Germline Pathogenic Variants Research Articles

Co-occurrence of germline pathogenic variants in a Brazilian cohort of patients with breast cancer.

e22532 Background: The estimated prevalence of germline pathogenic variants (PV) or likely pathogenic variants (LPV) in high and moderate penetrance genes is around 7-10% among women with breast cancer (BC). The emergence of next-generation sequencing (NGS) technology allowed multi-gene panel testing (MGPT) analysis at a lower cost. However, the detection of incidental findings with unknown significance (VUS) and challenges with variant interpretation increase substantially with MGPT. The effect of co-existing PV/LPV in two or more genes is still understudied. Here, we present the prevalence of concurrent germline LPV/PV in a cohort of Brazilian women with BC who underwent a MGPT in a single reference laboratory. Methods: Retrospective observational study using a laboratory cohort (Oncoclínicas Precision Medicine). This study includes women with BC who performed a germline MGPT (able to call SNVs, indels and CNVs) from 2019 to 2023. All patients were tested in a single reference laboratory (OC Precision Medicine) and originated from several Brazilian centers within the Oncoclínicas network. Two distinct germline NGS assays were used: breast and ovarian cancer (BOC) panel (36 genes) and a pan-cancer (PC) panel (105 genes). Results: In the overall cohort, 2,651 women with BC were included in this analysis. The median age at genetic testing was 51 years. 1,867 pts (70.4%) underwent a PC panel testing and the remaining 784 pts (29.6%) a BOC panel.Overall, 314 (12%) pts carrier of LP/PV in high- and/or moderate-penetrance genes. Two or more heterozygous LP/PV were found in 35 pts (1.32%), including 8 pts (1.02%) in the BOC panel and 27 pts (1.44%) in the PC panel subgroups. There were no differences in age of onset of BC in single vs co-occurring double mutants. The most frequent co-existing PV/LPV were found in BRCA2 (11) / BRCA1 (8) / PALB2 (4) / TP53 (3) and MUTYH (7) / CHEK2 (3) in the high and moderate penetrance genes, respectively. Six pts (0.23%) had a double heterozygous involving high and/or moderate penetrance genes. Interestingly, there was a case with four heterozygous variants in TP53, MUTYH, MUTYH and APC. Conclusions: In times of rapid incorporation of MGPT in the clinical practice, our real-world data showed that a small proportion of BC patients could be carriers of two or more germline heterozygous LP/PV in cancer genes. However, this represents a challenging scenario for patient and family management, especially in a co-occurrence of high and moderate penetrance genes.

Prevalence of Potentially Pathogenic Germline Variants Among Adult Patients in the Philippines With Solid Malignancies Who Underwent Tumor Genomic Profiling

Prevalence of Potentially Pathogenic Germline Variants Among Adult Patients in the Philippines With Solid Malignancies Who Underwent Tumor Genomic Profiling

Impact of hormone receptor status and tumor subtypes on clinical behavior and outcomes of breast cancer in young BRCA carriers.

