SCIENTIFIC BACKGROUND

ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MLH1, MLH3, MSH2, MSH3, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, RECQL, SMARCA4, SMARCB1, STK11, TP53, XRCC2

Scientific Background

With a share of approximately 30% of all cancers, breast cancer is by far the most common tumor in women in Europe. Ovarian cancer accounts for 3.3% of all new cancer cases in female patients. It is estimated that 5-10% of all breast cancers and 10-25% of ovarian cancers are hereditary. The characteristic features of hereditary breast and ovarian cancer are an early age of onset of the disease and/or a high incidence in the family. Genetic diagnosis is recommended if one of the following criteria is met in one patient or in a family:

 

  • high incidence of breast OR ovarian cancer in the family (2 or more women)
  • breast cancer at a young age (<50 years)
  • incidence of breast AND ovarian cancer in the family

 

Pathogenic variants in the BRCA1 or BRCA2 genes can be detected in about 24% of women or families to whom one of the above criteria applies. Pathogenic changes in one of the genes significantly increase the risk of breast and ovarian cancer, but are also associated with a slightly increased risk of other cancers, e.g., pancreatic, prostate and male breast cancer. Carriers are recommended to undergo more intensive screening medical check-ups and, if necessary, preventive measures (e.g., prophylactic mastectomy). The benefits and risks of radiotherapy should be considered in the case of ill patients, as there is an increased risk of secondary carcinomas in the radiation field.

 

A further 4% of patients who fulfill one of the indication criteria and in whom no BRCA1/2 variant has been detected are carriers of a genetic modification in the genes CHEK2 (1.5%), PALB2 (1.2%) or RAD51C (1%). While CHEK2 and PALB2 are associated with a moderately increased risk of breast cancer, RAD51C variants are associated with an increased risk of ovarian cancer. Intensive screening examinations are also recommended for these carriers. Discussions regarding prophylactic surgery, on the other hand, should depend on the affected gene and the family history of the person seeking advice.

 

The prevalence of pathogenic variants in other risk genes (e.g., ATM, BARD1, BRIP1, CDH1, NBN, RAD51D, TP53, PTEN, STK11) is below 1% in each case. In the case of inconspicuous findings after basic diagnostics (BRCA1, BRCA2, CHEK2, PALB2, RAD51C), the analysis of these genes in patients with statutory health insurance can currently only be carried out after a prior application to and cost acceptance declaration by the insurer. Some of these genes are the cause of other tumor predisposition syndromes, in which the risk of breast cancer is also significantly increased (CDH1/hereditary diffuse stomach cancer, STK11/Peutz-Jeghers syndrome, PTEN/Cowden syndrome, TP53/Li-Fraumeni syndrome).

 

References

Rebbeck et al. 2018, Hum Mutat 39:593 / Engel et al. 2018, BMC Cancer 18:562 / Schmutzler 2017, Geburtsh Frauenheilk 77:733 / Harter et al. 2017, PLoS One 12:e0186043 / Hahnen et al. 2017, Breast Care (Basel) 12:15 / Kast et al. 2016, J Med Genet 53:465 / Leitlinienprogramm Onkologie: S3-Leitlinie Früherkennung, Diagnose, Therapie und Nachsorge des Mammakarzinoms, Version 4.1, 2018 / Leitlinienprogramm Onkologie: S3-Leitlinie Diagnostik, Therapie und Nachsorge maligner Ovarialtumoren, Langversion 3.0, 2019

 

 

Genes in bold are recommended by International guidelines, including German expert panels and/or have been more often associated with specific cancers.

GENES

ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MLH1, MLH3, MSH2, MSH3, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, RECQL, SMARCA4, SMARCB1, STK11, TP53, XRCC2
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