More genetic markers for inherited testicular cancer identified
A new meta-analysis increased the number of genetic locations for disease
by 40 percent

Date:
July 29, 2021
Source:
University of Pennsylvania School of Medicine
Summary:
A meta-analysis of nearly 200,000 men revealed 22 new genetic
locations that could be susceptible to inherited testicular germ
cell tumors.



FULL STORY ==========================================================================
A meta-analysis of nearly 200,000 men revealed 22 new genetic locations
that could be susceptible to inherited testicular germ cell tumors
(TGCT) -- a 40 percent increase in the number of regions known to be
associated with the cancer. The new findings, published online in Nature Communications, could help doctors understand which men are at the highest
risk of developing the disease and signal them to screen those patients.


==========================================================================
The multi-institutional meta-analysis was conducted by researchers
from The international TEsticular CAncer Consortium (TECAC), led by
Katherine L.

Nathanson, MD,deputy director of Penn's Abramson Cancer Center and
Pearl Basser Professor of BRCA-Related Research in the Perelman School
of Medicine at the University of Pennsylvania.

In 2017, the TECAC reported an additional 12 loci. The new study brings
the total number to 78.

"This latest set of genetic locations is adding to our understanding
of the inherited drivers of testicular cancer, as we look to improve
screening among men who may be at high risk," Nathanson said. "Although
this cancer is curable, identifying these men earlier can help save
them from having to undergo certain treatments, such as chemotherapy,
which can have late and unwanted complications." Germ cell tumors
account for 95 percent of testicular cancer cases. TGCTs are the most
common cancer in the United States and Europe in white men between the
ages of 20 and 39. The number of cases has continued to rise over the
past 25 years in white men and more recently in Latino men. Despite
significant evidence that susceptibility to these tumors is hereditary,
CHEK2 is the only moderate penetrance gene in which pathogenic variants
have been associated with risk of the cancer.

Genome-wide association studies (GWAS) have been more successful,
identifying common variations associated with risk of the
disease. Nathanson and TECAC teams have used the method to find locations
on chromosomes -- called loci - - that contain variants associated with
an increased risk of germ cell tumors.



==========================================================================
In the latest study, TECAC researchers analyzed genetic data from 10,156 testicular germ cell tumor cases and 179,683 controls in the largest
GWAS of TGCT to date.

The study revealed 22 novel loci. When taken together, the results can
explain 44 percent of the father-to-son familial risk for testicular
cancer, the authors said. Men with a high polygenic risk score (in the
95th percentile) also had a 6.8-fold increased disease risk compared to
men at the median score.

Beyond the statistical significance of the new loci, the study
also demonstrated two relevant biological pathways tied to disease susceptibility, male germ cell development and chromosomal segregation
during cell division.

When these pathways go awry, they lead to TGCT tumorigenesis.

"Results from our investigation provide further understanding of the
genetic architecture of TGCT, enhance comprehension of the biology of
male germ cell development, and highlight biological pathways specifically important to TGCT," the authors wrote. "Importantly, we have established
a polygenic risk score that identifies men at highest risk of disease,
which could be potentially applied in men with other risk factors,
such as [undescended testes] or infertility, to be targeted for early
detection and disease mitigation." Next, researchers will begin to
further investigate the increase in TGCT cases observed among Latino men
and if the genetic variants observed in mostly white men also exist in
that population.

Nathanson is a co-senior author on the study, along with Peter
A. Kanetsky, PhD, MPH, of Moffitt Cancer Center.

TECAC is supported by the National Institutes of Health (U01
CA164947). The Penn GWAS study was supported by the Abramson Cancer Center
(P30 CA016520) and the NIH (CA114478). This research was also supported
in part by the California Cancer Research Program, and with awards from
the Robert E. and May R. Wright Foundation and the Whittier Foundation.

========================================================================== Story Source: Materials provided by University_of_Pennsylvania_School_of_Medicine. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. John Pluta, Louise C. Pyle, Kevin T. Nead, Rona Wilf, Mingyao
Li, Nandita
Mitra, Benita Weathers, Kurt D'Andrea, Kristian Almstrup,
Lynn Anson- Cartwright, Javier Benitez, Christopher D. Brown,
Stephen Chanock, Chu Chen, Victoria K. Cortessis, Alberto Ferlin,
Carlo Foresta, Marija Gamulin, Jourik A. Gietema, Chiara Grasso,
Mark H. Greene, Tom Grotmol, Robert J. Hamilton, Trine B. Haugen,
Russ Hauser, Michelle A. T.

Hildebrandt, Matthew E. Johnson, Robert Karlsson, Lambertus
A. Kiemeney, Davor Lessel, Ragnhild A. Lothe, Jennifer T. Loud, Chey
Loveday, Paloma Martin-Gimeno, Coby Meijer, Je're'mie Nsengimana,
David I. Quinn, Thorunn Rafnar, Shweta Ramdas, Lorenzo Richiardi,
Rolf I. Skotheim, Kari Stefansson, Clare Turnbull, David J. Vaughn,
Fredrik Wiklund, Xifeng Wu, Daphne Yang, Tongzhang Zheng, Andrew
D. Wells, Struan F. A. Grant, Ewa Rajpert-De Meyts, Stephen
M. Schwartz, D. Timothy Bishop, Katherine A.

McGlynn, Peter A. Kanetsky, Katherine L. Nathanson, Christian
Kubisch.

Identification of 22 susceptibility loci associated with testicular
germ cell tumors. Nature Communications, 2021; 12 (1) DOI:
10.1038/s41467-021- 24334-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210729083424.htm

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