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Diagnostics Biochemistry and molecular biology, Genetics and epigenetics, Oncology

Small But Mighty… Molecular Pathology

By our powers combined…

A newly created framework – “sc-linker” – combines single-cell RNA sequencing, epigenomic SNP-to-gene maps, and genome-wide association study (GWAS) statistics to identify the cell types and cellular processes genetic variants use to influence disease. The team detected subtle differences in SNP-to-gene mapping between tissues, with strong differences in disease heritability across cell types (1).

Two-faced collagen

Type I collagen remodeling is associated with differing outcomes for patients with pancreatic ductal adenocarcinoma (PDAC). Matrix-metalloproteinase-cleaved type I collagen activates discoidin domain receptor 1 (DDR1), signaling tumor growth; the intact protein triggers DDR1 degradation and hinders tumor growth (2).

Clear-headed hepatic health

Analysis of 9,491 cases combined with proton density fat fraction from 36,116 liver images has revealed 18 sequence variants associated with non-alcoholic fatty liver disease (3). Four variants linked with cirrhosis were found. Loss-of-function variants were found in MTARC1 and GPAM, indicating they may have potential as future drug targets.

Something to ASPYRE to

A highly sensitive model to detect gene fusions, called ASPYRE, shows rapid and consistent results even with low sample sizes. The method eliminates multiple instrument runs and uses pyrophosphorolysis to detect gene fusions from RNA and DNA simultaneously. The workflow and equipment are similar to standard PCR assays, with turnaround times under 24 hours (4).

Testing for treatment

The antibody-drug conjugate enfortumab vedotin has been approved to treat metastatic urothelial carcinoma (mUC). However, recent research reveals that expression of the treatment’s target – NECTIN-4 – is frequently decreased in mUC and 39.4 percent of metastases exhibit no membranous NECTIN-4 expression at all. The authors strongly recommend determining NECTIN-4 status prior to selecting treatment for mUC (5).

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  1. KA Jagadeesh, et al., “Identifying disease-critical cell types and cellular processes by integrating single-cell RNA-sequencing and human genetics,” Nat Genet, 54, 1479 (2022). PMID: 36175791.
  2.  H Su et al., “Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome,” Nature, 610, 366 (2022). PMID: 36198801.
  3. G Sveinbjornsson, et al., “Multiomics study of nonalcoholic fatty liver disease,” Nat Genet, 54, 1652 (2022). PMID: 36280732.
  4. ER Gray, et al., “Ultra-sensitive molecular detection of gene fusions from RNA using ASPYRE,” BMC Med Genomics, 15, 215 (2022). PMID: 36224552.
  5. N Klümper et al., “Membranous NECTIN-4 expression frequently decreases during metastatic spread of urothelial carcinoma and is associated with enfortumab vedotin resistance,” Clin Cancer Res, [Online ahead of print] (2022). PMID: 36534531.
About the Author
George Francis Lee

Deputy Editor, The Pathologist

Interested in how disease interacts with our world. Writing stories covering subjects like politics, society, and climate change.

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