Oral microbial community composition is associated with pancreatic cancer: A case-control study in Iran

Background Oral microbiota may be related to pancreatic cancer risk because periodontal disease, a condition linked to multiple specific microbes, has been associated with increased risk of pancreatic cancer. We evaluated the association between oral microbiota and pancreatic cancer in Iran. Methods A total of 273 pancreatic adenocarcinoma cases and 285 controls recruited from tertiary hospitals and a specialty clinic in Tehran, Iran provided saliva samples and filled out a questionnaire regarding demographics and lifestyle characteristics. DNA was extracted from saliva and the V4 region of the 16S rRNA gene was PCR amplified and sequenced on the MiSeq. The sequencing data were processed using the DADA2 plugin in QIIME 2 and taxonomy was assigned against the Human Oral Microbiome Database. Logistic regression and MiRKAT models were calculated with adjustment for potential confounders. Results No association was observed for alpha diversity with an average of 91.11 (standard deviation [SD] 2.59) sequence variants for cases and 89.42 (SD 2.58) for controls. However, there was evidence for an association between beta diversity and case status. The association between the Bray‐Curtis dissimilarity and pancreatic cancer was particularly strong with a MiRKAT P‐value of .000142 and specific principal coordinate vectors had strong associations with cancer risk. Several specific taxa were also associated with case status after adjustment for multiple comparisons. Conclusion The overall microbial community appeared to differ between pancreatic cancer cases and controls. Whether these reflect differences evident before development of pancreatic cancer will need to be evaluated in prospective studies.ISSN:2045-763

ARTICLE Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family

F amilial acute myeloid leukemia is rare and linked to germline mutations in RUNX1, GATA2 or CCAAT/enhancer binding protein-a (CEBPA). We re-evaluated a large family with acute myeloid leukemia originally seen at NIH in 1969. We used whole exome sequencing to study this family, and conducted in silico bioinformatics analysis, protein structural modeling and laboratory experiments to assess the impact of the identified CEBPA Q311P mutation. Unlike most previously identified germline mutations in CEBPA, which were N-terminal frameshift mutations, we identified a novel Q311P variant that was located in the C-terminal bZip domain of C/EBPa. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mu-tant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation, consistent with a loss-of-function mutation. From 45 years of follow up, we observed incomplete penetrance (46%) of CEBPA Q311P. This study of a large multi-generational pedigree reveals that a germline mutation in the C-terminal bZip domain can alter the ability of C/EBP-a to bind DNA and reduces transactivation, leading to acute myeloid leukemia

Whole-exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow-up of a large family.

Familial acute myeloid leukemia is rare and linked to germline mutations in RUNX1, GATA2 or CCAAT/enhancer binding protein-α (CEBPA). We re-evaluated a large family with acute myeloid leukemia originally seen at NIH in 1969. We utilized whole-exome sequencing to study this family, and conducted in silico bioinformatics analysis, protein structural modeling and laboratory experiments to assess the impact of the identified CEBPA Q311P mutation. Unlike most previously identified germline mutations in CEBPA, which were N-terminal frameshift mutations, we identified a novel Q311P variant that was located in the C-terminal bZip domain of C/EBPα. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mutant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation, consistent with a loss-of-function mutation. From 45 years of follow-up, we observed incomplete penetrance (46%) of CEBPA Q311P. This study of a large multi-generational pedigree reveals that a germline mutation in the C-terminal bZip domain can alter the ability of C/EBP-α to bind DNA and reduces transactivation, leading to acute myeloid leukemia