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

Öfverholm, Anna ; Törngren, Therese LU ; Rosén, Anna ; Arver, Brita ; Einbeigi, Zakaria ; Haraldsson, Karin LU ; Ståhlbom, Anne Kinhult ; Kuchinskaya, Ekaterina ; Lindblom, Annika and Melin, Beatrice , et al. (2023) In BMC Cancer 23. p.1-12
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... (More)

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.

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Contribution to journal
publication status
published
subject
keywords
Humans, Female, BRCA1 Protein/genetics, BRCA2 Protein/genetics, Genetic Predisposition to Disease, Breast Neoplasms/diagnosis, Genetic Testing, Ovarian Neoplasms/diagnosis, Protein Serine-Threonine Kinases/genetics, Triple Negative Breast Neoplasms/genetics, Hereditary Breast and Ovarian Cancer Syndrome/diagnosis, Germ-Line Mutation
in
BMC Cancer
volume
23
article number
738
pages
1 - 12
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85167704638
  • pmid:37563628
ISSN
1471-2407
DOI
10.1186/s12885-023-11229-y
language
English
LU publication?
yes
additional info
© 2023. BioMed Central Ltd., part of Springer Nature.
id
045d6748-4497-4c27-adba-b1534346a084
date added to LUP
2023-09-01 17:08:14
date last changed
2024-04-20 02:24:57
@article{045d6748-4497-4c27-adba-b1534346a084,
  abstract     = {{<p>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.</p><p>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.</p><p>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.</p><p>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.</p>}},
  author       = {{Öfverholm, Anna and Törngren, Therese and Rosén, Anna and Arver, Brita and Einbeigi, Zakaria and Haraldsson, Karin and Ståhlbom, Anne Kinhult and Kuchinskaya, Ekaterina and Lindblom, Annika and Melin, Beatrice and Paulsson-Karlsson, Ylva and Stenmark-Askmalm, Marie and Tham, Emma and von Wachenfeldt, Anna and Kvist, Anders and Borg, Åke and Ehrencrona, Hans}},
  issn         = {{1471-2407}},
  keywords     = {{Humans; Female; BRCA1 Protein/genetics; BRCA2 Protein/genetics; Genetic Predisposition to Disease; Breast Neoplasms/diagnosis; Genetic Testing; Ovarian Neoplasms/diagnosis; Protein Serine-Threonine Kinases/genetics; Triple Negative Breast Neoplasms/genetics; Hereditary Breast and Ovarian Cancer Syndrome/diagnosis; Germ-Line Mutation}},
  language     = {{eng}},
  month        = {{08}},
  pages        = {{1--12}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{BMC Cancer}},
  title        = {{Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer}},
  url          = {{http://dx.doi.org/10.1186/s12885-023-11229-y}},
  doi          = {{10.1186/s12885-023-11229-y}},
  volume       = {{23}},
  year         = {{2023}},
}