504 Background: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer (BC). Among young patients harboring germline BRCA1or BRCA2 (BRCA) pathogenic variants (PVs), most of the tumors arising in BRCA2carriers express hormone receptors, while most BC cases in BRCA1 carriers do not; however, limited evidence exists on the impact of hormone receptor status on clinical behavior and outcomes in young patients harboring BRCA PVs. Methods: This is an international, multicenter, hospital-based, retrospective cohort study including young patients (≤40 years) diagnosed with invasive BC between January 2000 and December 2020, harboring germline PVs in BRCA genes. Our analysis investigates the impact of hormone receptor status on clinical behavior and outcomes of BC. The type and pattern of recurrence and survival outcomes (disease-free survival [DFS], BC specific survival [BCSS] and overall survival [OS]) were first investigated according to hormone receptors expression (positive vs. negative), and then according to BC subtype (luminal A-like vs. luminal B-like vs. triple-negative vs. HER2-positive BC). Results: From 78 centers worldwide, 4,709 BRCA carriers were included in this analysis, of whom 2,143 (45.5%) had hormone receptor-positive and 2,566 (54.5%) hormone receptor-negative BC. Patients with hormone receptor-positive BC were more likely to harbor BRCA2 PVs while less frequently had grade 3 tumors and nodal involvement. Median follow-up was 7.88 (IQR 4.47-12.61) years. The rate of distant recurrences was higher in patients with hormone receptor-positive BC (13.1% vs. 9.6%, p<.001), while the rate of second primary BC was lower (9.1% vs. 14.7%, p<.001) when compared to patients with hormone receptor-negative disease. The 8-years DFS was 65.8% in patients with hormone receptor-positive and 63.4% in those with hormone receptor-negative BC. No differences in terms of OS nor BCSS were observed. The hazard ratio of hormone receptor-positive vs. negative disease changed over time for DFS, BCSS, and OS (p<.05 for interactions of hormone receptor status and survival time). Among the 4,363 patients eligible for subtypes analysis, 612 had luminal A-like, 1,038 luminal B-like, 2,373 triple-negative and 340 HER2-positive BC. Patients with Luminal A-like BC had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-years DFS: 60.8% in luminal A-like vs. 63.5% in triple-negative vs. 65.5% in HER2-positive and 69.7% in luminal B-like subtype). Conclusions: In young BRCAPVs carriers with early BC, hormone receptor status did not appear to be a positive prognostic factor. The differences in pattern of recurrence and second primary BC among hormone receptor-positive vs. negative disease warrants consideration in counseling patients on treatment, follow-up strategies and indication for risk-reducing surgery.

Mutations in Mismatch Repair Genes and Microsatellite Instability Status in Pancreatic Cancer.

Patients with pancreatic cancer (PC) showing mismatch repair (MMR) deficiency may benefit from immunotherapy. Microsatellite instability (MSI) is a hallmark of MMR deficiency (MMR-D). Here, we estimated the prevalence of MSI in PC, investigated germline and somatic mutations in the three MMR genes (MLH1, MSH2, and MSH6), and assessed the relationship between MMR genes mutations and MSI status in PC. Clinical specimens from PC patients were analyzed using targeted next-generation sequencing, including paired normal and tumor specimens from 155 patients, tumor-only specimens from 86 patients, and normal-only specimens from 379 patients. The MSI status of 235 PCs was assessed via PCR. Pathogenic/likely pathogenic (P/LP) germline variants in the MMR genes were identified in 1.1% of patients, while somatic variants were found in 2.6% of patients. No MSI-H tumors were detected. One patient carried two variants (P (VAF = 0.57) and LP (VAF = 0.25)) simultaneously; however, their germline/somatic status remains unknown due to the investigation focusing solely on the tumor and MSI analysis was not performed for this patient. MSI is rare in PC, even in tumors with MMR genes mutations. Our findings underscore the importance of assessing tumor MMR-D status in PC patients with confirmed Lynch syndrome when deciding whether to prescribe immunotherapy.

Clinical relevance of double heterozygosity revealed by next-generation sequencing of homologous recombination repair pathway genes in South African breast cancer patients

PurposeGenetically predisposed breast cancer (BC) patients represent a minor but clinically meaningful subgroup of the disease, with 25% of all cases associated with actionable variants in BRCA1/2. Diagnostic implementation of next-generation sequencing (NGS) resulted in the rare identification of BC patients with double heterozygosity for deleterious variants in genes partaking in homologous recombination repair of DNA. As clinical heterogeneity poses challenges for genetic counseling, this study focused on the occurrence and clinical relevance of double heterozygous BC in South Africa.MethodsDNA samples were diagnostically screened using the NGS-based Oncomine™ BRCA Expanded Research Assay. Data was generated on the Ion GeneStudio S5 system and analyzed using the Torrent Suite™ and reporter software. The clinical significance of the variants detected was determined using international variant classification guidelines and treatment implications.ResultsSix of 1600 BC patients (0.375%) tested were identified as being bi-allelic for two germline likely pathogenic or pathogenic variants. Most of the variants were present in BRCA1/2, including two founder-related small deletions in three cases, with family-specific variants detected in ATM, BARD1, FANCD2, NBN, and TP53. The scientific interpretation and clinical relevance were based on the clinical and tumor characteristics of each case.ConclusionThis study increased current knowledge of the risk implications associated with the co-occurrence of more than one pathogenic variant in the BC susceptibility genes, confirmed to be a rare condition in South Africa. Further molecular pathology-based studies are warranted to determine whether clinical decision-making is affected by the detection of a second pathogenic variant in BRCA1/2 and TP53 carriers.

Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort.

What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. N/A. The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.

Lynch syndrome in Mexican-Mestizo families: Genotype, phenotypes, and challenges in cascade testing among relatives at risk

Lynch syndrome (LS) is the most frequent cancer predisposition syndrome affecting the colon and rectum. A pathogenic variant (PV) disrupting one of the mismatch repair (MMR) genes is responsible for the disease. The spectrum of tumors in LS is heterogeneous and includes cancer of the colon and rectum (CRC), endometrium, ovaries, stomach, small bowel, urinary tract, bladder, pancreas, and skin. Knowledge of the phenotypic variation of patients with LS, the type and frequency of PVs, and cascade testing studies in the Latin American population is limited. The present study aims to recognize the PVs in MMR genes, describe the phenotype in Mexican-Mestizo patients and their relatives, and identify the acceptance rate of cascade testing of relatives at risk. We included 40 carriers of a MMR gene PV and 142 relatives that developed a LS-related neoplasm. Patients’ clinical data, number, and type of malignancies were obtained from their medical records. Amsterdam I-II, Bethesda criteria, and PREMM5® predictive model score were estimated. Available immunohistochemistry (IHC) reports were analyzed. Relatives at risk were determined from index cases pedigrees. The distribution of MMR gene mutations among 40 probands was: MLH1 (67.5 %), MSH2 (22.5 %), MSH6 (7.5 %), and PMS2 (2.5 %). Out of the 182 LS cases, 58 % exhibited the LS phenotype before age 50. The most common tumor was CRC, followed by endometrial cancer in women and gastric cancer in males. We found a 90.0 % concordance between the IHC and germline PV. The most frequent PV in our sample was MLH1 c.676C > T, occurring in 1/6 index cases. All probands disclosed their molecular test result to their family. Out of the 451 asymptomatic relatives at risk, 28.2 % underwent germline testing. Our results highlight the importance of conducting germline genetic studies in LS since it allows the establishment of appropriate cancer screening, risk-reducing measures, and genetic cascade testing among relatives at risk. Interestingly, we observed a significantly higher prevalence of the c.676C > T variant in MLH1, probably a singular characteristic of the Mexican-Mestizo population. New strategies to facilitate accurate communication between index cases and relatives should be implemented to improve the cascade testing acceptance rate.

The best linear unbiased prediction (BLUP) method as a tool to estimate the lifetime risk of pancreatic ductal adenocarcinoma in high-risk individuals with no known pathogenic germline variants

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the Western world. The number of diagnosed cases and the mortality rate are almost equal as the majority of patients present with advanced disease at diagnosis. Between 4 and 10% of pancreatic cancer cases have an apparent hereditary background, known as hereditary pancreatic cancer (HPC) and familial pancreatic cancer (FPC), when the genetic basis is unknown. Surveillance of high-risk individuals (HRI) from these families by imaging aims to detect PDAC at an early stage to improve prognosis. However, the genetic basis is unknown in the majority of HRIs, with only around 10–13% of families carrying known pathogenic germline mutations. The aim of this study was to assess an individual’s genetic cancer risk based on sex and personal and family history of cancer. The Best Linear Unbiased Prediction (BLUP) methodology was used to estimate an individual’s predicted risk of developing cancer during their lifetime. The model uses different demographic factors in order to estimate heritability. A reliable estimation of heritability for pancreatic cancer of 0.27 on the liability scale, and 0.07 at the observed data scale as obtained, which is different from zero, indicating a polygenic inheritance pattern of PDAC. BLUP was able to correctly discriminate PDAC cases from healthy individuals and those with other cancer types. Thus, providing an additional tool to assess PDAC risk HRI with an assumed genetic predisposition in the absence of known pathogenic germline mutations.

