Albain Chansavang

Abnormal enamel mineralization has been reported in genetic conditions associated with hypocalcemia but never with hypercalcemia. In the present study, we report 10 patients from 2 unrelated families in whom hypomineralized enamel co-segregated with hypercalcemia due to a complete deletion or frameshifting premature truncation (p.(Ser18Argfs*2)) of the guanine nucleotide–binding protein (G-protein) subunit α ₁₁ ( GNA11 ) gene. Both GNA11 variants were heterozygous and predicted to cause a loss of function of Gα ₁₁ . Multiproxy imaging analyses of naturally exfoliated primary teeth and clinically extracted permanent teeth from 2 affected patients revealed abnormal enamel mineralization, with constitutive patches of hypomineralization following no set pattern. In parallel, the study of wild-type mouse tooth germs using combined molecular and protein analyses showed Gna11 and Gα ₁₁ protein expression in ameloblasts at the secretion and maturation stages, as well as in odontoblasts, suggesting a role for Gα ₁₁ in tooth formation. Furthermore, the analysis of a mouse model of Familial Hypocalciuric Hypercalcemia 2 (FHH2) revealed delayed onset of enamel mineralization in the continuously growing incisors and hypomineralized enamel in both incisor and molars of heterozygous ( Gna11 Tm1b ^+/− ) mice, with defects that are very similar to those affecting human FHH2 teeth. In conclusion, our study reveals that abnormal enamel mineralization may occur in association with hypercalcemia due to loss-of-function GNA11 mutations, opening a new field of investigation and highlighting the need to include a dentist in the multidisciplinary team in charge of patients with monogenic calcium disorders.

Low-variant allele frequency (VAF) variants identified during germline testing may represent constitutional mosaicism or acquired somatic events restricted to hematopoietic cells. Although clonal hematopoiesis of indeterminate potential (CHIP) has emerged as an important source of interpretative pitfalls in hereditary cancer testing, its potential impact on the interpretation of CDKN1B variants has not been specifically emphasized. We aimed to determine whether low-VAF CDKN1B variants detected during routine germline testing for pituitary adenoma predisposition may represent clonal hematopoiesis rather than true constitutional alterations. We analyzed patients referred for routine genetic investigation of pituitary adenoma predisposition who has low-frequency CDKN1B variants identified in blood-derived DNA. Additional analyses were performed, including assessment of variant distribution in nonhematopoietic tissues, tumor DNA analysis, and investigation of CHIP-associated genes. Three unrelated patients carrying truncating CDKN1B variants were identified, with blood-derived VAFs ranging from 4% to 6%. Clinical presentations included 2 gonadotroph macroadenomas diagnosed later than age 70 years and 1 prolactin-secreting macroadenoma diagnosed before age 35. CDKN1B variants were absent in buccal swab DNA and from available pituitary tumor DNA. Additional pathogenic variants affecting CHIP-associated genes were identified in 2 individuals. Collectively, these findings supported a leukocyte-restricted origin of the CDKN1B variants and suggested CHIP as the most likely explanation. Low-frequency CDKN1B variants detected during blood-based germline testing should not automatically be interpreted as constitutional mosaicism or inherited endocrine tumor predisposition. Integration of tissue-specific analyses and consideration of CHIP-related findings are essential to avoid inappropriate genetic counseling, unnecessary familial investigations, and misleading surveillance recommendations.

Introduction:Next-generation sequencing performed for therapeutic decision-making in pediatric cancers provides an opportunity to identify germline variants associated with hereditary cancer predisposition and other actionable inherited conditions. Methods:Germline whole-exome sequencing (WES) was performed within the MAPPYACTS (MoleculAr Profiling for Pediatric and Young Adult Cancer Treatment Stratification) trial. Germline data were available for 674 patients with diverse relapsed or refractory malignancies. Families provided informed consent regarding disclosure of actionable germline findings. A multidisciplinary committee established a panel of 184 cancer predisposition genes with established surveillance recommendations and 49 medically actionable noncancer genes from the ACMG SF v3.1 list. Variants were analyzed using bioinformatic pipelines including quality filtering, ClinVar annotation, and computational pathogenicity assessment. Results:Overall, 98.6% of families consented to the disclosure of actionable genetic findings. Among 674 patients, 130 likely pathogenic or pathogenic variants (LPV/PV) were identified in 130 patients (19.3%) across 53 cancer predisposition genes. Based on inheritance patterns and clinical relevance, genetic counseling was recommended for 58 patients (8.6%). The most frequently altered genes were TP53 (n=17), DICER1 (n=5), and BRCA1 (n=4). Predisposition findings corresponded to the expected tumor spectrum in 48% of cases, and 35% had not been previously recognized. Additionally, 10 patients (1.5%) carried actionable LPV/PV in noncancer genes associated with cardiomyopathies, familial hypercholesterolemia, or transthyretin amyloidosis. Discussion:Systematic germline WES integrated into theranostic profiling may provide additional clinical value through the identification of actionable cancer predispositions and other inherited conditions. We propose recommendations for a structured, multidisciplinary framework to support clinical decision-making.

