Predisposition Genes Research Articles

Predisposition Footprints in the Somatic Genome of Wilms Tumors.

Approximately 10% of children with cancer harbor a mutation in a predisposition gene. In children with the kidney cancer Wilms tumor, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumorigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumor, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukemias), utilizing whole-genome sequencing, RNA sequencing, and genome-wide methylation, validating our findings in an independent cohort. Tumor development differed in children harboring a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high-risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Our findings indicate that predisposition may preordain Wilms tumorigenesis, suggesting a variant-specific approach to managing children merits consideration. Significance: Tumors that arise in children with a cancer predisposition may develop through the same mutational pathways as sporadic tumors. We examined this question in the childhood kidney cancer, Wilms tumor. We found that certain predispositions dictate the genetic development of tumors, with clinical implications for these children. See related commentary by Brzezinski and Malkin, p. 258.

Family-Level Impact of Germline Genetic Testing in Childhood Cancer: A Multi Family Member Interview Analysis

Objectives: Germline genetic testing is increasingly being integrated into pediatric oncology and a large number of families are interested. Current research on the psychological impact of germline genetic testing is limited by a main focus on individual outcomes in parents or children and little is known about its impact at the family level. Our study addresses that limitation by exploring parents’ lived experiences of how their family—as a whole—is affected by germline genetic testing for cancer predisposition. Methods: In six families who opted for germline genetic testing in the context of cancer predisposition, both parents of six ill children (five boys) with an average age of 9.67 years (SD = 3.77 years) were interviewed individually (N = 12). Germline genetic testing was performed by exome sequencing followed by analysis of a panel of childhood cancer predisposition genes in pediatric cancer patients and their parents. Their experiences were elicited through semi-structured interviews and the data were analyzed using Multi Family Member Interview Analysis. This qualitative study was conducted at Ghent University Hospital in Belgium. Results: The findings demonstrated that while germline genetic testing was generally viewed as a valuable and straightforward step in the child’s oncology trajectory, parents found it difficult to distinguish its impact from the overwhelming stressors of their child’s cancer diagnosis and treatment. However, parents recognized that the testing also significantly affected various family-level processes. Five main themes were identified: talking about germline genetic testing, being together matters (more), differences in coping with germline genetic testing between partners, feelings of guilt and mutual forgiveness, and concerns about the future health of the family. Conclusions: Given the expanded use of germline genetic testing in pediatric oncology, it is critical for clinicians to address the family-level impacts of germline genetic testing. Although families are affected by these issues, they often do not raise them due to the overwhelming challenges posed by the cancer diagnosis and treatment. Proactively addressing these themes could improve the support provided to families undergoing germline genetic testing for cancer predisposition.

Identification of new candidate genes for the hereditary predisposition to uveal melanoma: IGCMU trial

IntroductionUveal melanoma (UM) is a rare ocular cancer. While germline mutations in genes such as BAP1 and MBD4 account for approximately 20% of familial UM cases, the hereditary factors underlying the remaining cases remain unknown. Epidemiological studies have suggested an increased risk of prostate cancer, thyroid cancer, and leukemia among patients with UM, indicating potential unidentified genetic predispositions. This study aims to identify new candidate genes associated with a hereditary predisposition to UM.MethodsThis single-center study, conducted at Centre Jean Perrin, will involve the exome sequencing of 50 patients with UM who do not harbor known pathogenic variants in the BAP1 or MBD4 genes. The primary objective is to identify novel candidate genes associated with hereditary cancer predisposition among UM patients. A several-step-bioinformatic analysis will be conducted to identify the genes of interest. A secondary objective is to explore genes known to be involved in predisposition to other cancers, already described in the occurrence of uveal melanoma, but where an association has not been fully established yet. The study has begun in October 2024, with patient recruitment lasting 12 months. No follow-up period is planned, but the duration of the genetic analyses is estimated at six months, with the final study report expected by October 2026.DiscussionThe identification of novel hereditary predisposition genes for UM could significantly enhance genetic counselling and surveillance strategies for families affected. This study could also contribute to a better understanding of the genetic landscape of UM, potentially leading to more personalized and effective options for its detection.Trial registrationClinicalTrials.gov, identifier NCT06550674, registered in August 2024. Protocol: version 1.0, January 18th, 2024.