#234 Clinical spectrum and genetic variants of Alport syndrome and thin basement membrane nephropathy—single center experience

Abstract Background and aims Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are genetically heterogeneous kidney diseases that manifest with kidney involvement, AS also with hearing and visual impairment. Electron microscopic examination shows characteristic ultrastructural changes in the glomerular basement membrane (GBM) in AS and TBMN, but cannot reliably distinguish between the two entities. Therefore, molecular genetic studies and the identification of individual pathogenic variants in the target genes are crucial to confirm the diagnosis. The aim of our study is to determine the significance of the genetic variants associated with the ultrastructural changes of GBM found in the renal biopsy. Method We retrospectively analyzed records of patients from the University Medical Centre Ljubljana in which ultrastructural GBM changes characteristic for AS and TBMN were found in the renal biopsy, including their clinical, laboratory and histological features. Molecular genetic investigations were made using the new generation sequencing method (NGS) to determine germline pathogenic variants in genes directly related to AS and TBMN (COL4A3, COL4A4 and COL4A5) and in genes that are important in syndromes with a related clinical picture (COL4A6, CD151, LMX1B, MYH9, FN1 and MYO1E). The pathogenicity of variants was determined according to the Clinical Molecular Genetic Society best practice guidelines. Results The study included 73 patients with ultrastructurally confirmed thin GBM. Indications for kidney biopsy were chronic nephritis syndrome in 33 patients (45%), acute worsening of renal function in 16 (22%), nephrotic syndrome in 9 (12%), nephrotic proteinuria and chronic kidney disease in 6 (8%), isolated proteinuria in 5 (7%) and suspected vasculitis in 4 patients (6%). At the time of kidney biopsy average age was 50 ± 16 years, average creatinine 112 ± 70 µmol/L and average estimated glomerular filtration rate (eGFR) 65 ± 24 ml/min/1.73 m2, 7 patients had eGFR below 30 ml/min/1.73 m2. Average daily proteinuria was 2.4 ± 3.3 gr and 88% of patients had hematuria. 38% of them have hearing impairment and 43% had positive familiar history of kidney disease. We recorded 33 patients (45%) with genetic variants associated with AS or TBMN: 22 patients (67%) with pathogenic variants, 2 patients (6%) with likely pathogenic and 9 patients (27%) with variants of uncertain significance. The presence of a positive genetic analysis was associated with a higher level of hematuria (p = 0.003), a lower level of proteinuria (p = 0.004) and a positive family history of kidney disease (p &amp;lt; 0.001). It was also associated with hearing loss, but the association was not statistically significant (p = 0.099). Patients with genetic variants had similar eGFR to those with negative genetics (63.9 ml/min/1.73 m2 (58.3-69.4) vs 66.2 ml/min/1.73 m2 (60.0-72.3)), p = 0.698. We also found no differences in GBM thickness in patients without compared to those with identified gene variants (213 nm (160-315) vs. 209 nm (140-410)), p = 0.761. 32 patients (44%) had only focal chronic changes and ultrastructural changes of thin GBM present on kidney biopsy and 41 patients (56%) had also been diagnosed with other renal pathology. When comparing these two groups, patients without associated pathology had lower daily proteinuria (p = 0.048), higher level of hematuria (p = 0.021), frequent hearing impairment (p = 0.008) and also positive genetics analysis (p = 0.016). Conclusion We have shown that in patients with proven ultrastructural alterations in GBM, the presence of so far recognized genetic variants associated with AS and TBMN is 45%, and corresponds to the frequency of other phenotypic characteristics of AS, including hearing impairment and positive family history. In the future, additional clinical tools will be required to accurately determine the role of coexistent thin GBM on the prognosis of patients with other relevant kidney pathology and other genetic tools beyond NGS should be employed to explore other pathologic genetic variants associated with the AS spectrum.

