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Article

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

1
Molecular Diagnostics Laboratory, INRaSTES, National Center for Scientific Research “Demokritos”, 15341 Athens, Greece
2
Oncology Unit, Second Department of Surgery, Aretaieion Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece
3
Oncology Unit, General Clinic-Hospital “Euromedica”, 54645 Thessaloniki, Greece
4
Second Breast Unit, Mitera Private Hospital—Breast Center, 15123 Athens, Greece
5
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
6
Department of Medical Oncology, School of Health Sciences, Faculty of Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece
*
Author to whom correspondence should be addressed.
Academic Editor: Robert-Alain Toillon
Cancers 2021, 13(9), 2106; https://doi.org/10.3390/cancers13092106
Received: 31 March 2021 / Revised: 23 April 2021 / Accepted: 24 April 2021 / Published: 27 April 2021
(This article belongs to the Special Issue Estrogen Receptor-Positive (ER+) Breast Cancers)
CHEK2 germline pathogenic variants are identified at a relatively high frequency among hereditary breast cancer cases and are known to be associated with intermediate breast cancer risk i.e., 2–2.5-fold increase, compared to the general population. Histopathological characteristics and clinical outcomes of breast cancer patients who are CHEK2 carriers have not been thoroughly investigated. We have therefore sought to determine the CHEK2 variant spectrum and identify variants with possible founder effect, while investigating the clinicopathological features and outcomes of Greek patients who were CHEK2 carriers. Three variants have been identified as Greek founders. The vast majority of CHEK2-associated breast tumors were hormone receptor positive, underlying a possible benefit from chemoprophylaxis with tamoxifen. A trend for longer survival was observed in patients that underwent mastectomy and received hormone-therapy. Nearly half of patients underwent a risk-reducing surgery, which was not mandated according to current guidelines or relevant risks associated with CHEK2.
CHEK2 germline pathogenic variants predispose to breast cancer and possibly to other malignancies, with their spectrum and frequency being variable among populations. Τhe majority of CHEK2-associated breast tumors are hormone receptor positive; however, relevant clinical outcomes are not well defined. Herein, we illustrate the histopathological characteristics and clinical outcomes of 52 Greek breast cancer patients who are CHEK2 carriers. Genetic analysis was performed by Sanger/massively parallel sequencing, followed by MLPA. Subsequent haplotype analysis investigated possible founder effects. Blood relatives were offered cascade testing. CHEK2 variant spectrum was characterized by variability, while influenced by founder effects. The majority of carriers, i.e., 60.8%, were diagnosed with breast cancer before the age of 45. Notably, 91.5% of breast tumors were hormone receptor positive. Hormone therapy and mastectomy at diagnosis seem to have a positive trend on overall survival, after a median follow-up of 9.5 years. Remarkably, 41.9% of patients underwent risk-reducing surgery, one third of which involved salpingo-oophorectomy. Nearly half of families responded to cascade testing. Our data highlight the need for guideline-adherent choices, based on the evidence that CHEK2 carriers are at moderate risk for breast cancer and no risk for ovarian cancer, while underscore the possible role of chemoprevention with tamoxifen. View Full-Text
Keywords: CHEK2; hereditary breast cancer; founder effect; estrogen receptor; genetic testing CHEK2; hereditary breast cancer; founder effect; estrogen receptor; genetic testing
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MDPI and ACS Style

Apostolou, P.; Dellatola, V.; Papadimitriou, C.; Kalfakakou, D.; Fountzilas, E.; Faliakou, E.; Fountzilas, G.; Romanidou, O.; Konstantopoulou, I.; Fostira, F. CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects. Cancers 2021, 13, 2106. https://doi.org/10.3390/cancers13092106

AMA Style

Apostolou P, Dellatola V, Papadimitriou C, Kalfakakou D, Fountzilas E, Faliakou E, Fountzilas G, Romanidou O, Konstantopoulou I, Fostira F. CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects. Cancers. 2021; 13(9):2106. https://doi.org/10.3390/cancers13092106

Chicago/Turabian Style

Apostolou, Paraskevi, Vasiliki Dellatola, Christos Papadimitriou, Despoina Kalfakakou, Elena Fountzilas, Eleni Faliakou, Georgios Fountzilas, Ourania Romanidou, Irene Konstantopoulou, and Florentia Fostira. 2021. "CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects" Cancers 13, no. 9: 2106. https://doi.org/10.3390/cancers13092106

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