Peutz-Jeghers syndrome (PJS) is a very rare autosomal dominant disorder associated with an increased risk of gastrointestinal and gynecological cancers. However, risk estimates vary widely, due to the small size and retrospective nature of most studies, which may introduce recruitment bias. Accurate data are needed to improve cancer screening. The aim of this study was to estimate cancer risks in a large cohort of PJS patients. A total of 161 patients were included, half of whom were prospectively monitored as part of a surveillance network. This makes it one of the largest cohorts of PJS patients to date. We estimated age-dependent cancer risks using the Genotype Restricted Likelihood (GRL) method to correct for ascertainment bias. Standardized mortality ratios (SMRs) were calculated to assess mortality. PJS patients showed an increased risk of cancer, particularly early-onset cancers (cumulative risk before age 70: 18.1% in men, 36.8% in women). This resulted in excess mortality, especially among young women. The most frequent cancers were breast, lung, and cervical cancers. Small bowel was the site with the highest relative risk. Although the risk of pancreatic adenocarcinoma (PDAC) was elevated, it was much lower than had been reported previously (relative risk at age 50: 11.8). Degenerated intraductal papillary mucinous neoplasms (IPMN) may contribute to the risk of PDAC in PJS, while this carcinogenesis pathway accounts for only 10% of PDACs overall. We report an unexpectedly high risk of lung adenocarcinoma, calling into question the relevance of lung cancer screening in PJS.

Les variants pathogènes du domaine exonucléase de l'ADN polymérase epsilon (POLE) représentent un enjeu clinique majeur. Au niveau constitutionnel, ils prédisposent au développement de cancers, notamment colorectaux. Au niveau somatique, ils confèrent aux tumeurs un profil ultramuté caractérisé par une charge mutationnelle extrêmement élevée, signature moléculaire associée à une sensibilité accrue aux inhibiteurs de points de contrôle immunitaire. Néanmoins, l'interprétation de nombreux variants faux-sens demeure difficile, ce qui limite leur intégration en oncogénétique et en oncologie de précision. Pour répondre à ces défis, nous avons combiné deux approches complémentaires. D'une part, un test fonctionnel à haut débit basé sur une mutagenèse à saturation du domaine exonucléase de Pol epsilon de Saccharomyces cerevisiae a permis d'évaluer systématiquement l'impact des substitutions d'acides aminés. Après validation par des variants connus délétères, cette approche a généré la première carte fonctionnelle exhaustive du domaine. Elle révèle que les variants pathogènes se concentrent dans des régions structurales critiques : (i) la poche catalytique, (ii) une boucle modulant le positionnement de l'extrémité 3' du brin naissant et (iii) une structure hélice-boucle-hélice séparant les domaines exonucléase et polymérase. Hors de ces régions, la majorité des résidus tolèrent les substitutions. La confrontation avec des données cliniques, tant constitutionnelles que somatiques, confirme la pertinence du modèle, tout en soulignant les limites des prédicteurs bioinformatiques face à des données expérimentales directes. D'autre part, nous avons mené une analyse protéogénomique intégrée sur une cohorte de tumeurs comprenant des cas mutés POLE, MSI et avec variant constitutionnel de POLE. Cette approche combinant séquençage d'exome et de transcriptome, analyse protéomique et prédiction bioinformatique de néoantigènes a mis en évidence plusieurs points : les tumeurs mutées POLE présentaient un excès de variants faux-sens par rapport aux tumeurs MSI, une corrélation linéaire entre nombre de variants non-synonymes et densité antigénique, ainsi qu'une charge néoantigénique supérieure. L'intégration du typage HLA démontrait l'importance du contexte immunogénétique de l'hôte pour la présentation des néoantigènes. Enfin, l'approche protéomique confirmait l'expression de certains néopeptides issus de variants somatiques, validant leur potentiel immunogénique et confortant le modèle reliant hypermutabilité et réponse clinique à l'immunothérapie. Contrairement aux analyses exome-transcriptome seules, souvent limitées par l'absence d'expression détectable de certains variants, l'apport de la protéomique permettait d'élever le niveau de confiance dans la prédiction des néoantigènes et de révéler néoantigènes qui auraient autrement échappé à la détection. Ainsi, la combinaison d'un atlas fonctionnel expérimental des variants de POLE et d'une caractérisation protéogénomique intégrée des tumeurs permet d'éclairer à la fois les mécanismes structure-fonction et les conséquences immunologiques de ces variants. Cette double approche constitue une ressource précieuse pour l'annotation clinique, affine la prédiction de la réponse aux immunothérapies et ouvre la voie à des stratégies thérapeutiques personnalisées, incluant le développement de vaccins ou de thérapies cellulaires ciblant des néoantigènes spécifiques.

