The Testicular Cancer Consortium (TECAC): Filling knowledge gaps in the genetic etiology of testicular germ cell tumors

Abstract

Background.

The Testicular Cancer Consortium (TECAC) was established in 2012 and is comprised of researchers from over 25 centers in Europe and North America. TECAC’s overarching goal is to investigate the genetic susceptibility of testicular germ cell tumors (TGCT) to better understand their biology, impact prevention strategies, and inform treatment decisions.

Objectives.

To provide an overview of TECAC genetic and phenotypic holdings.

Materials and Methods.

TECAC has composed by-laws describing the consortium structure and governance, codified the processes for manuscript development and data transfer, and developed guidance for the transfer of biological samples and access to data.

Results.

TECAC has assembled a vast amount of genetic information on males with TGCT—including SNP-array data on over 13,500 cases, whole-exome sequencing data on over 4,500 cases, and low-pass whole-genome sequence data on over 2,700 cases. Genetic information on males without TGCT (controls) is derived from studies designed to assess risk factors for TGCT and from publicly available resources. When available, corresponding phenotypic information is collected and harmonized. Fifteen publications have resulted from genetic and phenotypic information curated by TECAC.

Discussion.

The sharing of genetic and phenotypic data by TECAC centers to inform large studies of TGCT susceptibility has led to novel insights into the genetic architecture of this cancer, including the roles of genes involved in male germ cell development, sex determination, chromosomal segregation, and RNA transcription. These findings would not have been achievable by individual centers or smaller collaborative efforts.

Conclusion.

We invite investigators from any discipline who have access to collections of germline DNA, somatic cell DNA, or genomic information on males with TGCT to consider joining TECAC to further strengthen our efforts to reduce the global burden of TGCT.

Introduction

Testicular germ cell tumors (TGCT) are the most common malignancies among young males aged 15 to 39 years in the world.¹ In recent decades, an increase in the incidence of TGCT has occurred in many populations with the highest incidence (7.0 or more per 100,000 males) now observed in Western, Northern, and Southern Europe and Oceania.² In the United States, incidence currently surpasses 6.0 per 100,000 males, having increased nearly 1% per year, on average, over the past two decades.^3,4 TGCT is considered a curable cancer, yet young males still die of the disease and survivors can have serious long-term sequelae of platinum-based chemotherapy treatment, which TGCT patients with metastatic disease receive.⁵ Familial aggregation of TGCT has been documented since the 1930s, and family history is a recognized risk factor^6-9. TGCT is highly heritable and population-based estimates derived from a genomic assessment of common SNPs range from 37% to nearly 50%.¹⁰ Nonetheless, high penetrance genes have not been identified. Thus, a comprehensive appreciation of the genetic architecture of TGCT may be an effective way to identify males at higher risk for whom early detection may improve outcomes.

The mission of the Testicular Cancer Consortium (TECAC) is to investigate genetic susceptibility of TGCT to better understand TGCT biology, and to inform prevention strategies and treatment decisions. Studies of large numbers of affected individuals are crucial to the discovery of small effects associated with common inherited genetic variants and the discovery of rare variants with larger effects, and collaborative efforts to attain these large numbers are common. Such efforts are particularly necessary when studying rare cancers like TGCT. This was the major motivation for establishing TECAC.

Early investigations of TGCT genetic susceptibility were focused on the discovery of high-penetrance genes that could account for familial aggregation of disease, and these efforts were conducted by members of the International Testicular Cancer Linkage Consortium (ITCLC) who pooled resources of families with two or more members affected with TGCT.¹¹ However, linkage analyses failed to identify individual loci that accounted for observed familial aggregation.¹² In 2008, the National Cancer Institute of the US (NCI) solicited grant applications designed to tether genetic epidemiology, biology, and classical epidemiology to further transdisciplinary cancer genomic research. TECAC was born in response to this research call, and 16 international research groups came together to respond to this Post Genome Wide Association Initiative. Many of the inaugural TECAC research groups had a history of collaboration, several as part of the ITCLC. Despite TECAC’s grant application not being selected to receive funding, we repurposed several of the scientific aims and subsequently were successful at obtaining initial funding (U01CA164947) in 2012 and a competitive continuation awarded in 2020. Currently, TECAC membership is composed of researchers from over 25 research centers across North America and Europe who from local ongoing or completed studies of TGCT have contributed summary genotypic data, individual-level genotyping data, and/or biological samples for de novo genotyping.