Incidental Germline Findings During Comprehensive Genomic Profiling of Pancreatic and Colorectal Cancer: Single-center, Molecular Tumor Board Experience.

Abstract Multidisciplinary molecular tumor boards (MTB) are already well established in many comprehensive cancer centers and play an important role in the individual treatment planning for cancer patients. Comprehensive genomic profiling of tumor tissue based on next-generation sequencing is currently performed for diagnostic and mainly predictive testing. If somatic genomic variants are identified, which are suspected to be pathogenic germline variants (PGVs), MTB propose genetic counseling and germline DNA testing. Commonly used comprehensive genomic profiling approaches of tumor tissue do not include a matched germline DNA control. Therefore, the detection of PGVs could be only predicted based on the content of tumor cells (CTC) in selected tumor area (%) and variant allele frequency score (%). For conclusion, the role of a medical geneticist is essential in these cases. The overall prevalence of PGVs in patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) is approximately 10%. In this single-center study, we present 37 patients with PDAC and 48 patients with CRC who were presented at MTB and tested using the large combined DNA/RNA sequencing panel. Content of tumor cells and variant allele frequency scores were evaluated in all tested patients. In case of suspicion of PGV and no previous genetic testing based on the standard guidelines, genetic counseling was recommended regardless of age, sex, and family history. In the PDAC subgroup, five patients were recommended by MTB for genetic counseling based on suspicious genetic findings. Based on a medical geneticist’s decision, germline DNA sequencing was performed in four of these cases, and all of them tested positive for PGV in the following genes: ATM, ATM, BRCA1, and BRCA2. In the CRC subgroup, no PGV was confirmed in the two patients genetically tested based on the MTB recommendations. Furthermore, we present data from our center’s registry of patients with PDAC and CRC who underwent genetic counseling and germline DNA testing based on the standard screening criteria. Our data confirm that comprehensive genomic profiling of tumor tissue can identify patients with hereditary forms of PDAC, who could remain unidentified by standard screening for hereditary forms of cancer.

A de novo germline pathogenic BRCA1 variant identified following an osteosarcoma pangenomic molecular analysis.

De novo germline pathogenic variants (gPV) of the BReast CAncer 1 (BRCA1) gene are very rare. Only a few have been described up to date, usually in patients with a history of ovarian or breast cancer. Here, we report the first case of an incidental de novo BRCA1 germline pathogenic variant which was identified within the framework of the Plan France Médecine Génomique (PFMG) 2025 French national tumor sequencing program. The proband was a 29-year-old man diagnosed with metastatic osteosarcoma. Tumor whole exome sequencing identified a BRCA1 c.3756_3759del p.(Ser1253Argfs*10) pathogenic variant without loss-of-heterozygosity. A low genomic instability score and the absence of single base substitution signatures of homologous recombination deficiency suggested that the BRCA1 variant was not driver in the osteosarcoma tumorigenesis. Germline whole genome sequencing asserted the germline nature of this variant, with a 36% allele frequency, suggesting a mosaicism caused by a post-zygotic mutational event. The proband's family (parents and siblings) were not carriers of this variant confirming the de novo occurrence. Tumor sequencing programs like the French PFMG 2025 have been implemented worldwide and may help identify new gPV, including de novo variants.