Multi-locus inherited neoplasia alleles syndromes in cancer: implications for clinical practice.

The popularity of multi-gene testing has identified more families with two or more pathogenic variants (PV) in cancer predisposition genes, also known as 'MINAS' (multilocus inherited neoplasia alleles syndromes). They are at risk of suboptimal treatment and management as little on this topic is known. We conducted a systematic review of published MINAS cases within cancer predisposition genes to understand their association with more severe presentations. We analysed 413 MINAS carriers, which included 33 novel cases from the Cancer Genetics Service, National Cancer Centre Singapore. Statistical tests were conducted to assess association between carrier characteristics and the number PV identified. Results suggest that MINAS carriers have more malignancies (31.7% vs 21.5% vs 10.3% %; p < 0.001), a younger median age of first cancer diagnosis (40.0 vs. 44.0 vs. 49.0 years; p < 0.001) and an early onset of cancer (defined as <5% PV-associated cancer risk at age of diagnosis) (24.9% vs 7.7% vs 4.7%; p < 0.001) compared to monoallelic and non-carriers. We also studied the association of clinical characteristics by the dominant or recessive nature of PV harboured, where more dominant-dominant (D-D) carriers reported multiple malignancies (34.0%), compared to dominant-recessive (D-R) (23.9%) and recessive-recessive (R-R) carriers (20%;) (p = 0.051). Our findings suggest that MINAS carriers are prone to more and younger malignancies and the dominant or recessive nature of PV within double carriers can affect clinical presentation. We suggest a framework to guide management based on the dominant or recessive nature of PV within double PV carriers.

Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing

High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls. This confirms enrichment for nearly all previously identified genes. Additionally, one-hundred-and-eleven HGSOC tumours from variant carriers were sequenced alongside other complementary studies, seeking evidence of biallelic inactivation as supportive evidence. PALB2 and ATM validate as HGSOC predisposition genes, with 6/8 germline carrier tumours exhibiting biallelic inactivation accompanied by characteristic mutational signatures. Among candidate genes, only LLGL2 consistently shows biallelic inactivation and protein expression loss, supporting it as a novel HGSOC susceptibility gene. The remaining candidate genes fail to validate. Integrating case-control analyses with tumour sequencing is thus crucial for accurate gene discovery in familial cancer studies.

A retrospective single-center pilot study of the genetic background of the transplanted kidney.

Renal cell carcinoma (RCC) is one of the most prevalent cancers in kidney transplant recipients (KTR). The hereditary background of RCC in native kidneys has been determined, implicating its clinical importance. This retrospective single-center pilot study aimed to identify a potential genetic predisposition to RCC of the transplanted kidney and outcome in KTR who underwent single kidney transplantation between January 2000 and December 2020 and manifested RCC of the transplanted kidney. Next-generation sequencing (NGS) based germline genetic analysis from peripheral blood-derived genomic DNA (gDNA) was performed in both the recipient and donor using a gene panel targeting 226 cancer predisposition genes. The calculated incidence of RCC of the transplanted kidney among 4146 KTR was 0.43%. In fifteen KTR and donors, NGS was performed. The mean KTR age at transplantation and the diagnosis of RCC was 50.3 years (median 54; 5-67 years) and 66 years (median 66; 24-79 years), respectively. The mean donor age at transplantation and graft age at RCC diagnosis was 39.7 years (median 42; 7-68 years) and 50.2 years (median 46; 20-83 years), respectively. The mean follow-up after RCC diagnosis was 47 months (median 39.1; 0-112 months). Papillary RCC was the most prevalent (n = 8), followed by clear cell RCC (n = 6) and unspecified RCC (n = 1). Thirteen RCCs were low-stage (pT1a/b) diseases, one was pT3, and one was of unknown stage. Most RCC was higher graded. No germline pathogenic cancer-predisposition variant was found in either KTR or donors except for several variants of uncertain significance. RCC of the transplanted kidney is very rare. Germline cancer-predisposition testing has identified several variants of uncertain significance, but no germline genetic predisposition to graft RCC in KTR. Further research is needed to assess the clinical relevance of genetic testing for cancer risk in KTR.