Here, we provide an overview of current TECAC genetic and phenotypic holdings and describe the structure of TECAC and the processes for data transfer and data access.

Materials and Methods

Charter and by-laws

In support of its mission, the overarching goal of TECAC is to develop and support collaborations between research teams to identify genetic susceptibility for TGCT, assess the risk of TGCT related to variation in risk alleles at these identified genes, evaluate statistical interaction among risk alleles and between risk alleles and environmental factors, and investigate additional features of TGCT of interest to the researchers. A charter and by-laws describing the organizational structure and function of the consortium were created to outline the agreement made between and among the members of TECAC. The Governing Council, consisting of one representative from each research team, provides for the development of strategic directions and a forum for discussion. At the time of writing, 26 investigators serve on the Governing Council. This council hears reports on the progress of research activities undertaken by TECAC and is the ultimate arbitrator of any disputes within TECAC. The TECAC Steering Committee is responsible for the executive management of the TECAC, including implementing the consortium’s strategic direction and coordination of various committees and working groups to assure forward momentum of research. The Steering Committee meets regularly on a bi-weekly basis. At the time of writing, six investigators serve on the Steering Committee (all of whom also serve on the Governing Council). The External Advisory Board provides guidance and advice to the Steering Committee and Governing Council. It consists of non-TECAC researchers who are invited to serve based on alignment of their expertise with the aims of the grant award supporting TECAC scientific efforts. At the time of writing, there are two external advisors. The Coordinating Center (University of Pennsylvania) is responsible for implementing the TECAC infrastructure.

TECAC members convene annually for a daylong in-person meeting to discuss ongoing efforts coordinated through TECAC, exchange findings from TGCT-related science undertaken by individual research teams, and identify potential areas of future collaboration. To maximize in-person engagement, the annual TECAC meeting is typically scheduled opportunistically to coincide with the dates of a large professional scientific meeting with international attendance alternating between the US and Europe. TECAC members also can attend the annual meeting virtually.

Scientific communications

A TECAC manuscript is defined as a report describing scholarly work that involves data from two or more TECAC participant research teams that have been aggregated by TECAC. To produce a TECAC manuscript, the topic of the manuscript must first be proposed, reviewed, and approved. The approval process begins with the submission of a concept proposal to the TECAC Steering Committee by the primary investigator, who takes the lead role in sponsoring the development of the proposal, conducting the work to complete its specific aims, overseeing the writing of the manuscript, and submitting the manuscript for publication. The Steering Committee completes an initial review of the concept proposal focusing on the scientific value of the proposed work and the feasibility and impact on TECAC and individual participant resources. Upon approval, the concept proposal is circulated to the Governing Council for review and approval. At any point in the approval process, changes to the concept proposal (e.g., augment or focus the scope of the proposed analysis, expand the proposed manuscript writing team to incorporate other participant teams undertaking similar work) may require the submission of an amended concept proposal. Following full approval of a concept proposal, the Coordinating Center facilitates access for the primary investigator of the proposal to the requisite data and/or specimens, or results of the relevant data analyses. The Coordinating Center also can provide support for the conduct of analyses. Once available from the primary investigator, a complete draft of a TECAC manuscript is circulated to the Steering Committee and then to members of the Governing Council for editing and approval. A minimum of four weeks is needed to complete the approval process for a concept proposal or TECAC manuscript. Guidelines further outlining the work process for approved concept proposals and authorship are available to TECAC members. Abstracts to be presented at local, national, or international scientific meetings reporting on results from TECAC data require approval from the Steering Committee prior to submission, a process that typically requires a minimum of one week. For accepted abstracts, a review of the final slide deck or poster by the Steering Committee is strongly encouraged prior to presentation.

