Familial Cancer最新文献

{"title":"A dual biomarker in non-small cell lung cancer that predicts Li Fraumeni syndrome : Lung cancer and Li Fraumeni.","authors":"Steven Sorscher","doi":"10.1007/s10689-024-00418-8","DOIUrl":"10.1007/s10689-024-00418-8","url":null,"abstract":"<p><p>Non-small cell lung cancer is the most common cause of cancer death globally. When apparent incidental pathogenic germline variants (PGVs) are uncovered with routine next generation sequencing (NGS) of NSCLCs, germline testing (GT) is recommended to confirm that PGV. Because it is far more common that an uncovered tumor TP53 variant is related to a somatic event than an incidental PGV, however, GT for Li Fraumeni syndrome (LFS) is not recommended based solely on uncovering a NSCLC TP53 variant. Because nearly all tumor EGFR variants are also somatic in origin, GT is not recommended based solely on uncovering a tumor EGFR variant.However, there is evidence that patients with coexisting NSCLC variants in both EGFR and TP53 have significant likelihoods of having LFS. For patients with LFS, there are recommended measures for prevention and early detection of LFS-associated cancers and cascade GT of relatives for LFS. Although co-existing genetic variants in NSCLC are not currently used as a biomarker for GT to identify patients with PGVs, given the evidence reviewed here, select patients with NSCLCs that harbor this dual biomarker (i.e., co-existing TP53/EGFR variants) might reasonably be considered for GT for LFS.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":" ","pages":"469-471"},"PeriodicalIF":1.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and genetic characteristics of carriers of the TP53 c.541C > T, p.Arg181Cys pathogenic variant causing hereditary cancer in patients of Arab-Muslim descent.","authors":"Johnathan Arnon, Aviad Zick, Myriam Maoz, Nada Salaymeh, Ahinoam Gugenheim, MazalTov Marouani, Eden Mor, Tamar Hamburger, Nagam Saadi, Anna Elia, Gael Ganz, Duha Fahham, Amichay Meirovitz, Luna Kadouri, Vardiella Meiner, Tamar Yablonski-Peretz, Shiri Shkedi-Rafid","doi":"10.1007/s10689-024-00391-2","DOIUrl":"10.1007/s10689-024-00391-2","url":null,"abstract":"<p><p>TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 (TP53): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospectively examined our genetic databases to identify all carriers of TP53 p.Arg181Cys. We reached out to carriers and their relatives and collected clinical and demographic data, lifestyle factors, carcinogenic exposures as well as additional blood samples for genetic testing and whole exome sequencing. Between 2005 and 2022 a total of 2875 cancer patients underwent genetic testing using genetic panels, whole exome sequencing or targeted TP53 assays. A total of 30 cancer patients, all of Arab-Muslim descent, were found to be carriers of TP53 p.Arg181Cys, the majority from Jerusalem and Hebron, two of which were homozygous for the variant. Carriers were from 24 distinct families of them, 15 families (62.5%) met updated Chompret criteria for LFS. Median age of diagnosis was 35 years-old (range 1-69) with cancers characteristic of LFS (16 Breast cancer; 6 primary CNS tumors; 3 sarcomas) including 4 children with choroid plexus carcinoma, medulloblastoma, or glioblastoma. A total of 21 healthy carriers of TP53 p.Arg181Cys were identified at a median age of 39 years-old (range 2-54)-19 relatives and 2 additional pediatric non-cancer patients, in which the finding was incidental. We report a shared haplotype of 350kb among carriers, limited co-morbidities and low BMI in both cancer patients and healthy carriers. There were no demographic factors or carcinogenic exposures unique to carriers who developed malignancy. Upon exome analysis no other known pathogenic variants in cancer predisposing genes were identified. TP53 p.Arg181Cys is a founder pathogenic variant predominant to the Arab-Muslim population in Jerusalem and Hebron, causing attenuated-LFS. We suggest strict surveillance in established carriers and encourage referral to genetic testing for all cancer patients of Arab-Muslim descent in this region with LFS-associated malignancies as well as family members of established carriers.