Nanopore adaptive sampling accurately detects nucleotide variants and improves the characterization of large-scale rearrangement for the diagnosis of cancer predisposition.

Molecular diagnosis has become highly significant for patient management in oncology. Here, 30 well-characterized clinical germline samples were studied with adaptive sampling to enrich the full sequence of 152 cancer predisposition genes. Sequencing was performed on Oxford Nanopore (ONT) R10.4.1 MinION flowcells with the Q20+ chemistry. In our cohort, 11 samples had large-scale rearrangements (LSR), which were all detected with ONT sequencing. In addition to perfectly detecting the locus of the LSR, we found a known MLPA amplification of exon 13 in the BRCA1 (NM_7294) gene corresponded to a duplication in tandem of both exons 12 and 13 of the reference NM_7300. Similarly, in another sample with a known total deletion of the BRCA1 gene, ONT sequencing highlighted this complete deletion was the consequence of a large deletion of almost 140000 bp carrying over five different genes. ONT sequencing was also able to detect all pathogenic nucleotide variants present in 16 samples at low coverage. As we analyzed complete genes and more genes than with short-read sequencing, we detected novel unknown variants. We randomly selected six new variants with a coverage larger than 10× and an average quality higher than 14, and confirmed all of them by Sanger sequencing, suggesting that variants detected with ONT (coverage >10× and quality score >14) could be considered as real variants. We showed that ONT adaptive sampling sequencing is suitable for the analysis of germline alterations, improves characterization of LSR, and detects single nucleotide variations even at low coverage. Adaptive sampling is suitable for the analysis of germline alterations. Improves the characterization of Large Scale Rearrangement and detects SNV at a minimum coverage of 10x. Allows flexibility of sequencing.

The importance of targeted next-generation sequencing based genomic profiling in the diagnosis of childhood acute myeloid leukemia: a single center experience.

The management of pediatric acute myeloid leukemia (AML) is based on the prognostic risk classification of initial leukemia. Targeted next-generation sequencing (NGS) is a reliable method used to identify recurrently mutated genes of pediatric AML and associated prognosis. In this study, we retrospectively evaluated the prognostic, and therapeutic utility of a targeted NGS panel covering twenty-five genes, in 21 children with de novo and 8 with relapsed or secondary AML. Results. Variants were detected in 44.8% of patients, and 63.2% of them were in the signaling pathway genes. The number of variants per patient and diversity increased with age. The panel results affected hematopoietic stem cell transplantation decisions, especially in core binding factor AML, and allowed the categorization of diseases according to current classifications. Panel results also pointed out predisposition to germline leukemia to the extent of the panel coverage. No targeted therapy was used based on the variants, and none of the variants were used to monitor minimal residual disease. Targeted NGS results, along with well-known genetic aberrations and treatment responses, can guide treatment modalities. The coverage of the routine panels should include proven mutations of childhood AML and germline leukemia predisposition genes.

Re-envisioning genetic predisposition to childhood and adolescent cancers.

Although cancer is rare in children and adolescents, it remains a leading cause of death within this age range, and genetic predisposition is the main known risk factor. Since the discovery of retinoblastoma-predisposing RB1 pathogenic germline variants in 1985, several additional high-penetrance cancer predisposition genes (CPGs) have been identified. Although few clinically recognizable genetic conditions display moderate cancer phenotypes, burden testing has revealed low-to-moderate penetrance CPGs. In addition to germline pathogenic variants in CPGs, postzygotic somatic mosaic CPG pathogenic variants acquired during embryonic development are increasingly recognized as factors that predispose children and adolescents to malignancies. Genome-wide association studies of various childhood and adolescent cancer types have identified some common low-risk cancer susceptibility alleles. Although the clinical utility of polygenic risk scores is currently limited in children and adolescents, polygenic risk scores developed for adults can predict subsequent cancer risks in childhood and adolescent cancer survivors. In this Review, I describe our current knowledge of genetic predisposition to childhood and adolescent cancers. Survival rates in children and adolescents with cancer and CPGs are often poor, necessitating better integration of genomic testing into clinical care to improve cancer prevention, surveillance and therapies.

