Browsing by Subject "HEREDITARY"

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  • Tyynismaa, Henna (2019)
    New therapies targeting metabolic vulnerabilities of specific tumor types have created wide interest in recent years. Through research now reported in the Journal by Gantner et al.,(1) metabolic precision therapy may become possible in patients with a rare eye disease, macular telangiectasia type 2, which leads to a progressive loss of central vision in both eyes in middle-aged or older persons.(2) The macula is the small area in the back of the eye that is responsible for high-resolution (i.e., sharp) vision. In the center of the macula is the fovea, which has the highest density of cone photoreceptor cells and . . .
  • German HNPCC Consortium; Dutch Lynch Syndrome Collaborative; Finnish Lynch Syndrome Registry; Engel, Christoph; Ahadova, Aysel; Seppälä, Toni T.; Lepistö, Anna; Renkonen-Sinisalo, Laura; Vasen, Hans F. (2020)
    BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P <.001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.
  • Olkinuora, Alisa; Nieminen, Taina T.; Mårtensson, Emma; Rohlin, Anna; Ristimäki, Ari; Koskenvuo, Laura; Lepistö, Anna; Swedish Extended Genetic Anal Colo; Gebre-Medhin, Samuel; Nordling, Margareta; Peltomäki, Päivi (2019)
    Purpose: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes. Methods: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of similar to 1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility. Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability. Conclusion: Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.
  • Ahadova, Aysel; Pfuderer, Pauline Luise; Ahtiainen, Maarit; Ballhausen, Alexej; Bohaumilitzky, Lena; Kösegi, Svenja; Müller, Nico; Tang, Yee Lin; Kosmalla, Kosima; Witt, Johannes; Endris, Volker; Stenzinger, Albrecht; von Knebel Doeberitz, Magnus; Bläker, Hendrik; Renkonen-Sinisalo, Laura; Lepistö, Anna; Böhm, Jan; Mecklin, Jukka-Pekka; Seppälä, Toni T.; Kloor, Matthias (2021)
    Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers). We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high-throughput coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs (n total = 95). Incident cancers presented with lower UICC and T stage compared to prevalent cancers (p < 0.0005). The majority of incident cancers (21/28) were detected after previous colonoscopy without any pathological findings. On the molecular level, incident cancers presented with a significantly lower KRAS codon 12/13 (1/23, 4.3% vs. 11/21, 52%; p = 0.0005) and pathogenic TP53 mutation frequency (0/17, 0% vs. 7/21, 33.3%; p = 0.0108,) compared to prevalent cancers; 10/17 (58.8%) incident cancers harbored one or more truncating APC mutations, all showing mutational signatures of mismatch repair (MMR) deficiency. The proportion of MMR deficiency-related mutational events was significantly higher in incident compared to prevalent CRC (p = 0.018). In conclusion, our study identifies a set of features indicative of biological differences between incident and prevalent cancers in LS, which should further be monitored in prospective LS screening studies to guide towards optimized prevention protocols.
