Definition of Biologically Distinct Groups of Conjunctival Melanomas According to Etiological Factors and Implications for Precision Medicine
AuthorsGardrat, Sophie; email: email@example.com
Houy, Alexandre; orcid: 0000-0001-6267-2353; email: firstname.lastname@example.org
Brooks, Kelly; email: Kelly.Brooks@qimrberghofer.edu.au
Cassoux, Nathalie; email: email@example.com
Barnhill, Raymond; email: firstname.lastname@example.org
Dayot, Stéphane; email: email@example.com
Bièche, Ivan; email: firstname.lastname@example.org
Raynal, Virginie; email: email@example.com
Baulande, Sylvain; email: firstname.lastname@example.org
Marais, Richard; email: Richard.Marais@cruk.manchester.ac.uk
Roman-Roman, Sergio; email: email@example.com
Stern, Marc-Henri; orcid: 0000-0002-8100-2272; email: firstname.lastname@example.org
Rodrigues, Manuel; orcid: 0000-0002-5443-0802; email: email@example.com
MetadataShow full item record
AbstractConjunctival melanoma (ConjMel) is a potentially deadly ocular melanoma, originating from partially sunlight-exposed mucosa. We explored the mutational landscape of ConjMel and studied the correlation with etiological factors. We collected 47 primary ConjMel samples and performed next-generation sequencing of 400 genes. Hotspot mutations in BRAF, NRAS, HRAS, and KIT were observed in 16 (34%), 5 (11%), 2, and 2 cases, respectively. Patients with BRAF and CDKN2A-mutated ConjMel tended to be younger while the NF1-mutated one tended to be older. The eight tumors arising from nevi were enriched in CTNNB1 mutations (63% vs. 8%; Fisher’s exact p-test = 0.001) compared to non-nevi ConjMel and five were devoid of BRAF, RAS, NF1, or KIT mutations, suggesting a specific oncogenic process in these tumors. The two KIT-mutated cases carried SF3B1 mutations and were located on sun-protected mucosa, a genotype shared with genital and anorectal mucosal melanomas. Targetable mutations were observed in ERBB2, IDH1, MET, and MAP2K1 (one occurrence each). Mutational landscape of ConjMel characterizes distinct molecular subtypes with oncogenic drivers common with mucosal and skin melanomas. CTNNB1 mutations were associated with nevus-derived ConjMel. Concomitant KIT/SF3B1 mutations in sun-protected cases suggest a common tumorigenic process with genital and anorectal mucosal melanomas.
CitationCancers, volume 13, issue 15, page e3836
DescriptionFrom MDPI via Jisc Publications Router
History: accepted 2021-07-26, pub-electronic 2021-07-30
Publication status: Published
Funder: European Commission; Grant(s): 667787
Funder: European Research Council; Grant(s): ERC-ADG-2014 671262
Funder: Cancer Research UK; Grant(s): A27412 and A22902
Funder: Institut Curie; Grant(s): #
Funder: Ligue Contre le Cancer; Grant(s): #
Funder: Institut National de la Santé et de la Recherche Médicale; Grant(s): #
Showing items related by title, author, creator and subject.
Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?Park, JooYong; email: firstname.lastname@example.org; Choi, Ji-Yeob; email: email@example.com; Choi, Jaesung; email: firstname.lastname@example.org; Chung, Seokang; email: email@example.com; Song, Nan; orcid: 0000-0002-9182-1060; email: firstname.lastname@example.org; Park, Sue K.; orcid: 0000-0001-5002-9707; email: email@example.com; Han, Wonshik; email: firstname.lastname@example.org; Noh, Dong-Young; email: email@example.com; Ahn, Sei-Hyun; email: firstname.lastname@example.org; Lee, Jong Won; email: email@example.com; et al. (MDPI, 2021-05-14)In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database StudyDominguez-Valentin, Mev; orcid: 0000-0001-7856-0057; email: Mev.Dominguez.Valentin@rr-research.no; Plazzer, John-Paul; orcid: 0000-0001-5114-4301; email: firstname.lastname@example.org; Sampson, Julian R.; email: Sampson@cardiff.ac.uk; Engel, Christoph; orcid: 0000-0002-7247-282X; email: email@example.com; Aretz, Stefan; orcid: 0000-0002-5228-1890; email: firstname.lastname@example.org; Jenkins, Mark A.; email: email@example.com; Sunde, Lone; email: firstname.lastname@example.org; Bernstein, Inge; email: email@example.com; Capella, Gabriel; orcid: 0000-0002-4669-7320; email: firstname.lastname@example.org; Balaguer, Francesc; orcid: 0000-0002-0206-0539; email: email@example.com; et al. (MDPI, 2021-06-28)Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
Development of Randomized Trials in Adults with Medulloblastoma—The Example of EORTC 1634-BTG/NOA-23Hau, Peter; orcid: 0000-0003-3894-5053; email: Peter.Hau@ukr.de; Frappaz, Didier; email: Didier.Frappaz@ihope.fr; Hovey, Elizabeth; email: Elizabeth.Hovey@health.nsw.gov.au; McCabe, Martin G.; orcid: 0000-0002-5138-0707; email: Martin.McCabe@manchester.ac.uk; Pajtler, Kristian W.; email: K.Pajtler@kitz-heidelberg.de; Wiestler, Benedikt; orcid: 0000-0002-2963-7772; email: B.Wiestler@tum.de; Seidel, Clemens; email: Clemens.Seidel@medizin.uni-leipzig.de; Combs, Stephanie E.; email: Stephanie.Combs@tum.de; Dirven, Linda; email: L.Dirven@lumc.nl; Klein, Martin; email: M.Klein@amsterdamumc.nl; et al. (MDPI, 2021-07-09)Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.