Proposal of new candidate genes of predisposition to serous ovarian cancer using whole-exome-sequencing of 16 patients with a familial form

International audienceHigh grade serous ovarian cancer 9th type of cancer 5th cause of death Late diagnostic and poor prognosis 15-20% of familial cancers : 2 Sporadic cancers Familial cancers 15-20% BRCA1/2 Unknown genes 50-85% MMR/RAD5

Early Onset Multiple Primary Tumors in Atypical Presentation of Cowden Syndrome Identified by Whole-Exome-Sequencing

International audienceA family with an aggregation of rare early onset multiple primary tumors has been managed in our oncogenetics department: the proband developed four early onset carcinomas between ages 31 and 33 years, including acral melanoma, bilateral clear cell renal carcinoma (RC), and follicular variant of papillary thyroid carcinoma. The proband's parent developed orbital lymphoma and small intestine mucosa-associated lymphoid tissue (MALT) lymphoma between 40 and 50 years old. Whole-exome-sequencing (WES) of the nuclear family (proband, parents, and sibling) identified in the proband a de novo deleterious heterozygous mutation c.1003C > T (p.Arg335∗) in the phosphatase and tensin homolog (PTEN) gene. Furthermore, WES allowed analysis of the nuclear family's genetic background, and identified deleterious variants in two candidate modifier genes: CEACAM1 and MIB2. CEACAM1, a tumor suppressor gene, presents loss of expression in clear cell RC and is involved in proliferation of B cells. It could explain in part the phenotype of proband's parent and the occurrence of clear cell RC in the proband. Deleterious mutations in the MIB2 gene are associated with melanoma invasion, and could explain the occurrence of melanoma in the proband. Cowden syndrome is a hereditary autosomal dominant disorder associated with increased risk of muco-cutaneous features, hamartomatous tumors, and cancer. This atypical presentation, including absence of muco-cutaneous lesions, four primary early onset tumors and bilateral clear cell RC, has not been described before. This encourages including the PTEN gene in panel testing in the context of early onset RC, whatever the histological subtype. Further studies are required to determine the implication of CEACAM1 and MIB2 in the severity of Cowden syndrome in our proband and occurrence of early onset MALT lymphoma in a parent

Detection Rate and Spectrum of Pathogenic Variations in a Cohort of 83 Patients with Suspected Hereditary Risk of Kidney Cancer

International audienceHereditary predisposition to cancer affects about 3–5% of renal cancers. Testing criteria have been proposed in France for genetic testing of non-syndromic renal cancer. Our study explores the detection rates associated with our testing criteria. Using a comprehensive gene panel including 8 genes related to renal cancer and 50 genes related to hereditary predisposition to other cancers, we evaluated the detection rate of pathogenic variants in a cohort of 83 patients with suspected renal cancer predisposition. The detection rate was 7.2% for the renal cancer genes, which was 2.41-fold higher than the estimated 3% proportion of unselected kidney cases with inherited risk. Pathogenic variants in renal cancer genes were observed in 44.5% of syndromic cases, and in 2.7% of non-syndromic cases. Incidental findings were observed in CHEK2, MSH2, MUTYH and WRN. CHEK2 was associated with renal cancer (OR at 7.14; 95% CI 1.74–29.6; p < 0.003) in our study in comparison to the gnomAD control population. The detection rate in renal cancer genes was low in non-syndromic cases. Additional causal mechanisms are probably involved, and further research is required to find them. A study of the management of renal cancer risk for CHEK2 pathogenic variant carriers is needed

Feedback of extended panel sequencing in 1530 patients referred for suspicion of hereditary predisposition to adult cancers

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Analysis of 11 candidate genes in 849 adult patients with suspected hereditary cancer predisposition

International audienceHereditary predisposition to cancer concerns between 5% and 10% of cancers. The main genes involved in the most frequent syndromes (hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome) were identified in the 1990s. Exploration of their functional pathways then identified novel genes for hereditary predisposition to cancer, and candidate genes whose involvement remains unclear. To determine the contribution of truncating variants in 11 candidate genes (BARD1, FAM175A, FANCM, MLH3, MRE11A, PMS1, RAD50, RAD51, RAD51B, RINT1, and XRCC2) to cancer predisposition in a population of interest, panel sequencing was performed in 849 patients with a suspected hereditary predisposition to cancer for whom a diagnostic panel of 38 genes identified no causal mutation. Sixteen truncating variants were found in FANCM (n = 7), RINT1 (n = 4), RAD50 (n = 2), BARD1, PMS1, and RAD51B. FANCM (adjusted P-value: .03) and RINT1 (adjusted P-value: 0.04) were significantly associated with hereditary breast and ovarian cancer. However, further studies are required to determinate the risk of cancer, including the segregation of the variants in the families of our cases. No mutation was identified in RAD51, MRE11A, FAM175A, XRCC2, or MLH3. The involvement of these genes in the hereditary predisposition to cancer cannot be ruled out, although if it exists it is rare or does not seem to involve truncating variants

Case Series of 11 <i>CDH1</i> Families (47 Carriers) Including Incidental Findings, Signet Ring Cell Colon Cancer and Review of the Literature