Data transfer

Each collaborating TECAC center is required to establish both a Materials Transfer Agreement (MTA) and a Data Transfer Agreement (DTA) with the University of Pennsylvania and the National Cancer Institute (NCI). As the Coordinating Cancer, the University of Pennsylvania manages genotyping and sequencing of center-submitted genetic data. The National Cancer Institute maintains the corresponding phenotype and clinical data. Contract negotiators from the University of Pennsylvania, the NCI, and each TECAC center collaborate to develop these agreements. Once finalized, they are fully executed upon signatures by the designated representatives at each center.

Genotypic data

Dependent upon local holdings and regulatory permissions, there are several opportunities for individual centers to contribute genetic information to TECAC efforts including the provision to the Coordinating Center of (i) biological samples, (ii) individual-level genotype data, and/or (iii) genetic analyses summary results.

Biological samples.

Centers are provided with guidance for transfer of germline DNA, which includes information on i) preparing DNA samples (methods of DNA quantification, diluent, concentration, volume, and total amount), ii) plating requirements (96-well plates) and sample details (plate ID, well location, local ID, disease status [e.g., TGCT case, control], DNA extraction method, DNA source, volume, concentration, total amount), and iii) packaging and shipping procedures. Received DNA aliquots are stored and prepared for centralized genotyping efforts. After genotypic analysis is completed, participating centers may request residual DNA to be stored at the Coordinating Center for future use or returned.

Individual-level genotype data.

For TECAC centers with existing genotype information (e.g., date from SNP-array and/or whole exome sequencing), individual-level genotypic information is provided to TECAC.

Summary results.

For TECAC centers that cannot share individual-level genotype data due to regulatory limitations, summary data are provided to TECAC.

Phenotype data

For TGCT cases and males with no personal history of TGCT, information on year of birth, race, ethnicity, family history of TGCT (first degree, second degree), personal history and laterality of cryptorchidism is requested. Height, weight, number of children fathered, and marital status is also requested for TGCT cases (at diagnosis) and males without TGCT (at reference date). For TGCT cases, information on diagnosis (year), tumor laterality, and histology (seminoma, non-seminoma, mixed [i.e., seminoma and non-seminoma]) is requested for each occurrence of TGCT. Phenotypic data are transferred to the (US) National Cancer Institute for extensive data cleaning and harmonization done under the supervision of TECAC members at the (US) National Cancer Institute.

TECAC is currently in the process of collecting information pertinent to patient outcomes from centers with access to such clinical data. Information being solicited includes clinical stage and pathology at date of diagnosis, first line treatment, disease relapse, treatments beyond first line, vital status and cause of death, medications, and diseases and conditions occurring after TGCT diagnosis whether attributable to treatment (e.g., late effects) or not. These data also will be aggregated, cleaned, and harmonized under the supervision of TECAC members at the (US) National Cancer Institute.

Data access

Investigators who submit a concept proposal that receives approval from the TECAC Steering and Governance Committees must sign a Data Use Agreement (DUA) to access the approved TECAC dataset and proceed with analysis. After the investigator returns the signed DUA to the Coordinating Center, data access is facilitated through Penn Medicine Academic Computing Services. All analyses must be conducted within a secure computing environment hosted at the University of Pennsylvania; data cannot be downloaded or accessed outside of this controlled setting.

Ethical considerations

For this article that provides a summary overview of TECAC processes, genetic and phenotypic holdings, and main findings to date, there is no requirement for inclusion of an ethics statement regarding human subjects research. Still, participants and corresponding data reported in TECAC publications cited in this article were originally collected and analyzed after obtaining approval from local ethics committees and after obtaining informed consent from participants.

