San Francisco, CA USA (UroToday.com) Dr. Katherine Nathanson of the University of Pennsylvania described inherited genetic susceptibility associated with testicular germ cell tumors. Testicular cancer is the most common cancer among white men aged 15-34 years. Over the last decade, the incidence has been rising in this population, while the incidence among black men remains low and has been relatively stable. Dr. Nathanson pointed out that all testicular cancer, both nonseminoma and seminoma, originate from a disruption in maturation of gonocytes early in development. Thus, the risk factors for developing germ cell cancers of various histologies are the same.
Men with a first-degree relative with testicular cancer have an increased of developing germ cell cancer. Having a brother with germ cell cancer increases the risk 8-10 fold, and having a father with germ cell cancer increases the risk 4-6 fold. It is not known precisely why the risk differs by relative. Approximately 40-50% of testicular cancers are believed to be associated with heritable risk factors. Genetic and environmental risk factors appear to be associated with approximately 25% of testicular cancer cases. Families with multiple testicular germ cell cases (“familial germ cell families”) do not appear to have an increased risk of other cancers or cancer syndromes. Testicular cancer risk appears to be polygenic, or associated with multiple common variants of genes, rather than associated with abnormalities in a single gene. Approximately 30 gene loci appear to be associated with testicular cancer, and a large majority are not associated with other cancer types.
The initial loci described in association with testicular cancer are at the KITLG, with a per allele odds ratio over three. This odds ratio for association with testicular cancer is the highest odds ratio, or strongest association, found for any cancer type. Dr. Nathanson noted that having a KITLG variant was necessary for the development of testicular cancer, but was not sufficient to cause the disease without other intervening factors. Normally KITLG works during embryonal development to guide the migration of germ cells, and mutations can be associated with improper migration. Mutations in KITLG loci explain approximately 33% of familial risk of testicular cancer. In addition, Dr. Nathanson’s group has developed a polygenic risk score, and find that patients with the top 1% of scores have a 10.4 fold increased risk of testicular cancer. Importantly, this translates only to a 5% absolute lifetime risk. At this point, there are no clear clinical actions to take in terms of early screening for this group of patients.
In addition to KITLG abnormalities, the group demonstrated that mutations in several biological pathways could increase the risk of testicular cancer. First, any abnormality that disrupts germ cell differentiation or maturation, and abnormalities that interrupt germ cell migration can all increase testicular cancer risk. Additionally disruptions in multiple other developmental pathways that are involved in DNA damage repair and chromosomal segregation genes. The group has also identified multiple additional genes involved in male germ cell maturation that may be associated with increased risk.
Ultimately there are multiple genetic abnormalities, both germ line and somatic, that are associated with increased risk of germ cell tumor. Up to 50% of testicular cancers appear to be associated with heritable mutations, and some of these can increase the risk by 10.4 fold. Because testicular cancer remains rare, the absolute risk, even among men with the highest risk abnormalities, is only 5%. Other than recommending routine self-exams, there are no additional screening studies recommended for men at highest risk of this disease.
Presented By:
Dr. Katherine L. Nathanson, MD
Abramson Cancer Center, University of Pennsylvania
Reported By:
Alicia K. Morgans, MD, at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Assistant Professor of Medicine Medical Oncologist
Vanderbilt - Ingram Cancer Center