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":" ","pages":"531-542"},"PeriodicalIF":1.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A content analysis of parents' reflections on pathogenic and uncertain pediatric oncology germline sequencing results.","authors":"Katianne M Howard Sharp, Mary Egan Clark, Niki Jurbergs, Annastasia Ouma, Lynn Harrison, Leslie Taylor, Kayla Hamilton, Rose B McGee, Regina Nuccio, Stacy Hines-Dowell, Jami S Gattuso, Michelle Pritchard, Belinda Mandrell, Kenneth P Tercyak, Liza-Marie Johnson, Kim E Nichols","doi":"10.1007/s10689-024-00417-9","DOIUrl":"10.1007/s10689-024-00417-9","url":null,"abstract":"<p><p>Germline genomic sequencing is increasingly integrated into pediatric cancer care, with pathogenic cancer-predisposing variants identified among 5-18% of affected children and variants of uncertain significance (VUS) in up to 70%. Given the potential medical implications for children and their families, parents' psychosocial responses to learning results are important to understand. Parents of children with cancer who learned their children's germline pathogenic or VUS results following paired tumor and germline genomic sequencing described their cognitive and affective responses to results in an open-ended write-in question after disclosure (M = 10 months post-disclosure; range = 1-28). Responses were coded and categorized using content analysis, then compared across results using chi-square and Fisher's exact test. Parents of children with pathogenic (n = 9), VUS (n = 52), and pathogenic plus VUS results (n = 9) described negative emotions, positive reactions, mixed emotions (i.e., positive and negative emotions), and neutral reactions. Negative emotions were described significantly more frequently with pathogenic results than VUS only (χ² = 5.19; p = .02), with peace of mind and empowerment only described for those with VUS. Parents also described approach(es) to coping (e.g., faith, plan of action) and reactions specific to the uncertainty of VUS (e.g., disappointment at no explanation for cancer etiology). A subset with VUS described decreasing worry/distress with increased understanding of results, whereas others displayed misconceptions regarding VUS. Screening for emotional adjustment is warranted for parents of children with cancer receiving pathogenic germline results, and screening for understanding is warranted with VUS. Findings highlight the importance of pre-and posttest genetic counseling.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":" ","pages":"551-561"},"PeriodicalIF":1.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benign tumors and non-melanoma skin cancers in patients with Fanconi anemia.","authors":"Aura Enache, Bia Sajjad, Burak Altintas, Neelam Giri, Lisa J McReynolds, Edward W Cowen","doi":"10.1007/s10689-024-00410-2","DOIUrl":"10.1007/s10689-024-00410-2","url":null,"abstract":"<p><p>Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) characterized by pathogenic variants in the FA/BRCA DNA repair pathway genes. Individuals with FA have an elevated risk of developing myelodysplastic syndrome, acute myeloid leukemia, and solid tumors. Hematopoietic cell transplantation (HCT) is the most effective treatment for FA related bone marrow failure but can increase the risk of cancer development. Information on benign tumors and NMSC is lacking in patients with FA. Our objective was to characterize patients with FA enrolled in the National Cancer Institute IBMFS Study who have experienced non-melanoma skin cancers (NMSC) and/or benign tumors (BT). A total of 200 patients diagnosed with FA were enrolled in the Institutional Review Board approved study \"Etiologic Investigation of Cancer Susceptibility in IBMFS: A Natural History Study\" (NCT00027274). Through medical records review, we identified 30 patients with at least one NMSC, either squamous or basal cell carcinoma, or benign tumor. The remaining 170 patients comprised the control group. Out of 200 patients, 12 had NMSC, 25 had benign tumors, with an age range of 11-64 and 0-56 years, respectively. The median age at HCT was 30.5 years for NMSC patients, 9 years for benign tumor patients, and 9.1 years for controls. The most common genotype observed was FANCA, followed by FANCC and FANCI. Benign tumors spanned diverse anatomical locations. Early onset NMSC in patients with FA compared to the general population emphasizes the need for consistent monitoring in patients with FA, while the diverse anatomical locations of benign tumors underscore the importance of comprehensive surveillance for timely interventions in managing symptomatology and heightened cancer risk.