Implementing a Shared Decision Model for Optimal Genetic Testing: Role of SMARCA4 Variants

Terry Marina^*
*Correspondence: Terry Marina, Department of Genomic Medicine, University of Pennsylvania, Philadelphia, USA, Email:

Description

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but highly aggressive malignancy that predominantly affects young women. It is characterized by rapid tumor growth, early metastasis and resistance to conventional treatment modalities. Recent research has shed light on the role of a specific genetic alteration in the pathogenesis of this deadly cancer— the SMARCA4 deleterious variant. In this article, we delve into the intricacies of SCCOHT, explore the implications of SMARCA4 gene mutations and emphasize the importance of genetic testing for both patients and at-risk family members.

SCCOHT accounts for a small fraction of ovarian cancers, but its aggressive nature makes it particularly devastating. Afflicting predominantly young women, SCCOHT presents with non-specific symptoms such as abdominal pain, bloating and weight loss. Diagnosing SCCOHT can be challenging due to its rarity and resemblance to other ovarian tumors. However, advances in genetic testing have significantly contributed to identifying the underlying genetic aberrations associated with SCCOHT. A major breakthrough in understanding SCCOHT came with the discovery of the SMARCA4 gene's involvement. The SMARCA4 gene encodes for a protein involved in chromatin remodeling, playing a critical role in gene expression regulation. Deleterious variants in the SMARCA4 gene lead to dysfunction in chromatin remodeling, resulting in uncontrolled cellular growth and the development of SCCOHT.

SMARCA4 gene mutations can occur as somatic mutations within tumor cells or as germline mutations, inherited from one or both parents. Somatic mutations are unique to the tumor and not present in other cells of the body, while germline mutations are hereditary and can be passed on to future generations. Understanding the inheritance pattern of SMARCA4 mutations is crucial for providing appropriate genetic counseling and testing for at-risk individuals. Given the potential hereditary nature of SMARCA4 mutations, cascade genetic testing becomes imperative in identifying at-risk family members. Cascade testing involves offering genetic testing to relatives of individuals who have been diagnosed with a specific genetic condition. Implementing a shared decision model helps optimize the process, considering the benefits, risks and personal preferences of the individuals involved. Genetic counseling plays a central role in guiding patients and their families through the testing process, providing information about the implications of testing and helping them make informed decisions.

Small cell carcinoma of the ovary, hypercalcemic type is a devastating cancer that poses significant challenges for diagnosis and treatment. The identification of the SMARCA4 deleterious variant as a key driver in SCCOHT has opened new avenues for understanding the disease's biology. Genetic testing, particularly cascade testing, plays a crucial role in identifying at-risk individuals and guiding appropriate management strategies. By utilizing a shared decision model and incorporating genetic counseling, healthcare professionals can optimize the testing process, empowering patients and families to make informed choices regarding their genetic health. Further research into the molecular mechanisms underlying SCCOHT and the development of targeted therapies holds promise for improving outcomes in this aggressive malignancy. Through collaborative efforts between researchers, clinicians and patients, we can strive towards better prevention, early detection and personalized treatment approaches for small cell carcinoma of the ovary, hypercalcemic type.

Genetic variations play a crucial role in the development of various diseases, including cancer. The SMARCA4 gene, a key regulator of chromatin remodeling, has garnered significant attention due to its association with diverse malignancies. Notably, deleterious variants in the SMARCA4 gene have been identified as drivers of both somatic and germline mutations. Understanding the distinction between these two types of variants is essential for comprehending disease mechanisms, informing clinical management and offering appropriate genetic counseling. This article delves into the intricacies of somatic and germline deleterious variants in the SMARCA4 gene, shedding light on their distinct implications in disease progression.

Somatic variants refer to genetic alterations that occur exclusively within the tumor cells of an affected individual. In the context of the SMARCA4 gene, somatic deleterious variants arise during the course of tumor development and are not present in the germline (reproductive cells). Somatic mutations in SMARCA4 are often associated with specific malignancies, such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and other rare tumors. These alterations disrupt the normal function of the SMARCA4 gene, leading to dysregulation of chromatin remodeling processes, uncontrolled cell growth and tumor formation. In contrast to somatic variants, germline variants are inherited from one or both parents and can be transmitted across generations. Individuals harboring germline deleterious variants in the SMARCA4 gene possess an increased predisposition to develop certain types of cancers. For instance, germline SMARCA4 mutations have been implicated in the development of SCCOHT, as well as familial schwannomatosis and rhabdoid tumor predisposition syndrome. Genetic counseling and testing are crucial for identifying individuals carrying germline variants, as they may require specialized surveillance and preventive measures.

Differentiating between somatic and germline variants in the SMARCA4 gene is of paramount importance in clinical practice. For patients with somatic variants, the focus lies primarily on tailored treatment strategies, such as targeted therapies aimed at restoring normal gene function or inhibiting downstream pathways. Conversely, individuals with germline variants necessitate a comprehensive evaluation of their cancer risk and the possibility of hereditary transmission to offspring. Genetic counseling provides valuable support, assisting patients and their families in understanding the implications of these variants, facilitating informed decision-making and offering recommendations for early detection and prevention strategies. Identification of a deleterious SMARCA4 variant in an affected individual should prompt cascade genetic testing within at-risk families. Cascade testing involves offering genetic testing to relatives of an individual who carries a known pathogenic variant. This approach helps identify other family members who may have inherited the variant, enabling early detection and tailored management plans. Cascade genetic testing, combined with genetic counseling, empowers at-risk individuals to make informed decisions regarding their health and facilitates the implementation of appropriate preventive measures.

Deleterious variants in the SMARCA4 gene can manifest as either somatic or germline mutations, each carrying distinct clinical implications. Somatic variants drive tumor development and guide personalized treatment approaches, while germline variants confer hereditary cancer risks, necessitating specialized surveillance and prevention strategies. Genetic counseling and cascade genetic testing play critical roles in identifying and managing individuals at risk, providing them with the knowledge and support necessary to make informed decisions about their health. By unraveling the complexities of these variants, we can pave the way for improved diagnostics, tailored therapies and enhanced cancer care.

Cascade genetic testing, also known as familial genetic testing, is a powerful tool in identifying individuals at risk of inheriting genetic disorders within families. It involves testing relatives of an individual known to carry a specific pathogenic genetic variant. This approach holds immense value in uncovering potential genetic risks, enabling early detection and implementing appropriate preventive measures. By incorporating a shared decision model, healthcare providers can optimize cascade genetic testing, ensuring that patients and their families are actively involved in the decision-making process. In this article, we explore the significance of cascade genetic testing, its benefits and the role of shared decision making in maximizing its potential.

Cascade genetic testing involves expanding genetic testing beyond the index case, the first individual diagnosed with a particular genetic condition. It aims to identify other at-risk family members who may carry the same genetic variant, providing an opportunity for early intervention and tailored management strategies. This proactive approach plays a crucial role in preventing the onset or progression of genetic disorders and guiding appropriate medical decisionmaking. Performing cascade genetic testing within at-risk families carries numerous benefits. It not only identifies individuals who may be at increased risk of developing a genetic disorder but also provides them with an opportunity to make informed decisions regarding their health and future reproductive choices. Cascade testing can help reduce uncertainty, alleviate anxiety and improve long-term outcomes by enabling early detection and implementing preventive measures [1-5].

Acknowledgement

None.

Conflict of Interest

None.

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