Tumor Signature Analysis Implicates Hereditary Cancer Genes in Endometrial Cancer Development

Kondrashova, Olga; Shamsani, Jannah; O’Mara, Tracy A.; Newell, Felicity; Reed, Amy E. McCart; Lakhani, Sunil R.; Kirk, Judy; Pearson, John V.; Waddell, Nicola; Spurdle, Amanda B.

doi:10.3390/cancers13081762

Cited by 6 publications

(4 citation statements)

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“…genes in other tumor types with much smaller series (Kondrashova et al, 2021;Stadler et al, 2021) and although several pedigrees with multiple tumor phenotypes have been reported, the data is insufficient to draw conclusions about a broader phenotypic spectrum of the disease. These findings warrant further investigation of non-OC/BC cancer phenotypes with big series and proper case-control studies to better clarify the phenotypic spectrum of the disease.…”

Section: Clinical Relevance and Future Perspectivesmentioning

confidence: 99%

A decade of RAD51C and RAD51D germline variants in cancer

et al. 2021

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Defects in DNA repair genes have been extensively associated with cancer susceptibility. Germline pathogenic variants (GPV) in genes involved in homologous recombination repair pathways predispose to cancers arising mainly in the breast and ovary, but also other tissues. The RAD51 paralogs RAD51C and RAD51D were included in this group 10 years ago when germline variants were associated with non-BRCA1/2 familial ovarian cancer. Here, we have reviewed the landscape of RAD51C and RAD51D germline variants in cancer reported in the literature during the last decade, integrating this list with variants identified by in-house patient screening. A comprehensive catalog of 341 variants that have been classified applying ACMG/AMP criteria has been generated pinpointing the existence of recurrent variants in both genes. Recurrent variants have been extensively discussed compiling data on population frequencies and functional characterization if available, highlighting variants that have not been fully characterized yet to properly establish their pathogenicity. Finally, we have complemented this data with relevant information regarding the conservation of mutated residues among RAD51 paralogs and modeling of putative hotspot areas, which contributes to generating an exhaustive update on these two cancer predisposition genes.

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Section: Clinical Relevance and Future Perspectivesmentioning

confidence: 99%

A decade of RAD51C and RAD51D germline variants in cancer

et al. 2021

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“…Our findings add to the debate about a role for BRCA1 in EC risk and propose PALB2 as a gene of interest for further study in this regard. Furthermore, germline and tumor signature analysis of EC sequence data from The Cancer Genome Atlas has provided support that germline loss‐of‐function variants in homologous recombination genes, including BRCA1 and PALB2 , can sometimes contribute to endometrial tumor development (Kondrashova et al, 2021). That is, irrespective of firm proof of the role of these genes in EC risk, identification of a BRCA1 or PALB2 variant in an individual with EC may have implications for use of targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

Case–case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer

et al. 2021

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Hereditary endometrial cancer (EC) is most commonly attributed to pathogenic variants in mismatch repair genes. Evidence supports the existence of additional genetic risk factors in the context of multiple cancer diagnoses and/or family history of EC. EC patients (n = 5292) referred for diagnostic multigene cancer panel testing were annotated for presence of a pathogenic gene variant; personal history of prior, concurrent, or subsequent cancer of another type; reported family history of Lynch syndrome or EC. The Pearson χ2 test was used to assess differences in gene variant prevalence between case sub‐groups defined by personal and/or family history of cancer/s, using cases with no family history of Lynch/EC as reference. Another cancer diagnosis was reported for 55% of EC cases. EC cases with a prior and reported family history of Lynch cancer were enriched for variants in MLH1 (p = 3.5 × 10−7), MSH2 (p = 3.1 × 10−7), and PMS2 (p = .02). Consistent with expectations for a breast cancer gene also predisposing to EC, the variant frequency was increased in EC patients with prior BC and family history of EC for BRCA1 (p = 1.7 × 10−5) and PALB2 (p = .0002). Strategic case–case analyses to address cohort ascertainment bias have provided a rationale to direct future studies of candidate hereditary EC genes.

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“…Mutational signatures from single nucleotide mutations were first described in breast cancer 70 and later characterised across many tumour types 16,17 and now include signatures from small insertions and deletions and chromosome structural variants. 17 These signatures can inform not only on how tumours develop, treatment selection and germline variant classification, [71][72][73] they may also guide long-term clinical management like follow-up frequency and therapeutic manipulation of recurrences and metastasis to improve PFS and OS in a variety of cancers. 63 Tumour burden and disease monitoring Early identification of tumour recurrence and effective tumour burden monitoring currently relies heavily on expensive and time-consuming radiological processes (CT/MRI/PET) or serial biopsies of tumours, which is often not practical.…”

Section: Tumour Clonality and Evolution Determines Tumour Aggressivenessmentioning

confidence: 99%