Multiple Onychopapillomas and BAP1 Tumor Predisposition Syndrome

BRCA1-associated protein (BAP1) tumor predisposition syndrome (TPDS) is a cancer genodermatosis associated with high risk of uveal and cutaneous melanoma, basal cell carcinoma, and multiple internal malignant neoplasms, including mesothelioma and renal cell carcinoma. Early detection of the syndrome is important for cancer surveillance and genetic counseling of family members who are at risk. To determine the prevalence of nail abnormalities in individuals with pathogenic germline variants in BAP1. In this prospective cohort study, individuals who were known carriers of pathogenic BAP1 germline variants were consecutively enrolled between October 10, 2023, and March 15, 2024. Dermatologic evaluation for nail abnormalities was performed, including a history of nail abnormalities and associated symptoms, physical examination, medical photography, and nail biopsy for histopathology. This was a single-center study conducted at the National Institutes of Health Clinical Center. Primary outcomes were the prevalence and spectrum of nail changes and histopathologic characterization. Among 47 participants (30 female [63.8%]; mean [SD] age, 46.4 [15.1] years) ranging in age from 13 to 72 years from 35 families, nail abnormalities were detected in 41 patients (87.2%) and included leukonychia, splinter hemorrhage, onychoschizia, and distal nail hyperkeratosis. Clinical findings consistent with onychopapilloma were detected in 39 patients (83.0%), including 35 of 40 individuals aged 30 years or older (87.5%). Nail bed biopsy was performed in 5 patients and was consistent with onychopapilloma. Polydactylous involvement with onychopapillomas was detected in nearly all patients who had nail involvement (38 of 39 patients [97.4%]). This study found that BAP1 TPDS was associated with a high rate of nail abnormalities consistent with onychopapillomas in adult carriers of the disease. Findings suggest that this novel cutaneous sign may facilitate detection of the syndrome in family members who are at risk and patients with cancers associated with BAP1 given that multiple onychopapillomas are uncommon in the general population and may be a distinct clue to the presence of a pathogenic germline variant in the BAP1 gene.

P24 Folliculin silencing in human hair follicles ex vivo upregulates intrafollicular mechanistic target of rapamycin complex 1 activity: a new model for studying Birt–Hogg–Dubé syndrome

Abstract Introduction and aims Birt–Hogg–Dubé (BHD) syndrome is a rare multisystem disorder caused by germline pathogenic variants in the FLCN gene. BHD skin tumours predominantly affect facial skin, confer a significant psychosocial burden, and there is a lack of nonsurgical therapies. Here we report a novel ex vivo human model to study the impact of FLCN loss in human hair follicles (HFs), the putative origin of BHD skin tumours. Methods Organ-cultured human anagen HFs and scalp skin were treated with small interfering RNA targeting FLCN (n = 2 donors) for 6 days ex vivo, followed by quantitative real-time polymerase chain reaction (qRT-PCR), and quantitative immunohistomorphometry (qIHM). Results Successful FLCN knockdown was confirmed at both the mRNA (34% reduction compared with nontargeting control levels measured by qRT-PCR) and protein level (12% reduction in FLCN expression measured by qIHM). In FLCN-silenced HFs (n = 14, two donors), our preliminary Results demonstrated an increase in p-S6 expression, a direct downstream kinase of mechanistic target of rapamycin complex (mTORC)1 signalling. This was spatially restricted to the hair bulb and proximal outer root sheath keratinocytes, and was significantly greater than quantified in nontargeting control HFs (P &amp;lt; 0.05). Conclusions FLCN silencing in ex vivo cultured, healthy human HFs and scalp skin provides a novel, instructive and accessible preclinical research model. We aim to delineate whether FLCN interacts with the key endogenous inhibitor of mTORC1 activity, TSC2, in future work, to gain insight into the role of FLCN in the pathobiology of BHD and the maintenance of healthy human HFs.

Expanding access to genetic testing for pancreatic cancer.

Among individuals with pancreatic ductal adenocarcinoma (PDAC) 5-10% have a pathogenic germline variant (PGV) in a PDAC susceptibility gene. Guidelines recommend genetic testing among all individuals with PDAC. Additionally, at-risk relatives of PDAC patients benefit from their own genetic education, risk assessment, and testing. Multigene panel testing (MGPT) can identify individuals with inherited cancer risk who can benefit from early cancer surveillance and risk reduction strategies. This manuscript discusses various healthcare delivery models for MGPT including traditional in-person genetic counseling, novel integrated in-person infrastructures, telemedicine genetics care via telephone- or video-visits and direct-to-consumer testing. Barriers and facilitators to care on the individual, provider, and system level are also outlined including specific considerations for historically marginalized communities.

