Introduction: The prevalence of pathogenic or likely pathogenic germline variants (PGV) in colorectal cancer (CRC) in young patients is seen in approximately one in five patients, with the majority ...of cases having gene variants associated with Lynch syndrome (LS). The primary aim was to describe the prevalence of 18 genes, all associated with hereditary polyposis and CRC, in a nationwide population of young CRC (yCRC) patients, and outline disease characteristics in patients with or without germline variants. Methods: We screened 98 patients aged 18–40 with CRC diagnosed in 2010–2013 for variants in MSH2, MSH6, MLH1, PMS2, EPCAM, APC, MUTYH, SMAD4, BMPR1A, STK11, PTEN, POLE, POLD1, NTHL1, AXIN2, MSH3, GREM1 and RNF43 using Next Generation Sequencing. Comparisons between patients’ characteristics in patients with PGV, and patients without germline variants (NPGV) were analyzed. Results: PGV were detected in twenty-four patients (24.5%), and twenty-one patients (21.1%) had variants in the mismatch repair (MMR) genes associated with LS. Variants in the APC and MUTYH genes were detected in 1% and 4%, respectively. Patients with NPGV had more advanced disease with adverse histopathological features. Conclusion: PGV was detected in one in four yCRC patients, and one in five yCRC patients had disease causing variants in the mismatch repair genes associated with LS.
Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded ...(FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder mutations. A high-throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild-type was possible in 25 out of 30 (83%) FFPE samples (age range 1-14 years), with a known variant status in BRCA1/2. No false positive was found. Unsuccessful identification was due to highly degraded DNA or presence of large intragenic deletions. In clinical use, a total of 201 FFPE samples (aged 0-43 years) were processed. Thirty-six samples were rejected because of highly degraded DNA or failed library preparation. Fifteen samples were investigated to search for a known variant. In the remaining 150 samples (aged 0-38 years), three variants known to affect function and one variant likely to affect function in BRCA1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE samples from non-tumor tissue. Accurate genetic counseling is achievable in families where variant testing would otherwise be impossible.
Glucose-6-phosphate is imported into the amyloplast of potato tubers and thought to constitute the precursor for starch synthesis in potato tubers. However, recently it was shown that ...glucose-1-phosphate can also be imported into the amyloplast and incorporated into starch via an ATP independent mechanism under special conditions. Nonetheless, glucose-6-phosphate is believed to be the quantitatively important precursor for starch synthesis in potato.
Potato tubers of the high yielding cv Kuras had low gene expression of plastidial phophoglucomutase (PGM) and normal levels of transcripts for other enzymes involved in starch metabolism in comparison with medium and low yielding cultivars as determined by DeepSAGE transcriptome profiling. The decrease in PGM activity in Kuras was confirmed by measuring the enzyme activity from potato tuber extracts. Contrary to expectations, this combination lead to a higher level of intracellular glucose-1-phosphate (G1P) in Kuras suggesting that G1P is directly imported into plastids and can be quantitatively important for starch synthesis under normal conditions in high yielding cultivars.
This could open entirely new possibilities for metabolic engineering of the starch metabolism in potato via the so far uncharacterized G1P transporter. The perspectives are to increase yield and space efficiency of this important crop. In the light of the increasing demands imposed on agriculture to support a growing global population this presents an exciting new possibility.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abbreviations APC APC regulator of WNT signaling pathway ATM ATM serine/threonine kinase BMPR1A bone morphogenetic protein receptor type 1A BRCA2 BRCA2 DNA repair associated CDKN2A cyclin-dependent ...kinase inhibitor 2A CHEK2 checkpoint kinase 2 CRC colorectal cancer EGFR epidermal growth factor receptor EORC early-onset rectal cancer FAP familial adenomatous polyposis HR homologous recombination KRAS Kirsten rat sarcoma viral oncogene homolog LP likely pathogenic LS Lynch syndrome MMR mismatch repair MSH2 mutS homolog 2 MUTYH mutY DNA glycosylase NF1 neurofibromin 1 P pathogenic PALB2 partner and localizer of BRCA2 PD-1 programmed cell death 1 POLD1 DNA polymerase delta 1, catalytic subunit RB1 RB transcriptional corepressor 1 VUS variant of uncertain significance Dear Editor, The incidence of rectal cancer has increased in patients younger than 50 years old during the last decade. A hereditary colorectal cancer (CRC) predisposition syndrome was confirmed in 11 patients, of whom seven were carriers of P variants in MMR (mismatch repair) genes, two presented with P variants in APC, and two had MUTYH biallelic P/LP variants. Clinical data and the status of mismatch repair protein expression in tumor samples are highlighted. Fanconi anemia; BER: base excision repair; NER: nucleotide excision repair; TSG: tumor suppressor gene Among the patients with a family history of cancer and no clinical diagnosis of LS, variants in homologous recombination (HR) genes were the most prevalent (12 patients, including 5 with P/LP variants).