Downstream Revenue Generated by Patients With Hereditary Cancer in the Multigene Panel Testing Era.

Patients with hereditary cancer syndromes face increased medical management recommendations to address their cancer risks. As multigene panels are the standard of testing today, more patients needing clinical intervention are being identified. This study calculates the downstream revenue (DSR) generated by patients ascertained by a genetic counselor (GC) with a hereditary cancer likely pathogenic/pathogenic variant (LPV/PV). Retrospective chart review was performed for patients seen in a high-volume cancer genetics clinic between October 1, 2009, and December 31, 2021, with LPV/PVs in hereditary cancer predisposition genes. DSR and work relative value units (wRVUs) were calculated for each patient before and after they met with a GC. Subgroup analyses calculated DSR/wRVUs from patients affected and unaffected with cancer and those whose genetic counseling visit was the first at the institution (naїve). A total of 978 patients were available for analysis after exclusions were applied. Patients generated $73.06 million (M) in US dollars (USD) in DSR and 54,814 wRVUs after their initial genetic counseling visit. Unaffected patients (n = 370, 37.8%) generated $11.38M (USD) and 13,879 wRVUs; affected patients (n = 608, 62.2%) generated $61.68M (USD) and 40,935 wRVUs. Naïve patients (n = 367, 37.5%) generated $15.39M (USD) and 11,811 wRVUs; established patients (n = 611, 62.5%) generated $57.67M (USD) and 43,003 wRVUs. Unaffected, naïve patients (n = 204, 20.9%) generated $5.48M (USD) and 5,186 wRVUs. By identifying patients with hereditary cancer, GCs can bring in substantial DSR for their institution. Naïve and unaffected patients provide the greatest GC value-add as these patients represent new business and revenue sources to the institution. As multigene panels continue to expand, the number of patients needing downstream services will increase. Recognizing patients at increased cancer risk will improve patient outcomes while simultaneously providing DSR for institutions.

Prevalence and Distribution of Unexpected Actionable Germline Pathogenic Variants Identified on Broad-Based Multigene Panel Testing Among Patients With Cancer.

In patients with a variety of malignancies undergoing multigene panel testing (MGPT), we examined the frequency of a pathogenic/likely pathogenic variant (PV) that would not have been predicted on the basis of the patient's personal and family history of cancer. This is a retrospective review of patients with cancer ascertained from a single academic cancer center who underwent broad-based MGPT of ≥20 cancer predisposition genes not selected on the basis of personal or family cancer history from 2015 to 2021. Low-penetrance variants and recessive inheritance genes were excluded. Deidentified pedigrees were analyzed to determine clinical suspicion of PV. MGPT was performed on 10,975 patients with cancer: 1,134 (10.3%) were found to have ≥1 PV in a moderate or highly penetrant cancer susceptibility gene. Three hundred seven (2.8%) of the PVs were not predicted on the basis of patient's personal cancer history alone, and 192 (1.7%) remained unsuspected after patient's cancer diagnosis and review of family cancer histories were considered. Unexpected PVs accounted for 16.9% of the 1,134 patients with a moderate- or high-penetrance PV. Most frequent unexpected variants were MITF (n = 18), PMS2 (n = 18), ATM (n = 17), BRIP1 (n = 17), HOXB13 (n = 14), SDHA (n = 12), CHEK2 (n = 11), BRCA2 (n = 7), MSH6 (n = 7), SDHC (n = 7), PALB2 (n = 6), and TP53 (n = 6). Low-penetrance or recessive variants were found in 519 (4.7%) patients. Variants of uncertain significance were found in 3,775 (34.4%). In patients with cancer, MGPT identified a rate of 1.7% PV in unexpected actionable cancer predisposition genes. Findings were more often unexpected (2.8%) when considering only the patient cancer history. These findings may justify consideration of broader MGPT panels in patients with cancer, given implications for subsequent surveillance, cascade testing, and treatment options dependent on specific findings.

