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

Abstract

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.

Keywords: CHEK2; estrogen receptor; founder effect; genetic testing; hereditary breast cancer.

Figure 1

CHEK2 pathogenic variant spectrum found among Greek breast cancer patients. Abbreviation used: N/A, not available.

Figure 2

RNA analysis of the CHEK2, c.592+3A>T pathogenic variant. (a) cDNA products visualized on an agarose gel, where the 412 bp and 264 bp bands correspond to wild-type and mutant allele, respectively, (b) Electropherogram of genomic DNA and (c) cDNA from the carrier patient, F1313, performed by Sanger sequencing and (d) schematic representation of the skipping event.

Figure 3

Kaplan-Meier Curves of 10-Year Survival among female patients with ER-positive breast cancer diagnoses, carrying a CHEK2 pathogenic variant. (a) Overall survival defined by administration of hormone-therapy. (b) Event-free survival defined by administration of hormone-therapy. (c) Overall survival defined by type of breast surgery. (d) Event-free survival defined by type of breast surgery.

Figure 4

Pedigrees of families, members of which carry the CHEK2 founder pathogenic variants, where haplotype analysis results are shown. Probands are represented by arrows. Disease-associated alleles are shown in red. Abbreviations used: ca, cancer; BrCa, breast cancer; CRC, colorectal cancer.