Ovarian carcinomas presenting homologous recombination deficiency (HRD), which is observed in about 50% of cases, are more sensitive to platinum and PARP inhibitor therapies. Although platinum ...resistant disease has a low chance to be responsive to platinum-based chemotherapy, a set of patients is retreated with platinum and some of them are responsive. In this study, we evaluated copy number alterations, HR gene mutations and HR deficiency scores in ovarian cancer patients with prolonged platinum sensitivity.
In this retrospective study (2005 to 2014), we selected 31 patients with platinum resistant ovarian cancer retreated with platinum therapy. Copy number alterations and HR scores were evaluated using the OncoScan® FFPE platform in 15 cases. The mutational profile of 24 genes was investigated by targeted-NGS.
The median values of the four HRD scores were higher in responders (LOH = 15, LST = 28, tAI = 33, CS = 84) compared with non-responders (LOH = 7.5, LST = 17.5, tAI = 23, CS = 47). Patients with high LOH, LST, tAI and CS scores had better response rates, although these differences were not statistically significant. Response rate to platinum retreatment was 22% in patients with CCNE1 gains and 83.5% in patients with no CCNE1 gains (p = 0.041). Furthermore, response rate was 54.5% in patients with RB1 loss and 25% in patients without RB1 loss (p = 0.569). Patients with CCNE1 gains showed a worse progression free survival (PFS = 11.1 months vs 3.7 months; p = 0.008) and a shorter overall survival (OS = 39.3 months vs 7.1 months; p = 0.007) in comparison with patients with no CCNE1 gains. Patients with RB1 loss had better PFS (9.0 months vs 2.6 months; p = 0.093) and OS (27.4 months vs 3.6 months; p = 0.025) compared with cases with no RB1 loss. Four tumor samples were BRCA mutated and tumor mutations were not associated with response to treatment.
HR deficiency was found in 60% of our cases and HRD medium values were higher in responders than in non-responders. Despite the small number of patients tested, CCNE1 gain and RB1 loss discriminate patients with tumors extremely sensitive to platinum retreatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Prevalence of germline variants of head and neck cancer at early ages is unexplored.•Whole exome sequencing revealed germline variants in DNA repair genes in yHNSCC.•FANCG, CDKN2A, TPP, and FAT1 ...germline variants is associated with HNSCC risk.•Somatic variants were commonly detected in TP53, CDKN2A, and PIK3CA.•Somatic and germline variants were confirmed in an independent cohort of yHNSCC.
The genetic predisposition to head and neck carcinomas (HNSCC) and how the known risk factors (papillomavirus infection, alcohol, and tobacco consumption) contribute to the early-onset disease are barely explored. Although HNSCC at early onset is rare, its frequency is increasing in recent years. Germline and somatic variants were assessed to build a comprehensive genetic influence pattern in HNSCC predisposition and patient outcome. Whole-exome sequencing was performed in 45 oral and oropharynx carcinomas paired with normal samples of young adults (≤49 years). We found FANCG, CDKN2A, and TPP germline variants previously associated with HNSCC risk. At least one germline variant in DNA repair pathway genes was detected in 67% of cases. Germline and somatic variants (including copy number variations) in FAT1 gene were identified in 9 patients (20%) and 12 tumors (30%), respectively. Somatic variants were found in HNSCC associated genes, such as TP53, CDKN2A, and PIK3CA. To date, 55 of 521 cases from the large cohort of TCGA presented < 49 years old. A comparison between the somatic alterations of TCGA-HNSCC at early onset and our dataset revealed strong similarities. Protein-protein interaction analysis between somatic and germline altered genes revealed a central role of TP53. Altogether, germline alterations in DNA repair genes potentially contribute to an increased risk of developing HNSCC at early-onset, while FAT1 could impact the prognosis.
