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PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. METHODS: Over the past 10 years, the National Institutes of Health–supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.

Background and AimsThe microbiome has long been suspected of a role in colorectal cancer (CRC) tumorigenesis. The mutational signature SBS88 mechanistically links CRC development with the strain ofEscherichia coliharboring thepksisland that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown.MethodsSBS88-positive CRCs were identified from targeted sequencing data from 5,292 CRCs from 17 studies and tested for their association with clinico-pathological features, oncogenic pathways, genomic characteristics and survival.ResultsIn total, 7.5% (398/5,292) of the CRCs were SBS88-positive, of which 98.7% (392/398) were microsatellite stable/microsatellite instability low (MSS/MSI-L), compared with 80% (3916/4894) of SBS88 negative tumors (p=1.5×10-28). Analysis of MSS/MSI-L CRCs demonstrated that SBS88 positive CRCs were associated with the distal colon (OR=1.84, 95% CI=1.40-2.42, p=1×10-5) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6×10-6) tumor sites compared with the proximal colon. The top seven recurrent somatic mutations associated with SBS88-positive CRCs demonstrated mutational contexts associated with colibactin-induced DNA damage, the strongest of which was theAPC:c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3×10-80). Large copy number alterations (CNAs) including CNA loss on 14q and gains on 13q, 16q and 20p were significantly enriched in SBS88- positive CRCs. SBS88-positive CRCs were associated with better CRC-specific survival (p=0.007; hazard ratio of 0.69, 95% CI=0.52-0.90) when stratified by age, sex, study, and by stage.ConclusionSBS88-positivity, a biomarker of colibactin-induced DNA damage, can identify a novel subtype of CRC characterized by recurrent somatic mutations, copy number alterations and better survival. These findings provide new insights for treatment and prevention strategies for this subtype of CRC.

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76–1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92–1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01–1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk.

Here we describe MyGene2, Geno2MP, VariantMatcher, and Franklin; databases that provide variant-level information and phenotypic features to researchers, clinicians, healthcare providers and patients. Following the footsteps of the Matchmaker Exchange project that connects exome, genome, and phenotype databases at the gene level, these databases have as one goal to facilitate connection to one another using Data Connect, a standard for discovery and search of biomedical data from the Global Alliance for Genomics and Health (GA4GH).

GeneMatcher (genematcher.org) is a tool designed to connect individuals with an interest in the same gene. Now used around the world to create collaborations and generate the evidence needed to support novel disease gene identification, GeneMatcher is a founding member of the Matchmaker Exchange (MME; matchmakerexchange.org) and strongest possible advocate for global data sharing including those in resource-limited environments. As of October 1, 2021, there are 12,531 submitters from 94 countries who have submitted 58,134 submissions with 13,498 unique genes in the database. Among these genes, 8970 (64%) have matched at least once and the total number of matches is 378,806, growing by about 10,000 per month. GeneMatcher submitters increase by 80-120 each month and submissions grow by800 per month, while unique genes and gene matches continue to grow steadily at rate of about 80 per month. The number of genes without a match peaked at 4371 in February of 2019 and despite the increase in the number of new submissions, the number of unique genes without a match continues to slowly decline, currently standing at 4,016. All submissions in GeneMatcher are available for matching across the MME.

Rare pathogenic variants in DNA repair genes have been found to influence risk of aggressive prostate cancer. We conducted a large case-only exome sequencing study to further understand the role of rare coding variation in aggressive prostate cancer in a study of 9,185 aggressive (prostate cancer death, metastatic disease, T4, or both T3 and Gleason≥8) and 8,361 non-aggressive cases (T1/T2 and Gleason≤6) of European ancestry from 19 international studies. Stage 1 samples (N=5,545) had whole exome-sequencing, and stage 2 samples (N=12,001) had targeted exome sequencing for 1,459 genes selected based on stage 1 results and previous evidence. Logistic regression models were used to evaluate gene-based tests and the aggregate effect of multiple genes to investigate whether carrying pathogenic/likely pathogenic/deleterious (P/LP/D) variants (18,759 identified) was associated with risk of aggressive prostate cancer, prostate cancer death (N=6,033), or metastatic disease (N=1,730) compared to non-aggressive disease. Gene-based tests were meta-analyzed across stages 1 and 2. BRCA2, ATM, and NBN had the most statistically significant gene-based results: BRCA2 P/LP/D variant carriers had 4.3-fold higher odds of aggressive disease (95% CI=3.15-5.86, P=4x10-20), 4.7-fold higher odds of prostate cancer death (95% CI=3.41-6.59, P=2x10-20), and 5.7-fold higher odds of metastatic disease (95% CI=3.71-8.76, P=2x10-15); ATM P/LP/D variant carriers had 2.2-fold higher odds of aggressive disease (95% CI=1.58-2.99, P=2x10-6), 2.2-fold higher odds of prostate cancer death (95% CI=1.52-3.05, P=2x10-5), and 3.0-fold higher odds of metastatic disease (95% CI=1.93-4.61, P=9x10-7); and NBN P/LP/D variant carriers had 5.9-fold higher odds of metastatic disease (95% CI=2.56-13.84, P=3x10-5). Among potentially novel genes with strong but not exome-wide significant statistical evidence were MMP19, involved in reproduction and metastasis, with carriers having 2.8-fold higher odds of prostate cancer death (95% CI=1.53-5.05, P=8x10-4); PKD2L2, involved in fertility, with carriers having 3.5-fold higher odds of prostate cancer death (95% CI=1.76-7.04, P=5x10-4); and SMPD1, involved in converting sphingomyelin to ceramide, with carriers having 5.3-fold higher odds of metastatic disease (95% CI=1.85-14.98, P=0.002). At least one P/LP/D variant within a subset of 24 previously curated candidate prostate cancer DNA repair genes was carried by 12.8% of aggressive cases (OR=1.48, 95% CI=1.34-1.64, P=3x10-14), 12.6% of cases who died due to prostate cancer (OR=1.47, 95% CI=1.31-1.65, P=3x10-11), and 15.1% of metastatic cases (OR=2.16, 95% CI=1.57-2.16, P=5x10-14) compared to 9.4% of non-aggressive cases. These findings support the importance of rare genetic variation in aggressive prostate cancer risk and may have important implications for prostate cancer risk stratification and screening. Citation Format: Burcu F. Darst, Ed Saunders, Tokhir Dadaev, Xin Sheng, Peggy Wan, Loreall Pooler, Lucy Y. Xia, Stephen Chanock, Sonja I. Berndt, Susan M. Gapstur, Victoria Stevens, Demetrius Albanes, Stephanie J. Weinstein, Vincent Gnanapragasam, Graham G. Giles, Tu Nguyen-Dumont, Roger L. Milne, Mark M. Pomerantz, Julie A. Schmidt, Ruth C. Travis, Timothy J. Key, Konrad H. Stopsack, Lorelei A. Mucci, William J. Catalona, Beth Marosy, Kurt N. Hetrick, Kimberly F. Doheny, Robert J. MacInnis, Melissa C. Southey, Rosalind A. Eeles, Fredrik Wiklund, Zsofia Kote-Jarai, David V. Conti, Christopher A. Haiman. Multi-stage exome sequencing study of 17,546 aggressive and non-aggressive prostate cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 688.