(UroToday.com) The 2022 ASCO annual meeting featured an oral abstract session on testicular cancer, including a presentation by Dr. Hong Truong discussing germline genetics of germ cell tumors, and implications for genetic testing and clinical management. Epidemiologic studies on germ cell tumors in men have shown germ cell tumors have a high heritability (37-49%). Patients with a family history of germ cell tumors have an increased relative risk of 2-12x. Furthermore, pathogenic variants in CHEK2 are associated with an increased risk of testicular cancer germ cell tumor. Yet, the genetic mechanisms underlying the development of germ cell tumors in these men remain essentially unknown. Dr. Truong and colleagues sought to determine the prevalence of pathogenic or likely pathogenic germline variants in cancer predisposition genes in men with germ cell tumors and to identify clinical and pathologic factors associated with the presence of pathogenic or likely pathogenic variants.
This study retrospectively identified men with testicular or mediastinal germ cell tumors who underwent matched tumor-germline sequencing of ≥ 310 genes as part of an institutional genomic profiling initiative from April 2015 to December 2020. The presence of germline variants in clinically actionable genes (>76) associated with hereditary cancer syndromes was analyzed. Clinicopathologic characteristics, including primary site, histology, and family history were assessed by the presence of pathogenic or likely pathogenic variants and compared using Fisher’s exact test. A summary of the methods is as follows:
The study included 477 men, 69 (15%) with mediastinal-germ cell tumor and 408 (85%) with testicular-germ cell tumors. The median age of diagnosis was 30 years (interquartile range 24 – 39). A total of 81% had non-seminoma, 5% had localized disease, 46%, 14%, and 34% had good, intermediate, and poor risk advanced disease, respectively, and 6% had family history of germ cell tumors. The baseline characteristics are as follows:
Among men with testicular-germ cell tumors, 4% had bilateral testicular-germ cell tumors. Pathogenic or likely pathogenic variants in clinically actionable genes were identified in 52 (11%) men in the entire cohort:
Men with mediastinal-germ cell tumor had higher frequency of pathogenic or likely pathogenic variants compared to those with testicular-germ cell tumors (21% vs 10%, p = 0.02). A total of 7 men with mediastinal-germ cell tumor and 20 with testicular-germ cell tumor had pathogenic or likely pathogenic variants in moderate or high penetrance cancer predisposition genes (p = 0.09). Most pathogenic or likely pathogenic variants in both mediastinal-germ cell tumor (73%) and testicular-germ cell tumor (77%) were in genes involved in DNA damage repair pathways. The spectrum of moderate or high penetrance DNA damage repair genes identified is shown as follows:
Family history and histology (seminoma vs. non-seminoma) were not associated with the presence of a pathogenic or likely pathogenic variants in the overall cohort (p = 0.8 and 0.7, respectively). Bilateral disease was not associated with the presence of pathogenic or likely pathogenic variants in men with testicular-germ cell tumor (p = 0.4). Pathogenic variants in germ cell tumor cases as compared to the general population is as follows:
Based on these (and others) results, there may be implications of positive germline testing results for patients with TP53, CHEK2, ATM, PALB2, and BRCA1/2 mutations, as highlighted in the following table:
The strengths of the current study are that (i) there was well-annotated clinical information, including personal and family history, available, (ii) it is the largest unselected cohort of mediastinal germ cell tumor patients with germline sequencing, and (iii) there was matched tumor and normal sequencing available. The limitations of this study are that (i) it was a single institutional cohort, and (ii) it may not reflect the general population of patients with germ cell tumors, given that more patients had advanced disease, and there was a high proportion of patients with Ashkenazi Jewish ancestry (9/56, 16%, pathogenic germline variants were founder mutations).
Dr. Truong concluded this presentation by discussing germline genetics of germ cell tumors, and implications for genetic testing and clinical management with the following summary points:
- Approximately 1 in 6 men with mediastinal-germ cell tumor carried a pathogenic or likely pathogenic variant in a clinically actionable cancer susceptibility gene and 10% had a pathogenic or likely pathogenic variant in a high-risk gene such as TP53 and PMS2
- Patients with mediastinal germ cell tumor should be considered for genetic evaluation
- As men with germ cell tumors tend to develop disease in early adulthood, identification of germline pathogenic or likely pathogenic variant has significant implications for enhanced cancer screening and surveillance, cascade testing for at-risk family members, and potential preconception genetic counseling
Presented by: Hong Truong, MD, Memorial Sloan Kettering Cancer Center, New York, NY
Co-Authors: Vignesh Ravichandran, Yelena Kemel, Andrea Knezevic, Jack Patrick Gleeson, Nicole Benfante, Maria Bromberg, Mary Bolos, Gabriella Joseph, Richard Matulewicz, Joel Sheinfeld, Samuel Aaron Funt, Deaglan Joseph McHugh, Dean F. Bajorin, Mark Donoghue, Zsofia Kinga Stadler, Darren R. Feldman
Affiliations: Memorial Sloan Kettering Cancer Center, New York, NY, MMUH, Dublin, Ireland
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.