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02-08-2018 | Breast cancer | Editorial | Article

Developing polygenic risk scores for breast cancer

Gareth Evans MD, FRCP
The potential for inheritance of breast cancer risk has been speculated on since Paul Broca reported on the apparent hereditary nature of breast cancer in his wife’s family in 1866 [1]. This was confirmed by epidemiological studies in the 1980s and, finally, with identification of the high-risk genes BRCA1 (1994) and BRCA2 (1995), which together account for around 3% of breast cancers that are due to single high-risk genes (around 4% of all breast cancers). Additional high-risk genes (lifetime risk ≥40%) TP53, PTEN, STK11, CDH1, and PALB2, as well as moderate-risk genes (lifetime risk 20–35%), notably ATM and CHEK2, have been identified. Generally, high-risk genes with pathogenic variants are rare (less than one in 500, and most less than one in 5,000) compared to around one in 200 for the two well-known, moderate-risk genes. Together, all of the high/moderate-risk genes account for little more than 25% of the inherited component of breast cancer [2]. Twin studies have shown that around 27% of breast cancer has an inherited component [3], despite less than 20% of women with breast cancer having a family history of the disease. This is partly due to the fact that nowhere near all women who carry genetic variants will develop breast cancer, and half of the variants will be inherited from a man, who has an average lifetime risk of 0.1%.

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