Genetic predisposition is identified in 5–10% of prostate cancer patients. Although genetic testing is more frequently proposed, international recommendations are lacking. This study evaluates the impact of germline analysis on management of prostate cancer patients. Retrospective descriptive data were collected from prostate cancer patients who attended oncogenetic counselling between 2018 and 2021. Data included clinical and tumoral characteristics, and genomic analysis. Comparative analysis was performed between patients with germline pathogenic variants (PVs) and non-carriers using non-parametric tests. Fourteen out of the 168 patients (8.3%) had a PV, primarily in DNA repair genes (N = 13/14), including BRCA1/2 (N = 5). Twenty-five patients (14.9%) had variants of undetermined significance. Patients with PVs were more likely to have synchronous metastatic extension (79% vs 43%, p = 0.02) and a Gleason score ≥8 (82% vs 53%, p = 0.11). Significant enrichment of ATM PVs compared to a healthy control cohort was observed with an odds ratio of 32.5 [15.8–67.0] (p < 0.05). Three of five patients with BRCA1/2 PVs received DNA repair-targeted treatment. This cohort provides insights into the impact of oncogenetic counselling on prostate cancer patients’ management. It highlights the need to refine referral criteria based on disease stage and Gleason score and to further investigate ATM PVs. The data also underscore the importance of developing a care pathway with clear criteria for germline and/or somatic analysis to improve theranostic outcomes.

We assessed retrospectively the prevalence of pathogenic germline variants (PGV) in 268 French adult patients diagnosed with colorectal cancer (CRC) before age 41, stratified by phenotype. APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH3, MSH6, MUTYH, NTHL1, POLE, POLD1, PTEN, PMS2, SMAD4, STK11 and TP53 were analyzed. Overall, 21.6% of cases carried a PGV. A high prevalence was observed in Mismatch Repair-deficient (MMRd) CRC (60.1%, MMR genes) and polyposis-associated CRC (48%, APC, MUTYH and MSH3-biallelic, POLE). Only 2.3% of patients with MMR proficient and without polyposis carried a PGV. The genes involved in this third group were POLE and MSH2, and three out of four cases had either two synchronous CRC or a CRC family history. Phenotypic features should be taken into account for testing decision. Evaluating the cost-effectiveness of testing all CRC cases < 41 years, as well as how it aligns with the constraints of various healthcare systems, is warranted.

We assessed retrospectively the prevalence of pathogenic germline variants (PGVs) in 271 French adult patients diagnosed with colorectal cancer (CRC) before age 41, stratified by phenotype. APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH3, MSH6, MUTYH, POLE, POLD1, PTEN, PMS2, SMAD4, and STK11were analysed. Overall, 21.4% of cases carried a PGV. A high prevalence was observed in Mismatch Repair-deficient (MMRd) CRC (59.7%, MMR genes) and CRC associated with polyposis (48%, APC, biallelic MUTYH and MSH3, POLE). In contrast, MMR-proficient, non-polyposis cases only had a 1.7% prevalence. The only gene involved in this third group was POLE, and two out of three cases had either two synchronous CRC or a CRC family history. PGV prevalence is dependent on CRC phenotype, questioning the need for systematic germline testing in early-onset cases. A more targeted approach, focusing on MMRd CRC, or CRC associated with polyposis, might be warranted.