Pre-operative 5-fluoracil-based chemoradiotherapy (nCRT) is the standard treatment for patients with locally advanced rectal cancer (LARC). Patients with pathological complete response (pCR-0% of ...tumor cells in the surgical specimen after nCRT) have better overall survival and lower risk of recurrence in comparison with incomplete responders (pIR). Predictive biomarkers to be used for new therapeutic strategies and capable of stratifying patients to avoid overtreatment are needed. We evaluated the genomic profiles of 33 pre-treatment LARC biopsies using SNP array and targeted-next generation sequencing (tNGS). Based on the large number of identified genomic alterations, we calculated the genomic instability index (GII) and three homologous recombination deficiency (HRD) scores, which have been reported as impaired DNA repair markers. We observed high GII in our LARC cases, which was confirmed in 165 rectal cancer cases from TCGA. Patients with pCR presented higher GII compared with pIR. Moreover, a negative correlation between GII and the fraction of tumor cells remaining after surgery was observed (ρ = -0.382,
= 0.02). High HRD scores were detected in 61% of LARC, of which 70% were incomplete responders. Using tNGS (105 cancer-related genes, 13 involved in HR and 5 in mismatch repair pathways), we identified 23% of cases with mutations in HR genes, mostly in pIR cases (86% of mutated cases). In agreement, the analysis of the TCGA dataset (
= 145) revealed 21% of tumors with mutations in HR genes. The HRD scores were shown to be predictive of better response to PARP-inhibitors and platinum-based chemotherapy in breast and ovarian cancer. Our results suggest that the same strategy could be applied in a set of LARC patients with HRD. In conclusion, we identified high genomic instability in LARC, which was related to alterations in the HR pathway, especially in pIR. These findings suggest that patients with impaired HRD would clinically benefit from PARP-inhibitors and platinum-based therapy.
Abstract
Rectal cancer (ReCa) patients with locally advanced disease present a high risk of locoregional recurrence and death by the disease. Preoperative neoadjuvant chemoradiotherapy (nCRT) and ...total mesorectal surgery have been used to reduce these events. However, nCRT has resulted in significant morbidity and up to 30% of patients present pathologic incomplete response (pIR) and ~20% develop distant metastasis or minimal regression to stable disease. These findings reinforce the relevance of identifying predictive markers of response to therapy. Genomic instability (GI) is one of the cancer hallmarks. Patterns of genomic alterations (gains, losses, and cnLOH) and the mutational profile have resulted in prognostic and predictive signatures in several cancer types. Targeted next-generation sequencing (105 cancer-related genes panel, including 13 genes involved in the homologous recombination-HR and, 5 in the mismatch repair-MMR pathways) was performed in 31/33 pretreatment ReCa biopsies. 33 samples were evaluated by SNP array to identify the GI index and the HR deficiency (HRD) scores (LST: large-scale transitions, tAI: telomeric allele imbalance, HRD-LOH: loss of heterozygosity). The GI index represents the fraction of the altered genome and the HRD scores (LST, tAI, HRD-LOH) are reported as markers of deficiency in DNA repair by HR pathway. We found 161 mutations in 51 genes; TP53 (84%), APC (81%) and KRAS (45%) were more frequently mutated. No survival differences were observed among the subgroups studied according to the presence of two APC mutations, KRAS, and TP53 mutations or lacking APC mutations. Overall, a high burden of genomic alterations was observed in ReCa samples. The median GI index was 0.358, much higher than those observed in breast cancer. Patients with complete pathologic response (pCR) presented higher GI index (0.475) compared to pIR (0.294). A significant difference was observed grouping responders (TRG 0+1) and nonresponders (TRG 2+3) (p = 0.043). The GI index of chromosome 12 was higher in pCR (p=0.019). Deficient mismatch repair indicates ineffectiveness of 5-FU used in the nCRT. Three tumors presented mutations in MLH3 or MSH6. An additional analysis performed in HR pathway genes revealed that 7/31 cases presented mutations. Three of these seven ReCa showed high tAI scores, indicating sensitivity to platinum-based therapy. HR-defective tumors have been associated with better platinum response rates. In addition, five cases presented PTEN loss; five, PIK3CA mutations; and one case, BRAF mutation. These alterations have been reported as promising predictors for treatment response in colorectal cancer. The involvement of HR pathway or other driver mutations in the response to therapy in rectal cancers remains unclear. Comprehensive studies in a large set of cases are required to confirm the predictive value of these alterations in rectal cancer.
Citation Format: Luisa Matos do Canto, Simon J. Larsen, Bruna E. Catin Kupper, Maria D. Ferreira de Souza Begnami, Cristovam Scapulatempo Neto, Jan Baumbach, Annabeth Høgh Petersen, Mads Malik Aagaard Jørgensen, Samuel Aguiar, Silvia R. Rogatto. Mutational profile and genomic instability according to response to therapy in rectal carcinomas abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5360.
Pathogenic sequence variants (PSV) in
or
(
) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in
were associated with risk of overall prostate cancer or ...high grade (Gleason 8+) prostate cancer using an international sample of 65
and 171
male PSV carriers with prostate cancer, and 3,388
and 2,880
male PSV carriers without prostate cancer. PSVs in the 3' region of
(c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 HR = 1.78; 95% confidence interval (CI), 1.25-2.52;
= 0.001, as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95;
= 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68;
= 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54;
= 0.0002). No genotype-phenotype associations were detected for PSVs in
. These results demonstrate that specific
PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
PDF