Targeted Variant Assessments of Human Endogenous Retroviral Regions in Whole Genome Sequencing Data Reveal Retroviral Variants Associated with Papillary Thyroid Cancer.

Papillary thyroid cancer (PTC) is one of the fastest-growing cancers worldwide, lacking established causal factors or validated early diagnostics. Human endogenous retroviruses (HERVs), comprising 8% of human genomes, have potential as PTC biomarkers due to their comparably high baseline expression in healthy thyroid tissues, indicating homeostatic roles. However, HERV regions are often overlooked in genome-wide association studies because of their highly repetitive nature, low sequence coverage, and decreased sequencing quality. Using targeted whole-genome sequence analysis in conjunction with high sequencing depth to overcome methodological limitations, we identified associations of specific HERV variants with PTC. Analyzing WGS data from 138 patients with PTC generated through The Cancer Genome Atlas project and 2015 control samples from the 1000 Genomes Project, we examined the mutational variation in HERVs within a 20 kb radius of known cancer predisposition genes (CPGs) differentially expressed in PTC. We discovered 15 common and 13 rare germline HERV variants near or within 20 CPGs that distinguish patients with PTC from healthy controls. We identified intragenic-intronic HERV variants within RYR2, LRP1B, FN1, MET, TCRVB, UNC5D, TRPM3, CNTN5, CD70, RYR1, RUNX1, CRLF2, and PCDH1X, and three variants downstream of SERPINA1 and RUNX1T1. Sanger sequencing analyses of 20 thyroid and 5 non-thyroid cancer cell lines confirmed associations with PTC, particularly for MSTA HERV-L variant rs200077102 within the FN1 gene and HERV-L MLT1A LTR variant rs78588384 within the CNTN5 gene. Variant rs78588384, in particular, was shown in our analyses to be located within a POL2 binding site regulating an alternative transcript of CNTN5. In addition, we identified 16 variants that modified the poly(A) region in Alu elements, potentially altering the potential to retrotranspose. In conclusion, this study serves as a proof-of-concept for targeted variant analysis of HERV regions and establishes a basis for further exploration of HERVs in thyroid cancer development.

Decreased SNCA Expression in Whole-Blood RNA Analysis of Parkinson's Disease Adjusting for Lymphocytes.

Blood-based RNA transcriptomics offers a promising avenue for identifying biomarkers of Parkinson's Disease (PD) progression and may provide mechanistic insights into the systemic biological processes underlying its pathogenesis beyond the well-defined neurodegenerative features. Previous studies have indicated an age-dependent increase in neutrophil-enriched gene expression, alongside a reduction in lymphocyte counts, in individuals with PD. These immune cell changes can obscure disease-relevant transcriptomic signals. In this study, we performed differential expression (DE) analysis of whole-blood RNA sequencing data from PD cohorts, incorporating a correction for immune cell-enriched gene expression, particularly neutrophil-related pathways, to improve the resolution of PD-associated molecular changes. Using 1,254 Parkinson's Progression Markers Initiative (PPMI) samples with complete blood count (CBC) data, we developed a predictive model to estimate neutrophil percentages in a 6,987 PPMI and Parkinson's Disease Biomarkers Program (PDBP) samples. We mitigated the confounding effects of immune cell-enriched gene expression by integrating predicted neutrophil percentages as a covariate in DE analysis. This approach revealed a consistent and significant downregulation of SNCA across all PD cohorts, a finding previously obscured by immune cell signatures. Lowered SNCA expression was found in individuals with known predisposition genes (e.g., SNCA, GBA, LRRK2) and in non-genetic PD cohorts lacking known pathogenic mutations, suggesting it may represent a key transcriptomic hallmark of the disease.

Germline Variant Spectrum in Southern Italian High-Risk Hereditary Breast Cancer Patients: Insights from Multi-Gene Panel Testing.