Results

TECAC has assembled genetic information on 16,200 males with TGCT from multiple sources in Europe and North America. This total incorporates genotype data from existing external resources and genetic data obtained through centralized efforts conducted by TECAC. For these men, information on common genetic variants is available from SNP-array platforms (13,500 men; Table 1) or low-pass whole-genome sequencing (2700 men; Table 2). For 3,800 of these men, information on rare (and common) genetic variation is also available from whole-exome sequencing (Table 2). Genetic information on males without TGCT derives from studies designed to assess risk of TGCT or from publicly available resources in which genotyping has been conducted on a broad study sample for multiple purposes. Phenotypic information is available on over 12,700 TGCT cases (Table 3), representing most centers contributing individual-level data to TECAC. However, the degree of completeness of phenotypic information varies by TECAC center and reflects differences in survey instruments completed upon enrollment onto center-specific study protocols and/or differences in the availability of information through other means, e.g., electronic patient record, pathology reports, national disease registries.

Table 1.

Summary of SNP-array data available through TECAC.

Resource/Site	Males with TGCT	Males without TGCT	Data	Imputation backbone	Reference
Copenhagen University Hospital, DK	183	363	Summary statistics	1000 Genomes	Dalgaard et al.28
deCODE Genetics, IS	300	151,991	Summary statistics	(WGS)	Gudbjartsson et al.29
Institute of Cancer Research, UK	985	4,945	Individual genotype	1000 Genomes	Litchfield et al.30
Karolinska Institutet, SE/Oslo Metropolitan University, NO/Cancer Registry of Norway, NO	1,326	6,687	Summary statistics	1000 Genomes	Kristiansen et al.31
National Cancer Institute, US	582	1,056	Individual genotype	1000 Genomes	Schumacher et al.16
Oncoarray	3,198	2,937	Individual genotype	HRC	Litchfield et al.32
Penn Medicine Biobank, US	112	1,336	Individual genotype	HRC	Verma et al.33
TECAC
Fred Hutchinson Cancer Center, US	472	986	Individual genotype	HRC	Pluta et al.19
Karolinska Institutet, SE/Oslo Metropolitan University, NO/Cancer Registry of Norway, NO	866	184	Individual genotype	HRC	Pluta et al.19
MD Anderson Cancer Center, US	271	37	Individual genotype	HRC	Pluta et al.19
Oslo University Hospital, NO	660	0	Individual genotype	HRC	Pluta et al.19
Princess Margaret Cancer Center, CA	380	0	Individual genotype	HRC	Pluta et al.19
Radboud University, NL	299	1212	Individual genotype	HRC	Pluta et al.19
Universities of Leeds and Newcastle, UKa	381	239	Individual genotype	HRC	Pluta et al.19
University of Groningen, NL	487	0	Individual genotype	HRC	Pluta et al.19
University of Padova, IT	323	336	Individual genotype	HRC	Pluta et al.19
University of Pennsylvania, US	252	616	Individual genotype	HRC	Pluta et al.19
University of Regensburg, DE	427	426	Individual genotype	HRC	Pluta et al.19
University of Southern California, US	406	0	Individual genotype	HRC	Pluta et al.19
University of Turin, IT	180	275	Individual genotype	HRC	Pluta et al.19
Yale University, US	194	361	Individual genotype	HRC	Pluta et al.19
The Cancer Genome Atlas (TCGA)	139	0	Individual genotype	HRC	Shen et al.34
UK Biobank, UK	697	8,716	Summary statistics	HRC	Bycroft et al.35
University of Pennsylvania, US	481	919	Individual genotype	1000 Genomes	Kanetsky et al.15

Abbreviations: HRC, haplotype reference consortium; WGS, whole-genome sequencing; TECAC, Testicular Cancer Consortium; TGCT, testicular germ cell tumors.

^aSome sample duplication exists in the Oncoarray and Universities of Leeds and Newcastle sample sets.

Table 2.

Summary of sequencing data available through TECAC.

