TY - JOUR
T1 - Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer
AU - Öfverholm, Anna
AU - Törngren, Therese
AU - Rosén, Anna
AU - Arver, Brita
AU - Einbeigi, Zakaria
AU - Haraldsson, Karin
AU - Ståhlbom, Anne Kinhult
AU - Kuchinskaya, Ekaterina
AU - Lindblom, Annika
AU - Melin, Beatrice
AU - Paulsson-Karlsson, Ylva
AU - Stenmark-Askmalm, Marie
AU - Tham, Emma
AU - von Wachenfeldt, Anna
AU - Kvist, Anders
AU - Borg, Åke
AU - Ehrencrona, Hans
N1 - © 2023. BioMed Central Ltd., part of Springer Nature.
PY - 2023/8/10
Y1 - 2023/8/10
N2 - 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.
AB - 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.
KW - Humans
KW - Female
KW - BRCA1 Protein/genetics
KW - BRCA2 Protein/genetics
KW - Genetic Predisposition to Disease
KW - Breast Neoplasms/diagnosis
KW - Genetic Testing
KW - Ovarian Neoplasms/diagnosis
KW - Protein Serine-Threonine Kinases/genetics
KW - Triple Negative Breast Neoplasms/genetics
KW - Hereditary Breast and Ovarian Cancer Syndrome/diagnosis
KW - Germ-Line Mutation
U2 - 10.1186/s12885-023-11229-y
DO - 10.1186/s12885-023-11229-y
M3 - Article
C2 - 37563628
SN - 1471-2407
VL - 23
SP - 1
EP - 12
JO - BMC Cancer
JF - BMC Cancer
M1 - 738
ER -
