Somatic genetic alterations in synchronous and metachronous low‐grade serous tumours and high‐grade carcinomas of the adnexa

Abstract

Aims

Low‐grade serous carcinomas (LGSCs) and their precursor serous borderline tumours (SBTs) characteristically harbour mutations in BRAF, KRAS and NRAS but rarely in TP53, whereas high‐grade serous carcinomas (HGSCs) are characterised by frequent TP53 mutations but rare BRAF, KRAS and NRAS mutations. In a small subset of cases, LGSCs and/or SBTs develop high‐grade tumours including HGSCs and poorly differentiated carcinomas (PDCs). Here we sought to define the repertoire of somatic genetic alterations in low‐grade serous tumours and synchronous or metachronous high‐grade adnexal carcinomas.

Methods and Results

DNA extracted from five SBTs/LGSCs and synchronous or metachronous HGSCs/PDCs and matched normal tissue was subjected to massively‐parallel sequencing targeting all exons and selected non‐coding regions of 341 cancer‐related genes. The low‐grade and high‐grade tumours from a given case were related, and shared mutations and copy number alterations. Progression from low‐grade to high‐grade lesions was observed, and involved acquisition of additional mutations and copy number alterations or shifts from subclonal to clonal mutations. Only two (a HGSC and a PDC) of the five high‐grade tumours investigated harboured TP53 mutations, whereas NRAS and KRAS hotspot mutations were seen in two and one HGSCs, respectively.

Conclusions

Our results suggest that progression from SBT to HGSC may take place in a subset of cases, and that at least some of the rare HGSCs lacking TP53 mutations may be derived from a low‐grade serous precursor.

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