Investigating the causal role of MRE11A p.E506* in breast and ovarian cancer

Islam Elkholi ,Clara Nogué,François Rousseau,Manon De Ladurantaye,Somayyeh Fahiminiya,Massimo Di Iorio,Diane Provencher,Olga Aleynikova,Walter H Gotlieb,Anne‐Marie Mes‐Masson ,Jean‐François Côté ,Mohammad Reza Akbari ,Bárbara Rivera ,Suzanna L Arcand,Patricia N Tonin,Hyerim Han,Sylvie Giroux,Supriya Behl,Nancy Hamel,William D Foulkes

doi:10.1038/s41598-021-81106-w

Abstract

The nuclease MRE11A is often included in genetic test panels for hereditary breast and ovarian cancer (HBOC) due to its BRCA1-related molecular function in the DNA repair pathway. However, whether MRE11A is a true predisposition gene for HBOC is still questionable. We determined to investigate this notion by dissecting the molecular genetics of the c.1516G > T;p.E506* truncating MRE11A variant, that we pinpointed in two unrelated French-Canadian (FC) HBOC patients. We performed a case–control study for the variant in ~ 2500 breast, ovarian, and endometrial cancer patients from the founder FC population of Quebec. Furthermore, we looked for the presence of second somatic alterations in the MRE11A gene in the tumors of the carriers. In summary, these investigations suggested that the identified variant is not associated with an increased risk of developing breast or ovarian cancer. We finally performed a systematic review for all the previously reported MRE11A variants in breast and ovarian cancer. We found that MRE11A germline variants annotated as pathogenic on ClinVar often lacked evidence for such classification, hence misleading the clinical management for affected patients. In summary, our report suggests the lack of clinical utility of MRE11A testing in HBOC, at least in the White/Caucasian populations.

Highlights

The nuclease MRE11A is often included in genetic test panels for hereditary breast and ovarian cancer (HBOC) due to its BRCA1-related molecular function in the DNA repair pathway
A few months later, a 55 years-old woman diagnosed with ovarian high-grade serous carcinoma tested negative for BRCA1/2 and PALB2 in a broad HBOC clinical panel (Ref.[11] for the panel), the same truncating variant c.1516G > T;p.E506* in MRE11A was identified (Fig. 1a,b)
Given the variant’s low frequency in public databases, we hypothesized that this rare MRE11A variant might be a candidate founder pathogenic variant (PV) for HBOC in French Canadians (FCs)

Summary

Introduction

The nuclease MRE11A is often included in genetic test panels for hereditary breast and ovarian cancer (HBOC) due to its BRCA1-related molecular function in the DNA repair pathway. Couch et al screened around 2000 breast cancer patients for germline variants using a 17-gene sequencing panel and defined two truncating variants in MRE11A6, as well.

Results

Conclusion