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":" ","pages":"583-590"},"PeriodicalIF":1.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant transcription caused by an intronic non-canonical CDH1 variant.","authors":"Ahmed Bouras, Chloé Grand-Masson, Cedrick Lefol, Eric Ruano, Fabienne Prieur, Qing Wang","doi":"10.1007/s10689-024-00361-8","DOIUrl":"10.1007/s10689-024-00361-8","url":null,"abstract":"","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":" ","pages":"671-673"},"PeriodicalIF":1.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139680973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Clinician perspectives on policy approaches to genetic risk disclosure in families.","authors":"Amicia Phillips, Danya F Vears, Ine Van Hoyweghen, Pascal Borry","doi":"10.1007/s10689-024-00409-9","DOIUrl":"10.1007/s10689-024-00409-9","url":null,"abstract":"","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":" ","pages":"703"},"PeriodicalIF":1.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Report of the sixth meeting of the European Consortium 'Care for CMMRD' (C₄CMMRD), Paris, France, November 16th 2022.","authors":"Léa Guerrini-Rousseau, Richard Gallon, Marta Pineda, Laurence Brugières, Stéphanie Baert-Desurmont, Carole Corsini, Volodia Dangouloff-Ros, Mark A J Gorris, Christine Haberler, Pauline Hoarau, Marjolijn C Jongmans, Matthias Kloor, Jan Loeffen, Charlotte Rigaud, Julie Robbe, Roseline Vibert, Dilys Weijers, Katharina Wimmer, Chrystelle Colas","doi":"10.1007/s10689-024-00403-1","DOIUrl":"10.1007/s10689-024-00403-1","url":null,"abstract":"<p><p>Biallelic germline pathogenic variants in one of the four mismatch repair genes (MSH2, MSH6, MLH1 and PMS2) cause a very rare, highly penetrant, childhood-onset cancer syndrome, called constitutional mismatch repair deficiency (CMMRD). The European consortium \"Care for CMMRD\" (C4CMMRD) was founded in Paris in 2013 to facilitate international collaboration and improve our knowledge of this rare cancer predisposition syndrome. Following initial publications on diagnostic criteria and surveillance guidelines for CMMRD, several partners collaborating within the C4CMMRD consortium have worked on and published numerous CMMRD-related clinical and biological projects. Since its formation, the C4CMMRD consortium held meetings every 1-2 years (except in 2020 and 2021 due to the Covid 19 pandemic). The sixth C4CMMRD meeting was held in Paris in November 2022, and brought together 42 participants from nine countries involved in various fields of CMMRD healthcare. The aim was to update members on the latest results and developments from ongoing research, and to discuss and initiate new study proposals. As previously done for the fifth meeting of the C4CMMRD group, this report summarizes data presented at this meeting.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":" ","pages":"447-457"},"PeriodicalIF":1.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A de novo germline pathogenic BRCA1 variant identified following an osteosarcoma pangenomic molecular analysis.","authors":"Adrien Mouren, Albain Chansavang, Nadim Hamzaoui, Arunya Srikaran, Pierre Laurent-Puig, Laetitia Marisa, Sixtine De Percin, Audrey Lupo, Frédérique Larousserie, Hélène Blons, Anais L'Haridon, Nelly Burnichon, Eric Pasmant, Camille Tlemsani","doi":"10.1007/s10689-024-00393-0","DOIUrl":"10.1007/s10689-024-00393-0","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":" ","pages":"627-634"},"PeriodicalIF":1.