bims-ovdlit 2022-09-11 papers

Issue of 2022–09–11
three papers selected by
Lara Paracchini, Humanitas Research

Future Oncol. 2022 Sep 05.

Considerations in the implementation of multicancer early detection tests.

Keywords: cancer screening; early detection; multicancer early detection test

DOI: https://doi.org/10.2217/fon-2022-0120

Cancers (Basel). 2022 Aug 27. pii: 4157. [Epub ahead of print]14(17):

Homologous Recombination Deficiency Scar: Mutations and Beyond-Implications for Precision Oncology.

Alexander M A van der Wiel, Lesley Schuitmaker, Ying Cong, Jan Theys, Arne Van Hoeck, Conchita Vens, Philippe Lambin, Ala Yaromina, Ludwig J Dubois.

Homologous recombination deficiency (HRD) is a prevalent in approximately 17% of tumors and is associated with enhanced sensitivity to anticancer therapies inducing double-strand DNA breaks. Accurate detection of HRD would therefore allow improved patient selection and outcome of conventional and targeted anticancer therapies. However, current clinical assessment of HRD mainly relies on determining germline BRCA1/2 mutational status and is insufficient for adequate patient stratification as mechanisms of HRD occurrence extend beyond functional BRCA1/2 loss. HRD, regardless of BRCA1/2 status, is associated with specific forms of genomic and mutational signatures termed HRD scar. Detection of this HRD scar might therefore be a more reliable biomarker for HRD. This review discusses and compares different methods of assessing HRD and HRD scar, their advances into the clinic, and their potential implications for precision oncology.

Keywords: DNA repair; biomarkers; cancer; homologous recombination; homologous recombination deficiency; homologous recombination deficiency scar; precision oncology

DOI: https://doi.org/10.3390/cancers14174157

Nat Commun. 2022 09 06. 13(1): 4487

The mutational signatures of formalin fixation on the human genome.

Qingli Guo, Eszter Lakatos, Ibrahim Al Bakir, Kit Curtius, Trevor A Graham, Ville Mustonen.

Clinical archives of patient material near-exclusively consist of formalin-fixed and paraffin-embedded (FFPE) blocks. The ability to precisely characterise mutational signatures from FFPE-derived DNA has tremendous translational potential. However, sequencing of DNA derived from FFPE material is known to be riddled with artefacts. Here we derive genome-wide mutational signatures caused by formalin fixation. We show that the FFPE-signature is highly similar to signature 30 (the signature of Base Excision Repair deficiency due to NTHL1 mutations), and chemical repair of DNA lesions leads to a signature highly similar to signature 1 (clock-like signature due to spontaneous deamination of methylcytosine). We demonstrate that using uncorrected mutational catalogues of FFPE samples leads to major mis-assignment of signature activities. To correct for this, we introduce FFPEsig, a computational algorithm to rectify the formalin-induced artefacts in the mutational catalogue. We demonstrate that FFPEsig enables accurate mutational signature analysis both in simulated and whole-genome sequenced FFPE cancer samples. FFPEsig thus provides an opportunity to unlock additional clinical potential of archival patient tissues.

DOI: https://doi.org/10.1038/s41467-022-32041-5