdoid features). The architecture is heterogeneous and disordered, with pseudofollicles [
1,
2].
The SCCHT grows rapidly and shows poor response to available chemotherapies. Overall survival of affected patients is generally short; it largely depends on a clinical stage and ranges from 5 months to several years at the FIGO I stage, and 2–23 months at the FIGO III stage [
3].
Familial occurrence of the SCCHT has been described in a few reports, and it led to death of young first degree relatives [
4-
7]. Thus, identification of patients at risk of development of this neoplasm and its early detection might improve the prognosis.
Until recently, the SCCHT remained a mystery in terms of histogenesis and molecular background [
2,
8-
10]. In year 2013, our research group has described its development in association with an ovarian immature teratoma and brought to light its similarity to atypical teratoid/rhabdoid tumor of the central nervous system (AT/RT). Based on these findings and the fact that some AT/RTs may develop due to
SMARCA4 gene mutations [
11], we performed an analysis of this gene and identified
SMARCA4-inactivating mutations in two SCCHT analyzed [
12]. Subsequently, other groups have also found
SMARCA4 mutations in this neoplasm [
13-
15] and all these findings suggest that the SCCHT is an ovarian rhabdoid tumor.
The SMARCA4 gene encodes an ATP-dependent helicase BRG1 which belongs to the SWI/SNF (mating type SWItching defective/Sucrose Non Fermenting) complex and is involved in epigenetic regulation of gene expression via chromatin remodeling. The importance of different SMARCA4 alterations, their penetrance and traits of inheritance are just beginning to be explored. In this study we present germline alterations of the SMARCA4 gene in two patients diagnosed with the SCCHT; one of these alterations was present in three generations of the proband’s relatives.
Discussion
SMARCA4 gene alterations have recently been found to underlie a development of the ovarian small cell carcinoma of hypercalcemic type [
12-
15]. In this study we present two patients with novel germline
SMARCA4 alterations. The pedigree chart of one family shows that the c.3760G > T; p.(Glu1254*)
SMARCA4 mutation, occurring across three generations, was inherited in an autosomal manner.
This is only the fifth family with the ovarian SCCHT and the
SMARCA4 germline mutation, after four pedigrees published by Witkowski et al. [
15]. In each family of the latter study, the mutation of
SMARCA4 gene was carried by a mother and a daughter, and all of them were affected by an ovarian cancer, mostly the SCCHT. In one of those families, similarly to our results, the mutation was also identified in the proband’s father. Interestingly, in both our and the Witkowski’s et al. [
15] study, all examined offsprings carried the germline
SMARCA4 mutation detected in their ancestors. Since not all mutation carriers have been diagnosed with cancer, the penetrance of the
SMARCA4 gene appears incomplete. This has also been raised by Hasselblatt et al. [
17] on the basis of data on children with AT/RT carrying a germline
SMARCA4 mutation, and their families.
Recently, other groups have also found germline
SMARCA4 mutations in patients with the SCCHT [
13,
14], however, they did not present a pedigree analysis. In accordance with our results, all
SMARCA4 germline mutations described to date caused a premature stop codon or altered splice site, and were associated with somatic loss of the wild-type allele and SMARCA4/BRG1 protein expression in the tumors [
11,
13-
15,
18,
19].
In mammalian cells, the SWI/SNF complex exhibits the tumor suppressor activity, and SMARCA4/BRG1 protein is one of its two most essential subunits. Malfunction of the complex may negatively affect cell migration, nuclear hormone receptors signaling, embryonic stem cell programs, lineage-specific differentiation and cell proliferation [
20]. The both germline alterations in the
SMARCA4 gene reported by our research team occurred in the important ATPase domain (functioning as the motor units that convert ATP energy to mechanical movement) [
21].
Mutations in the
SMARCA4 gene appear to be associated with various cancers including malignant melanoma, non-small cell lung cancer, head and neck and pancreatic cancer [
22]. Families with germline
SMARCA4 mutations have been reported to develop malignant rhabdoid tumors (SCCHT, AT/RT, renal rhabdoid tumor) and yolk sac tumor (YST), all belonging to the group of embryonal tumors [
15,
17,
18]. Our study apparently adds two tumor types to the spectrum of cancers observed in carriers of
SMARCA4 mutations, i.e., the ovarian immature teratoma and carcinoma of the parotid gland. The immature teratoma showed diminished expression of the BRG1 protein compared with normal tissues, thus it presumably retained one wt
SMARCA4 allele [
12]. As to the parotid gland carcinoma, we do not know whether there was LOH at the gene locus in this tumor. However, other authors describing
SMARCA4 mutations in different cancers did not evaluate LOH as well (Shain & Pollack [
22]). Haploinsufficiency of the
SMARCA4 gene should also be taken into account as a potential mechanism of tumor progression, since it was previously reported by Bultman et al. for heterozygous
Smarca4 (+/−) mice developing mammary tumors [
23].
Previously, we demonstrated foci of immature teratoma (a germ cell tumor) in two ovarian SCCHT (including the first one presented in this study) [
12]. Thus, some SCCHT appear to originate from immature teratoma, as many other secondary tumors developing in this pluripotential neoplasm, and this does not contradict their assignment to the group of rhabdoid tumors. In one of their recent studies, Witkowski et al. [
19] found a germline
SMARCA4 mutation in a patient with an original diagnosis of ovarian immature teratoma and suggested that it might have been a malignant rhabdoid tumor. As we have demonstrated, rhabdoid tumors may develop in association with the immature teratoma and this neoplasm may be observed in the
SMARCA4 mutation carriers.
The penetrance of the
SMARCA4 gene appears to be limited, and factors that modify it are to be discovered. Based on pedigrees described by Witkowski et al. [
15] and our study, it appears that female carriers are more susceptible to cancers than males. Due to high aggressiveness of the SCCHT, it seems reasonable to offer the patients with this cancer and their families a molecular diagnostics of the
SMARCA4 gene.
SMARCA4 mutation carriers should be subjected to thorough observation, including ultrasonographic and magnetic resonance imaging of potentially affected organs. Since the SCCHT develops to age 44, an option might be a prophylactic oophorectomy in older patients who completed their families, provided that they would be informed that the risk of the disease has not yet been determined. It appears that women from families with more than one female members affected by the SCCHT are at particular risk of developing this neoplasm.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
JM-S participated in coordination of the study, carried out a molecular analysis, drafted the manuscript. LS carried out a molecular analysis, drafted the manuscript. DN participated in interviewing the family members and collecting data. AD-M, AB, BK, JP-H, AP, IKR performed a molecular analysis. JK designed and coordinated the study, participated in interviewing the patients and their family members, collected data and tumors, made a histopathological evaluation of the tumors, drafted the final version of the manuscript. All authors read and approved the final manuscript.