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of a major Lynch Syndrome-causing MLH1 founder variant in a large-scale genotyped cohort.","authors":"Lauri J Sipilä, Mervi Aavikko, Janne Ravantti, Samantha Martin, Teijo Kuopio, Laura Lahtinen, FinnGen, Päivi Peltomäki, Jukka-Pekka Mecklin, Lauri A Aaltonen, Toni T Seppälä","doi":"10.1007/s10689-024-00400-4","DOIUrl":"10.1007/s10689-024-00400-4","url":null,"abstract":"<p><p>Some 50% of Finnish Lynch Syndrome (LS) cases are caused by a founder variant in MLH1, in which the entire exon 16 has been lost due to an Alu-mediated recombination event. We piloted detecting the variant in FinnGen, a large genotyped cohort comprising approximately 10% of the current Finnish population, and validated the MLH1 founder variant status of identified individuals residing in the Central Finland Biobank catchment area. A consensus sequence flanking the deletion was identified in whole genome sequences of six LS individuals with the founder variant. Genotype data of 212,196 individuals was queried for regional matches to the consensus sequence. Enrichment of cancer and age at cancer onset was compared between matching and non-matching individuals. Variant status was validated for a subset of the identified individuals using a polymerase chain reaction assay. Allelic matches in a chosen target region was detected in 348 individuals, with 89 having a cancer diagnosis (Bonferroni-adjusted p-value = 1), 20 a familial cancer history (p-adj. < .001), with mean age of onset of cancer being 53.6 years (p-adj. = .002). Eighteen of potential variant carriers had been sampled by the Central Finland Biobank, of which four (22%) were validated as true variant carriers. The workflow we have employed identifies MLH1 exon 16 deletion variant carriers from population-wide SNP genotyping data. An alternative design will be sought to limit false positive findings. Large genotyped cohorts provide a potential resource for identification and prevention of hereditary cancer.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":" ","pages":"647-652"},"PeriodicalIF":1.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections - a nationwide Danish cohort study with long-term follow-up.","authors":"J G Karstensen, M D Wewer, S Bülow, Tvo Hansen, H Højen, A M Jelsig, T P Kuhlmann, J Burisch, H C Pommergaard","doi":"10.1007/s10689-024-00415-x","DOIUrl":"10.1007/s10689-024-00415-x","url":null,"abstract":"<p><strong>Background: </strong>Familial adenomatous polyposis (FAP) predisposes individuals to duodenal adenomas. This study describes the histopathological features of endoscopic and surgical specimens from the duodenum, as well as genotype-phenotype associations.</p><p><strong>Methods: </strong>All known FAP patients were included from the Danish Polyposis Register. FAP patients were defined as having more than 100 cumulative colorectal adenomas and/or having a known germline pathogenic variant in the APC gene. Endoscopic procedures, histopathology, and genetics were evaluated.</p><p><strong>Results: </strong>Of 500 FAP patients, 70.6% underwent esophagogastroduodenoscopy (EGD) at least once. Of these, 59.2% presented with detectable duodenal adenomas. The most severe morphology was tubular in 62.7% patients, tubulovillous in 25.4%, and villous in 12.0%, while the most severe dysplasia was low-grade in 67.5% patients, high-grade in 25.4%, and 6.7% had adenocarcinoma. In 6.2% of FAP patients, duodenal resection was recommended, including 29% with duodenal adenocarcinoma. The risk of duodenal surgery was 1.31 per 1,000 person-years (median age: 53 years). The predominant reason for surgery was extensive polyposis (67.7%). Of the patients who underwent duodenal resection, a median of six (IQR: 4-8) EGDs were performed within five years prior to surgery, but 67.6% and 83.9% never underwent a duodenal polypectomy or endoscopic mucosa resection, respectively. Of note, seventeen of 500 patients (3.4%) developed duodenal adenocarcinoma, of which 47% were advanced at diagnosis. Genetic evaluations revealed various pathogenic variants in the APC gene, with no strong genotype-phenotype association.</p><p><strong>Conclusions: </strong>The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance. Nevertheless, the need for duodenal surgery persists and should together with endoscopic practice be monitored in national registers.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":" ","pages":"607-615"},"PeriodicalIF":1.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}