Hereditary breast cancer accounts for 5-10% of all cases, with pathogenic variants in BRCA1/2 and other susceptibility genes playing a crucial role. This study elucidates the prevalence and spectrum of germline variants in 13 cancer predisposition genes among high-risk hereditary breast cancer patients from Southern Italy. We employed next-generation sequencing (NGS) to analyze 254 individuals selected through genetic counseling. Pathogenic or likely pathogenic variants were identified in 13% (34/254) of patients, with 54% of these variants occurring in non-BRCA1/2 genes. Notably, we observed a recurrent BRCA1 c.4964_4982del founder mutation, underscoring the importance of population-specific genetic screening. The spectrum of variants extended beyond BRCA1/2 to include PALB2, ATM, TP53, CHEK2, and RAD51C, highlighting the genetic heterogeneity of breast cancer susceptibility. Variants of uncertain significance were detected in 20% of patients, emphasizing the ongoing challenge of variant interpretation in the era of multi-gene panel testing. These findings not only enhance our understanding of the genetic landscape of breast cancer in Southern Italy but also provide a foundation for developing more targeted, population-specific approaches to genetic testing and counseling, ultimately contributing to the advancement of precision medicine in oncology.

An evaluation of genetic predisposition to congenital anomalies and pediatric cancer supports KAT6B as a novel neuroblastoma susceptibility gene

PurposeAlthough congenital anomalies are among the strongest risk factors for developing pediatric cancer, the genetic underpinnings remain unclear. Therefore, we evaluated germline susceptibility in children with congenital anomalies and cancer. MethodsThrough the Genetic Overlap Between Anomalies and Cancer in Kids Study, we recruited 47 participants with anomalies and cancer, along with their biological families. Genome sequencing was performed, focusing on single-nucleotide variants, indels, and structural variants. Pathogenic or likely pathogenic variants were identified by the American College of Medical Genetics and Genomics classification. ResultsWe identified pathogenic or likely pathogenic variants in 23.4% (11 of 47) of participants. These variants encompassed (1) 4 genes associated with both anomalies and cancer (WT1, USP9X, PTPN1, and LZTR1), (2) 2 established cancer predisposition genes (TP53 in 2 participants and PAX5), and (3) 4 genes that are associated with anomalies (MMUT, FBN1, COL3A1, and KAT6B). We further investigated the role of KAT6B on neuroblastoma in a gene-based analysis from 409 neuroblastoma cases and 952 controls. This analysis demonstrated a significant enrichment of rare, predicted deleterious variants (P = .017), with odds ratios ranging from 2 to 4 based on the conditions we applied. ConclusionThis study demonstrates a molecular diagnostic yield of 23.4% in participants with both anomalies and cancer. Additionally, the findings further implicate the role of KAT6B as a novel neuroblastoma predisposition gene.

Genome-first determination of the prevalence and penetrance of eight germline myeloid malignancy predisposition genes: a study of two population-based cohorts.

It is estimated that 10% of individuals with a myeloid malignancy carry a germline susceptibility. Using the genome-first approach, in which individuals were ascertained on genotype alone, rather than clinical phenotype, we quantified the prevalence and penetrance of pathogenic germline variants in eight myeloid malignancy predisposition (gMMP) genes. ANKRD26, CEBPA, DDX41, MECOM, SRP72, ETV6, RUNX1 and GATA2, were analyzed from the Geisinger MyCode DiscovEHR (n = 170,503) and the United Kingdom Biobank (UKBB, n = 469,595). We identified a high risk of myeloid malignancies (MM) (odds ratio[OR] all genes: DiscovEHR, 4.6 [95% confidential interval (CI) 2.1-9.7], p < 0.0001; UKBB, 6.0 [95% CI 4.3-8.2], p = 3.1 × 10-27), and decreased overall survival (hazard ratio [HR] DiscovEHR, 1.8 [95% CI 1.3-2.6], p = 0.00049; UKBB, 1.4 [95% CI 1.2-1.8], p = 8.4 × 10-5) amongst heterozygotes. Pathogenic DDX41 variants were the most commonly identified, and in UKBB showed a significantly increased risk of MM (OR 5.7 [95% CI 3.9-8.3], p = 6.0 × 10-20) and increased all-cause mortality (HR 1.35 [95% CI 1.1-1.7], p = 0.0063). Through a genome-first approach, this study genetically ascertained individuals with a gMMP and determined their MM risk and survival.