Men with metastatic prostate cancer carrying a pathogenic germline variant in breast cancer genes: disclosure of genetic test results to relatives

Some patients with metastatic prostate cancer carry a pathogenic germline variant (PV) in a gene, that is mainly associated with an increased risk of breast cancer in women. If they test positive for such a PV, prostate cancer patients are encouraged to disclose the genetic test result to relatives who are at risk in case the carrier status changes the relatives’ medical care. Our study aimed to investigate how men who learned they carry a PV in BRCA1, BRCA2, PALB2, CHEK2 or ATM disclosed their carrier status to at-risk relatives and to assess the possible psychological burden for the carrier and their perception of the burden for relatives. In total, 23 men with metastatic prostate cancer carrying a PV completed the IRI questionnaire about family communication; 14 also participated in a semi-structured interview. Patients felt highly confident in discussing the genetic test result with relatives. The diagnosis of prostate cancer was experienced as a burden, whereas being informed about genetic testing results did in most cases not add to this burden. Two patients encountered negative experiences with family communication, as they considered the genetic test result to be more urgent than their relatives. This mixed-methods study shows that metastatic prostate cancer patients with a PV in genes mainly associated with increased risk of breast cancer feel well-equipped to communicate about this predisposition in their families. Carriers felt motivated to disclose their genetic test result to relatives. Most of them indicated that the disclosure was not experienced as a psychological burden.

Centralization of care for rare genetic syndromes associated with cancer: improving outcomes and advancing research on VHL disease.

Von Hippel-Lindau (VHL) disease is a rare genetic syndrome caused by a germline pathogenic variant in one VHL allele. Any somatic event disrupting the other allele induces VHL protein (pVHL) loss of function, ultimately leading to patients developing multiple tumours in multiple organs at multiple timepoints, and reducing life expectancy. Treatment of this complex, rare disease is often fragmented, as patients visit specialist clinicians in isolation at different medical centres. Consequently, patients can receive sub-optimal treatment that results in decreased quality of life and a poor experience of health care systems. In 2021, we established a comprehensive clinical centre at San Raffaele Hospital, Milan, devoted to VHL disease. The centre provides a structured programme for the diagnosis, surveillance and treatment of patients alongside research into VHL disease and involves a multidisciplinary team of dedicated physicians. This programme demonstrates the benefits of care centralization, including concentration of knowledge and services, synergy and multidisciplinary management, improved networking and patient resources, reducing health care costs, and fostering research and innovation. VHL disease provides an ideal model to assess the advantages of centralizing care for rare disease and represents an unparalleled opportunity to broaden our understanding of cancer biology in general.

Population-specific validation and comparison of the performance of 77- and 313-variant polygenic risk scores for breast cancer risk prediction.

The polygenic risk score (PRS) allows the quantification of the polygenic effect of many low-penetrance alleles on the risk of breast cancer (BC). This study aimed to evaluate the performance of two sets comprising 77 or 313 low-penetrance loci (PRS77 and PRS313) in patients with BC in the Czech population. In a retrospective case-control study, variants were genotyped from both the PRS77 and PRS313 sets in 1329 patients with BC and 1324 noncancer controls, all women without germline pathogenic variants in BC predisposition genes. Odds ratios (ORs) were calculated according to the categorical PRS in individual deciles. Weighted Cox regression analysis was used to estimate the hazard ratio (HR) per standard deviation (SD) increase in PRS. The distributions of standardized PRSs in patients and controls were significantly different (p < 2.2×10-16) with both sets. PRS313 outperformed PRS77 in categorical and continuous PRS analyses. For patients in the highest 2.5% of PRS313, the risk reached an ORof3.05 (95% CI,1.66-5.89; p=1.76×10-4). The continuous risk was estimated as an HRper SDof1.64 (95% CI,1.49-1.81; p<2.0×10-16), which resulted in an absolute risk of 21.03% at age 80 years for individuals in the 95th percentile of PRS313. Discordant categorization into PRS deciles was observed in 248 individuals (9.3%). Both PRS77 and PRS313 are able to stratify individuals according to their BC risk in the Czech population. PRS313 shows better discriminatory ability. The results support the potential clinical utility of using PRS313 in individualized BC risk prediction.

