bims-ovdlit 2022-04-17 papers

Issue of 2022–04–17
four papers selected by
Lara Paracchini, Humanitas Research

Ann Oncol. 2022 Apr 07. pii: S0923-7534(22)00681-0. [Epub ahead of print]

For Ovarian Cancer PARPi maintenance therapy: more is better, right?

DOI: https://doi.org/10.1016/j.annonc.2022.04.004

Clin Cancer Res. 2022 Apr 10. OF1-OF12

The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma.

BriTROC-1 Investigators

PURPOSE: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors.
EXPERIMENTAL DESIGN: We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I-IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study.
RESULTS: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic.
CONCLUSIONS: Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-1643

Oncogene. 2022 Apr 14.

MUTYH-associated tumor syndrome: The other face of MAP.

Luigi Magrin, Daniele Fanale, Chiara Brando, Lidia Rita Corsini, Ugo Randazzo, Marianna Di Piazza, Vittorio Gurrera, Erika Pedone, Tancredi Didier Bazan Russo, Salvatore Vieni, Gianni Pantuso, Antonio Russo, Viviana Bazan.

MUTYH gene is involved in the base excision repair (BER) mechanism and its pathogenic alterations are associated with colorectal polyposis and cancer. MUTYH-associated polyposis (MAP) is a condition which is inherited in an autosomal recessive manner. MAP patients, beyond colorectal cancer (CRC), may develop other types of tumors, including duodenal, breast, ovarian, pancreatic, bladder and skin cancers. Carriers of biallelic MUTYH likely pathogenic/pathogenic variants exhibit a high lifetime risk of CRC, though cancer risk evidence becomes less clear when monoallelic carriers and extraintestinal tumors are considered. However, several studies recently reported an increased genetic susceptibility to cancer also for carriers of germline monoallelic MUTYH mutations. Moreover, experimental evidence highlighted the MUTYH involvement in many other biological functions. In future, MUTYH mutation carriers might benefit from new target therapies involving the use of PD-1 or KRAS inhibitors. Therefore, "MUTYH-associated tumor syndrome" might be the most appropriate term, due to the multiplicity of tumors observed in MAP patients and different biological contexts in which MUTYH acts as a "playmaker". In this Review, we will investigate the impact of germline mono- and biallelic MUTYH mutations on cancer risk, providing a proposal for clinical surveillance of mutation carriers.

DOI: https://doi.org/10.1038/s41388-022-02304-y