Resource/Site	Males with TGCT	Males without TGCT	Platform
Whole-exome sequencing
Centro Nacional de Investigaciones Oncológicas, ES	19
Dana Farber Cancer Institute, US	49		Xgen-exome-research panel
Institute of Cancer Research, UK	919		Illumina TruSeq Exome
National Cancer Institute, US/University Pennsylvania, US	249		NimbleGen SeqCap EZ Exome v3.0
Penn Medicine Biobank, US	136		xGEN Exome Hyb v2 plus
University of Pennsylvania, US	33		SureSelect Human All Exon v6
University of Pennsylvania, US	887		Twist Comprehensive Exome
TECAC
Centro Nacional de Investigaciones Oncológicas, ES	30		Twist WES v2
Fred Hutchinson Cancer Center, US	110	253	Twist WES v2
Karolinska Institutet, SE/Oslo Metropolitan University, NO/Cancer Registry of Norway, NO	327	9	Twist WES v2
Oslo University Hospital, NO	182		Twist WES v2
Princess Margaret Cancer Center, CA	113		Twist WES v2
Radboud University, NL	74	89	Twist WES v2
Universities of Leeds and Newcastle, UK	93		Twist WES v2
University of Groningen, NL	134		Twist WES v2
University of Padova, IT	89	26	Twist WES v2
University of Pennsylvania, US	74	14	Twist WES v2
University of Regensburg, DE	69	64	Twist WES v2
University of Southern California, US	2		Twist WES v2
University of Turin, IT	28	15	Twist WES v2
Yale University, US	50	12	Twist WES v2
The Cancer Genome Atlas (TCGA)	150		NimbleGen HGSC VCRome 2.1
Whole-genome sequencing
TECAC
Centro Nacional de Investigaciones Oncológicas, ES	556	663	Low pass WGS
Institute of Cancer Research, UK	626	95	Low pass WGS
MD Anderson Cancer Center, US	356	206	Low pass WGS
Memorial Sloan Kettering Cancer Center, US	25	0	Low pass WGS
Princess Margaret Cancer Center, CA	256	45	Low pass WGS
University of Florence, IT	81	71	Low pass WGS
University of Groningen, NL	383	68	Low pass WGS
University of Minnesota, US	54	0	Low pass WGS
University of Padova, IT	77	81	Low pass WGS
University of Pennsylvania, US	289	0	Low pass WGS
University of Turin, IT	69	12	Low pass WGS

Abbreviations: WES, whole-exome sequencing; WGS, whole-genome sequencing; TECAC, Testicular Cancer Consortium; TGCT, testicular germ cell tumors.

Table 3.

Harmonized phenotype data available through TECAC.