Genetic Predisposition to Sarcoma: What Should Clinicians Know?

Pathogenic germline variants in the setting of several associated cancer predisposition syndromes (CPS) may lead to the development of sarcoma. We would consider testing for a CPS in patients with a strong family history of cancer, multiple primary malignancies, and/or pediatric/adolescent/young adult patients diagnosed with other malignancies strongly associated with CPS. When a CPS is diagnosed in a patient with sarcoma, additional treatment considerations and imaging options for those patients are required. This applies particularly to the use of radiation therapy, ionizing radiation with diagnostic imaging, and the use of alkylating chemotherapy. As data and guidelines are currently lacking for many of these scenarios, we have adopted a shared decision-making process with patients and their families. If the best chance for cure in a patient with CPS requires utilization of radiation therapy or alkylating chemotherapy, we discuss the risks with the patient but do not omit these modalities. However, if there are treatment options that yield equivalent survival rates, yet avoid these modalities, we elect for those options. Considering staging imaging and post-therapy evaluation for sarcoma recurrence, we avoid surveillance techniques that utilize ionizing radiation when possible but do not completely omit them when their use is indicated.

Pancreatic neuroendocrine tumors in French VHL mutation carriers: a multicentric retrospective study.

Von Hippel-Lindau disease (VHL) is a rare autosomal dominant hereditary cancer-predisposition syndrome caused by germline pathogenic variants (PV) in VHL gene. It is associated with a high penetrance of benign and malignant vascular tumors in multiples organs, including pancreatic neuroendocrine tumors (PanNETs), whose long-term natural history is ill-known. Patients with both documented germline PV in VHL gene and PanNETs included in the French PREDIR database between 1995 and 2022 were included. Primary endpoint was the proportion of patients with PanNET-related metastases and secondary endpoint was overall survival (OS). Genotype/phenotype correlations were studied. We included 121 patients with 259 PanNETs. Median age at diagnosis was 38 years. Median follow-up was 89.5 months. PanNET surgical resection was performed in 51 patients. Overall, 29 patients (24%) had metastases (5 synchronous, 10 metachronous), with a higher risk in case of larger PanNET size (p=0.0089; best threshold 28 mm) and grade 2 PanNET (p=0.048), and a pejorative prognostic impact (p=0.043). Patients with PV in VHL exon 1 had larger PanNETs (p=0.018), more often metastatic disease (48% vs 11.5%; p < 0.001) and a trend toward shorter OS (p=0.16). The risk of metastases associated to VHL-related PanNETs remains low (24%) but increases with tumor size >28 mm, higher grade and in case of PV located VHL exon 1. These data might help improving the management of these patients, who should be referred to an expert center.

High Frequency of BRCA2 c.5576_5579del Carriers in Kakogawa, Japan.

Certain germline pathogenic variants (PVs), known as founder mutations, have been frequently observed in specific regions and ethnic groups. In Japan, several pathogenic variants of BRCA1/2 have been identified as founder mutations, with their distribution varying across different regions. This retrospective study aimed to further investigate the detailed distribution and correlation between genotype and clinical features among breast cancer patients. This study was conducted at Kobe University Hospital and three collaborating institutions. It included breast cancer patients who underwent BRCA1/2 genetic testing between July 1, 2018, and March 31, 2021, and were found to have germline PVs. Clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2 c.5576_5579del and those with other PVs. Additionally, the detection rate of BRCA2 c.5576_5579del was compared with that observed in a previous report. A total of 38 breast cancer patients were included; PVs in BRCA1 and BRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2 c.5576_5579del carriers. BRCA2 c.5576_5579del carriers were more likely to develop triple negative breast cancers among all BRCA2 PV carriers. BRCA2 c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital. BRCA2 c.5576_5579del was detected with a particularly high frequency in Hyogo Prefecture, especially in Kakogawa city. In the future, a survey of the distribution of the BRCA2 c.5576_5579del carriers may provide more clarity regarding their localization.