  • Yu, Hongyao; Hemminki, Akseli; Sundquist, Kristina; Hemminki, Kari (2019)
    BACKGROUND: Many studies have indicated that colon and rectal cancers differ in etiology and histology. OBJECTIVE: The aim of this study was to investigate whether the associations of colon and rectal cancers with any other (discordant) cancer were site specific. DESIGN: A novel approach was implemented in which cancer risks were analyzed in families with increasing numbers of family members diagnosed with defined cancers. The novel assumption was that, for a true familial association, the risk should increase by the number of affected family members. In separate analyses, familial risks were calculated after the exclusion of putative families with hereditary nonpolyposis colorectal cancer. SETTINGS: The study was conducted using the Swedish Family-Cancer Database. MAIN OUTCOME MEASURES: The outcome measure was relative risk. RESULTS: Relative risks of colorectal cancer and colon cancer were higher when family members were diagnosed with colon cancer than when family members were diagnosed with rectal cancer (incidence rate ratio for colorectal: 1.82 (95% Cl, 1.74-1.90) vs 1.61 (95% Cl, 1.51-1.71); incidence rate ratio for colon: 1.92 (95% Cl, 1.83-2.02) vs 1.56 (95% CI, 1.45-1.69)). Relative risks for 10 discordant cancers were increased in colon or rectal cancer families, whereas none of the relative risks differed significantly between colon and rectal cancers. After deleting hereditary nonpolyposis colorectal cancer families, the relative risks of endometrial and ovarian cancers were no longer significant. LIMITATIONS: Genetic data are unavailable in the database. CONCLUSIONS: Our results suggested that familial risks for colon cancer were higher than risks for rectal cancer in families of patients with colorectal cancer and colon cancer. The relationships of lung cancer and nervous system cancer with colorectal cancer were site specific. The associations of colon and rectal cancers with lung cancer, myeloma, and cancer of unknown primary appeared not to point out known syndromes and may suggest involvement of a novel predisposition.
  • Graf, Alexandra; Enyedi, Marton Zsolt; Pinter, Lajos; Kriston-Pal, Eva; Jaksa, Gabor; Balind, Arpad; Ezer, Eva; Horvath, Peter; Sukosd, Farkas; Kiss, Erno; Haracska, Lajos (2021)
    Simple Summary Germline and somatic BRCA1/2 mutations may define therapeutic targets and refine cancer treatment options. However, routine BRCA diagnostic approaches cannot reveal the exact time and origin of BRCA1/2 mutation formation, and thus, the fine details of their contribution to tumor progression remain less clear. We established a diagnostic pipeline using high-resolution microscopy and laser microcapture microscopy to test for BRCA1/2 mutations in tumors at the single-cell level, followed by deep next-generation sequencing of various tissues from the patient. To demonstrate the power of our approach, here we present a detailed analysis of an ovarian cancer patient, in which we describe constitutional somatic mosaicism of a BRCA2 mutation. Characterization of the mosaic mutation at the single-cell level contributes to a better understanding of BRCA mutation formation and supports the concept that the combination of single-cell and next-generation sequencing methods is advantageous over traditional mutational analysis methods. Germline mutations in the BRCA1 and BRCA2 genes are responsible for hereditary breast and ovarian cancer syndrome. Germline and somatic BRCA1/2 mutations may define therapeutic targets and refine cancer treatment options. However, routine BRCA diagnostic approaches cannot reveal the exact time and origin of BRCA1/2 mutation formation, and thus, the fine details of their contribution to tumor progression remain less clear. Here, we establish a diagnostic pipeline using high-resolution microscopy and laser microcapture microscopy to test for BRCA1/2 mutations in the tumor at the single-cell level, followed by deep next-generation sequencing of various tissues from the patient. To demonstrate the power of our approach, here, we describe a detailed single-cell-level analysis of an ovarian cancer patient we found to exhibit constitutional somatic mosaicism of a pathogenic BRCA2 mutation. Employing next-generation sequencing, BRCA2 c.7795G>T, p.(Glu2599Ter) was detected in 78% of reads in DNA extracted from ovarian cancer tissue and 25% of reads in DNA derived from peripheral blood, which differs significantly from the expected 50% of a hereditary mutation. The BRCA2 mutation was subsequently observed at 17-20% levels in the normal ovarian and buccal tissue of the patient. Together, our findings suggest that this mutation occurred early in embryonic development. Characterization of the mosaic mutation at the single-cell level contributes to a better understanding of BRCA mutation formation and supports the concept that the combination of single-cell and next-generation sequencing methods is advantageous over traditional mutational analysis methods. This study is the first to characterize constitutional mosaicism down to the single-cell level, and it demonstrates that BRCA2 mosaicism occurring early during embryogenesis can drive tumorigenesis in ovarian cancer.