Characteristic	Males with TGCT n=12,759	Males without TGCT n=10,806
Center [n (%)]
Centro Nacional de Investigaciones Oncológicas, ES	650 (5.1)	750 (6.9)
Copenhagen University Hospital, DK	367 (2.9)	0 (0)
Fred Hutchinson Cancer Center, US	540 (4.2)	1280 (11.8)
Institute of Cancer Research, UK	970 (7.6)	2537 (23.5)
Karolinska Institutet, SE/Oslo Metropolitan University, NO/Cancer Registry of Norway, NO	2013 (15.8)	0 (0)
MD Anderson Cancer Center, US	1001 (7.8)	350 (3.2)
Memorial Sloan Kettering Cancer Center, US	32 (0.3)	0 (0)
National Cancer Institute, US (FTCS)	249 (2.0)	1455 (13.5)
National Cancer Institute, US	767 (6.0)	929 (8.6)
Oslo University Hospital, NO	738 (5.8)	380 (3.5)
Princess Margaret Cancer Center, CA	861 (6.7)	68 (0.6)
Radboud University, NL	316 (2.5)	1274 (11.8)
Ulm University, DE	461 (3.6)	1 (0)
Universities of Leeds and Newcastle, UK	1116 (8.7)	196 (1.8)
University of Florence, IT	94 (0.7)	86 (0.8)
University of Southern California, US	583 (4.6)	0 (0)
University of Groningen, NL	506 (4.0)	4 (0)
University of Padova, IT	506 (4.0)	516 (4.8)
University of Pennsylvania, US	373 (2.9)	0 (0)
University of Turin, IT	260 (2.0)	467 (4.3)
Yale University, US	356 (2.8)	513 (4.7)
Race [n (%)]
White	8905 (95.5)	7866 (94.0)
Black	70 (0.8)	114 (1.4)
Asian	87 (0.9)	96 (1.1)
Native American	17 (0.2)	21 (0.3)
Other	242 (2.6)	271 (3.2)
Missinga	3438	2438
Ethnicity [n (%)]
Non-Hispanic	7013 (94.3)	6108 (96.3)
Hispanic	420 (5.7)	232 (3.7)
Missinga	5326	4466
Marital status [n (%)]
Single	1345 (45)	715 (36.8)
Not single	1643 (55)	1230 (63.2)
Missinga	9771	8861
Height (in.) [mean, (sd)]	70.76 (3)	70.52 (3)
Weight (lbs.) [mean (sd)]	185.84 (35)	187.21 (35)
Number of children [n (%)]
0	2810 (58.2)	3354 (53.9)
1	749 (15.5)	785 (12.6)
2	893 (18.5)	1374 (22.1)
3	272 (5.6)	535 (8.6)
4	81 (1.7)	130 (2.1)
5+	24 (0.5)	50 (0.8)
Missinga	7930	4578
Family history of TGCT [n (%)]b
No	7275 (92.6)	6096 (87.0)
Yes	585 (7.4)	907 (13.0)
Missinga	4899	3803
Cryptorchidism [n (%)]
No	6026 (90.2)	7097 (98.7)
Yes	655 (9.8)	96 (1.3)
Missinga	6078	3613
Histology [n (%)]
Seminoma	5332 (48.9)	-
Nonseminoma	3577 (32.8)	-
Mixed	1981 (18.2)	-
Missinga	1859	-
Number of TGCT per man [n (%)]
One	6206 (94.7)	-
Two	345 (5.3)	-
Missinga	6208	-

Abbreviations: FTCS, Familial Testicular Cancer study; TECAC, Testicular Cancer Consortium; TGCT, testicular germ cell tumors.

^aMost missingness results from studies that did not collect this information.

^bFamily history of 1^st or 2^nd degree relative with TGCT.

Analyses of genetic information have resulted in publications reporting on genetic susceptibility to TGCT arising from candidate studies of the sex determination and DNA repair pathways,^13,14 genome-wide association studies,^15-19 and a transcriptome-wide association study²⁰ (Table 4). Over 100 genetic loci have been associated with TGCT susceptibility, most identified from these TECAC investigations, and all studies have been led by TECAC investigators. Combined data from SNP-arrays have been used to conduct a genome-wide association study of cryptorchidism, a strong TGCT risk factor; findings suggest RBFOX paralogs may play a role in risk of undescended testes.²¹ Combined data from SNP-arrays also have been used to determine genetically inferred peripheral blood leukocyte telomere length, for which there was no evidence of an association with TGCT susceptibility.²² Analyses of assembled exome data have identified CHEK2 as a TGCT moderate-penetrance locus and the roles of genes involved in chromosomal segregation and protein-targeting in TGCT etiology.^23,24 Genotypes available from TECAC also have been used in efforts to functionally characterize the pan-cancer susceptibility locus housing CLPTM1L finding an allele-specific influence of rs36115365 on TERT expression.²⁵ TECAC genotypes were also used to conduct a pan-cancer analysis of common genetic variation,²⁶ which revealed the distinctive genetic nature of TGCT arising from the larger effect sizes for susceptibility variants compared to most other cancers.

Table 4.

Published articles using genetic information assembled by TECAC.

