Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer

Abstract

Background: Genetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting.

Methods: Women with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records.

Results: In 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding.

Conclusions: This study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.

Keywords: BRCA1; BRCA2; Breast cancer; Cancer; Genetic testing; Hereditary breast cancer; Hereditary cancer; Hereditary ovarian cancer; Ovarian cancer.

Fig. 1

Flowchart summarizing the study cohort. *Cancer diagnoses confirmed against patient records including pathology reports, quality registries for breast and ovarian cancer, and/or the national cancer registry. HBOC = Hereditary breast and ovarian cancer

Fig. 2

Lollipop plots showing the location and frequency of PVs in BRCA1, BRCA2, CHEK2 and ATM. The gene model at the bottom of each plot shows exons in alternating shades of gray with untranslated regions thinner. Gene domains or other regions of interest are shown in colors defined by the legend below each gene model. The gene domain or region abbreviations are explained with references in Additional file 2: Table S6. The x-axis shows amino acid residue numbering according to the selected RefSeq protein for each gene. The number of carriers for each unique variant is indicated by the height and size of each lollipop and the inscribed number in the marker. The shape, color and location of the lollipops show the type of variant with structural variants below the gene model (red circle: large deletion, dark blue square: large duplication, green diamond: alu insertion) and other variants above (orange circle: frameshift, cyan circle: stop gain, pale yellow square: missense, purple diamond: intronic or synonymous splice variants, pale green diamond: exonic missense splice variant). Lollipops for variants in introns are placed at the border between adjacent exons. The horizontal bars above the gene model indicate the extent of large deletions (red) and large duplications (dark blue). All structural variants are labeled with a short form alias (the corresponding HGVS descriptions can be found in Additional file 2: Table S1) and the more common of the other variants are labeled with HGVS descriptions. Corresponding lollipop plots for BARD1, BRIP1, CDH1, PALB2, PTEN, RAD51C, RAD51D and TP53 are shown in Additional file 3: Fig. S1