Germline pathogenic variants in E-cadherin (CDH1) confer high risk of developing lobular breast cancer and diffuse gastric cancer (DGC). The cumulative risk of DGC in CDH1 carriers has been recently reassessed (from 40–83% by age 80 to 25–42%) and varies according to the presence and number of gastric cancers in the family. As there is no accurate estimate of the risk of gastric cancer in families without DGC, the International Gastric Cancer Linkage Consortium recommendation is not straightforward: prophylactic gastrectomy or endoscopic surveillance should be proposed for these families. The inclusion of CDH1 in constitutional gene panels for hereditary breast and ovarian cancer and for gastrointestinal cancers, recommended by the French Genetic and Cancer Consortium in 2018 and 2020, leads to the identification of families with lobular cancer without DGC but also to incidental findings of pathogenic variants. Management of CDH1 carriers in case of incidental findings is complex and causes dilemmas for both patients and providers. We report eleven families (47 CDH1 carriers) from our oncogenetic department specialized in breast and ovarian cancer, including four incidental findings. We confirmed that six families did not have diffuse gastric cancer in their medical records. We discuss the management of the risk of diffuse gastric cancer in Hereditary Lobular Breast Cancer (HLBC) through a family of 11 CDH1 carriers where foci were identified in endoscopic surveillance. We also report a new colon signet ring cancer case in a CDH1 carrier, a rare aggressive cancer included in CDH1-related malignancies

Rare duplication of the CDC73 gene and atypical hyperparathyroidism‐jaw tumor syndrome: A case report and review of the literature

International audienceBackgroundHyperparathyroidism jaw-tumor syndrome (HPT-JT) is the rarest familial cause of primary hyperparathyroidism, with an incidence <1/1000000, caused by a pathogenic variant in the CDC73 (or HRPT2) gene that encodes parafibromin, a protein involved in many cellular mechanisms. Patients with HPT-JT have a 15–20% of risk of developing parathyroid carcinoma, whereas it accounts for only 1% of all cases of primary hyperparathyroidism. Patients also develop jaw tumors in 30% of cases, kidney abnormalities in 15% of cases, and uterine tumors in 50% of patients.Case ReportHere are report two atypical cases of HPT-JT with variable expressivity in the same family. In front of an isolated primary hyperparathyroidism at 28 years of age of incidental discovery following a weight gain, the propositus benefited a first-line panel by Next-Generation Sequencing of the genes involved in familial hyperparathyroidism: CaSR, CDC73, MEN1, and RET. Genetic testing revealed the presence of a pathogenic germline variation CDC73: c.687_688dup; p.Val230Glufs*28, found only in nine families in the literature and allowing the diagnosis of HPT-JT. Given a history of primary hyperparathyroidism at 52 years and adenomyosis, the patient's mother also underwent a genetic analysis that found her daughter's variation and established her inherited trait.ConclusionIn view of the clinical and genotypic heterogeneity, we confirm the interest of using an extended gene panel for the diagnosis of familial primary hyperparathyroidism. CDC73 variations could be more frequent than described in the literature. The association of primary hyperparathyroidism with uterine involvement could be a new indication for analysis

Is BRCA2 involved in early onset colorectal cancer risk?

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Diagnosis of PTEN mosaicism: the relevance of additional tumor DNA sequencing. A case report and review of the literature

Abstract Background PTEN hamartoma syndrome (PHTS) is an autosomal dominant disorder characterized by pathogenic variants in the tumor suppressor gene phosphatase and tensin homolog ( PTEN ). It is associated with an increased risk of muco-cutaneous features, hamartomatous tumors, and cancers. Mosaicism has been found in a few cases of patients with de novo PHTS, identified from blood samples. We report a PHTS patient with no variant identified from blood sample. Constitutional PTEN mosaicism was detected through sequencing of DNA from different tumoral and non-tumoral samples. Case presentation Our patient presented clinical Cowden syndrome at 56 years of age, with three major criteria (macrocephaly, Lhermitte Duclos disease, oral papillomatosis), and two minor criteria (structural thyroid lesions, esophageal glycogenic acanthosis). Deep sequencing of PTEN of blood leukocytes did not reveal any pathogenic variants. Exploration of tumoral (colonic ganglioneuroma, esophageal papilloma, diapneusia fibroids) and non-tumoral stomach tissues found the same PTEN pathogenic variant (NM_000314.4 c.389G > A; p.(Arg130Gln)), with an allelic frequency of 12 to 59%, confirming genomic mosaicism for Cowden syndrome. Conclusions This case report, and review of the literature, suggests that systematic tumor analysis is essential for patients presenting PTEN hamartoma syndrome in the absence of any causal variant identified in blood leukocytes, despite deep sequencing. In 65 to 70% of cases of clinical Cowden syndrome, no pathogenic variant in the PTEN is observed in blood samples: mosaicism may explain a significant number of these patients. Tumor analysis would improve our knowledge of the frequency of de novo variations in this syndrome. Finally, patients with mosaicism for PTEN may not have a mild phenotype; medical care identical to that of heterozygous carriers should be offered

Le Personnage tragique

Le thème du personnage tragique sert ici de point d’ancrage pour prendre en compte l’évolution historique et formelle du paradigme tragique. Les interrogations et contributions portent sur la lisibilité des mutations historiques du personnage tragique dans les textes et les mises en jeu produits à des époques différentes. Le domaine culturel italien sert de base et d’exemple pour préciser la fonction du personnage tragique, ce mystérieux sujet, et en déceler une éventuelle évolution, entre le XIIe siècle et nos jours. On abordera le personnage tragique comme fonction narrative, théâtrale ou opératique : les études portent sur des textes de théâtre, sur les traités de poétique, sur des réécritures de modèles qu’ils soient antiques ou shakespearien, et sur des mises en scène du XXe siècle