Abstract
Approximately 18% of ovarian cancers have an underlying genetic predisposition and many of the genetic alterations have become intervention and therapy targets. Although mutations in MutY homolog (MUTYH) are best known for MUTYH associated polyposis and colorectal cancer, it plays a role in the development of ovarian cancer. In this review, we discuss the function of the MUTYH gene, mutation epidemiology, and its mechanism for carcinogenesis. We additionally examine its emerging role in the development of ovarian cancer and how it may be used as a predictive and targetable biomarker. MUTYH mutations may confer the risk of ovarian cancer by the failure of its well-known base excision repair mechanism or by failure to induce cell death. Biallelic germline MUTYH mutations confer a 14% risk of ovarian cancer by age 70. A monoallelic germline mutation in conjunction with a somatic MUTYH mutation may also contribute to the development of ovarian cancer. Resistance to platinum-based chemotherapeutic agents may be seen in tumors with monoallelic mutations, but platinum sensitivity in the biallelic setting. As MUTYH is intimately associated with targetable molecular partners, therapeutic options for MUTYH driven ovarian cancers include programed-death 1/programed-death ligand-1 inhibitors and poly-adenosine diphosphate ribose polymerase inhibitors. Understanding the function of MUTYH and its associated partners is critical for determining screening, risk reduction, and therapeutic approaches for MUTYH-driven ovarian cancers.
Highlights
Ovarian cancer, which generally refers to cancers originating from the ovary, fallopian tube, and peritoneum, is the deadliest gynecologic cancer, responsible for taking the lives of approximately 14,000 women in the United States this year [1]
We anticipate that as we learn more about mitogen-activated protein kinase kinase (MEK) inhibitor usage in ovarian cancer, somatic testing for this gene, especially in patients with MutY homolog (MUTYH) germline mutations, may aid treatment decisions as it does in colorectal cancer [90]
Biallelic MUTYH mutation is associated with an increased risk of ovarian cancer
Summary
Ovarian cancer, which generally refers to cancers originating from the ovary, fallopian tube, and peritoneum, is the deadliest gynecologic cancer, responsible for taking the lives of approximately 14,000 women in the United States this year [1]. Other gene mutations that confer ovarian cancer risk include those involved in the development of Lynch syndrome, or hereditary non-polyposis colorectal cancer. These include mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2, MSH6), post-meiotic segregation increased 2 (PMS2), and epithelial cell adhesion molecule (EPCAM). Germline mutations in the mutY homolog (MUTYH) base excision repair gene, is best known for their role in MUTYH-associated polyposis (MAP), an autosomal recessive condition that confers a 63% risk of colorectal cancer by age 60 [12].
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