Title of article	Year	Reference	PMID
A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility	2011	Kanetsky, et al.15	21551455
Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23	2013	Schumacher, et al.16	23462292
Meta-analysis identifies four new loci associated with testicular germ cell tumor	2013	Chung, et al.17	23666239
Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors	2014	Koster, et al.14	24943593
Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148	2017	Fang, et al.25	28447668
Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor	2017	Wang, et al.18	28604732
Subphenotype meta-analysis of testicular cancer genome-wide association study data suggests a role for RBFOX family genes in cryptorchidism susceptibility	2018	Wang, et al.21	29618007
Association of inherited pathogenic variants in checkpoint kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors	2019	AlDubayan, et al.23	30676620
Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers	2020	Zhang, et al.26	32620889
Lack of pathogenic germline DICER1 variants in males with testicular germ-cell tumors	2020	Vasta, et al.36	33158809
Genetically inferred telomere length and testicular germ cell tumor risk	2021	Brown, et al.22	33737296
Identification of 22 susceptibility loci associated with testicular germ cell tumors	2021	Pluta, et al.19	34301922
Association study between polymorphisms in DNA methylation-related genes and testicular germ cell tumor risk	2022	Grasso, et al.13	35700037
Germline exome sequencing for men with testicular germ cell tumor reveals coding defects in chromosomal segregation and protein-targeting genes	2024	Pyle, et al.24	37246069
Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study	2025	Ugalde-Morales, et al.20	39999848

Abbreviations: TECAC, Testicular Cancer Consortium.

At the time of writing, TECAC’s ongoing genetic analyses include a next-sequential genome-wide association study and a next-sequential transcriptome-wide association study using information from over 16,200 males with TGCT, and an exome-wide association study of common and rare genetic variation using information from over 3800 males with TGCT.

Discussion

The sharing of genetic and phenotypic data by TECAC centers to inform large studies of TGCT susceptibility has led to novel insights into the genetic architecture of these malignancies that would have been unachievable if conducted by individual centers or smaller collaborative efforts. Investigations conducted by TECAC investigators have discovered or confirmed the pivotal role that male germ cell development, sex determination, chromosomal segregation, and RNA transcription play in the etiology of TGCT. These findings have implications for a wide range of applications beyond TGCT control, including specification of germ cells from somatic cells and treating infertility. TECAC investigators have ongoing efforts to functionally characterize selected validated TGCT susceptibility loci.

The return on investment for continued genetic studies (e.g., through deep sequencing) to discover ‘missing heritability’ is unknown. Expanding TECAC’s centralized holdings to other biological sample types would enable alternative -omic (e.g., metabolomic, proteomic) studies of TGCT, but these efforts will require significant financial investment and substantial coordination due to likely dependence of TGCT risk on timing of non-genomic traits and exposures. However, several areas of inquiry concerning TGCT susceptibility, disease progression, and outcomes can build upon the current known genetic architecture of TGCT. Possibilities include studies that may lead to risk stratification and personalized care by learning how host genetics influence response to treatment and platinum sensitivity, disease progression, and the development of late effects; and TECAC’s current efforts to assemble data on patient outcomes will provide a resource to examine these questions. Other investigations designed to identify how inherited genetics affect somatic cell landscapes of TGCT may deepen understanding of the oncogenic process and thereby influence treatment paradigms. Because steadily rising TGCT incidence in much of Europe, North America, and Oceania implicates non-genomic environmental exposures, robust studies exploring how genetic and environmental factors may jointly influence TGCT development are needed to inform individualized strategies for primary prevention of TGCT. Because there are few established environmental risk factors for TGCT, emerging “exposome” methodology may overcome challenges to exposure assessment that arise in conventional studies of joint contributions of host genetics and environmental factors, most of which are believed to act during fetal gestation or early life. Finally, studies are warranted to assess susceptibility in genetically admixed populations as well as to investigate the interplay of TGCT genetic architecture and other conditions—cryptorchidism, hypospadias, and subfertility—that with TGCT constitute testicular dysgenesis syndrome.²⁷

To begin to address some of these research areas, the science focus of TECAC has expanded beyond genetic epidemiology over the past decade of collaboration. It now also builds upon the broad spectrum of research and clinical expertise of investigators who have joined TECAC, including the areas of developmental and germ cell biology, classical epidemiology, disparities, medical genetics, fertility, surgery, functional genetics, and survivorship. We invite investigators, especially those outside North America and Europe, from any discipline who have access to collections of germline DNA, somatic cell DNA, or genomic information related to TGCT to consider joining TECAC to further strengthen our efforts to reduce the global burden of these malignancies.