Multi-ethnic heterozygote frequencies of cancer susceptibility genes to inform counseling of reproductive risk.

Pathogenic germline variants (PGVs) in a subset of cancer predisposition genes (CPGs) are associated with adult-onset autosomal dominant (AD) cancer susceptibility and life-limiting autosomal recessive (AR) disease. Counseling in adult cancer genetics clinics regarding reproductive risk for PGV heterozygotes is limited. Estimated heterozygote frequencies across ancestries were calculated for AD CPGs with AR risk (ATM, BRCA1, BRCA2, BRIP1, FH, NBN, MLH1, MSH2, MSH6, PMS2, RAD51C, SDHA, SDHB, and SDHD) from gnomADv.3.0, the Penn Medicine Biobank, and FLOSSIES. Average frequencies of heterozygotes with PGVs across ancestries for BRCA1 and BRCA2 were 0.33% ± 0.41% and 0.43% ± 0.36%, with variability cross-ancestry from 0.06% to 1.32% and 0.17% to 1.29%, respectively. ATM had the next highest PGV heterozygote frequency (0.31% ± 0.12%) and SDHD the lowest (0.01% ± 0.01%) average PGV heterozygote frequency. Heterozygote PGV frequencies from gnomAD were similar as cancer-free individuals in Penn Medicine Biobank and higher than in the FLOSSIES data. Heterozygote frequency estimates for AD CPGs that cause AR disease provides information to facilitate discussions regarding reproductive risk. Future studies are needed to assess whether utilization of these data will influence couples' reproductive risk planning.

MA13.12 Prevalence of Pathogenic or Likely Pathogenic Germline Variants in Cancer Predisposition Genes in Selected Lung Adenocarcinoma Patients

MA13.12 Prevalence of Pathogenic or Likely Pathogenic Germline Variants in Cancer Predisposition Genes in Selected Lung Adenocarcinoma Patients

POLD3 haploinsufficiency is linked to non-syndromic sensorineural adult-onset progressive hearing and balance impairments.

Hearing impairment (HI) is a significant health concern globally, influenced by genetic and environmental factors. We had identified a homozygous pathogenic variant in POLD3 in a Lebanese patient with an autosomal congenital recessive syndromic hearing loss (MIM#620869). This variant was found at heterozygous state in the parents, who developed progressive hearing impairment around age 40. We conducted a thorough clinical and genetic assessment of sixteen family members, including physical exams, audiometry and vestibular function evaluations. Additionally, gene expression analysis of the Pold3 gene was performed in mice using RNAscope. Twelve individuals were heterozygous for the variant in POLD3, of whom eight showed bilateral adult-onset HI, typically starting around ages 40-50, and two older patients displaying unilateral vestibular weakness. Additionally, two carriers of the variant developed cancer at an early age. RNAscope confirmed Pold3 expression in auditory and vestibular neurons. Exome sequencing analysis excluded the presence of pathogenic variants in any known hearing impairment or cancer predisposition genes. We present herein, for the first time, evidence of a heterozygous pathogenic POLD3 variant associated with a novel form of autosomal dominant progressive adult-onset hearing and vestibular impairments. We also highlight the necessity for further exploration of the role of POLD3 in cancer predisposition.

The guidelines for clinical practice for carriers of germline mutations in the Lynch syndrome predisposition genes MLH1, MSH2, MSH6, PMS2 and large deletions of EPCAM (4.2024).

The guidelines for clinical practice for carriers of pathogenic variants in clinically relevant genes predisposing to Lynch syndrome and colorectal cancer define the steps of primary and secondary prevention that should be provided to the individuals at high risk of developing hereditary cancer in the Czech Republic. The drafting of the guidelines was organized by the Oncogenetics Working Group of the Society for Medical Genetics and Genomics of J. E. Purkyně Czech Medical Society, in cooperation with representatives of oncology, oncogynecology, and gastroenterology. The guidelines are based on the current recommendations of the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO) and take into account the capacity of the Czech healthcare system.