From <b><i>BRCA1</i></b> to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

Abstract

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; There has been huge progress over the last 30 years in identifying the familial component of breast cancer. &lt;b&gt;&lt;i&gt;Summary:&lt;/i&gt;&lt;/b&gt; Currently around 20% is explained by the high-risk genes &lt;i&gt;BRCA1&lt;/i&gt; and &lt;i&gt;BRCA2&lt;/i&gt;, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes &lt;i&gt;ATM&lt;/i&gt; and&lt;i&gt; CHEK2&lt;/i&gt;. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. &lt;b&gt;&lt;i&gt;Key-Messages:&lt;/i&gt;&lt;/b&gt; There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as &lt;i&gt;CDH1&lt;/i&gt; and &lt;i&gt;TP53&lt;/i&gt;, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.

Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer

“…A GWAS of 1145 post-menopausal patients identified four separate SNPs in the FGFR2 intron associated with breast cancer susceptibility, and meta-analyses of a large cohort of case control studies indicate that such FGFR2-susceptibility SNPs are present across ethnic groups and in different breast cancer sub-groups, predominately hormone receptor-positive disease [ 232 ]. Based on FGFR2 interaction with other genetic and environmental factors (reviewed in [ 233 ]), FGFR2 may contribute to polygenic risk scoring in breast cancer family history clinics. However, this small contributory role to breast susceptibility is insufficient to support FGFR inhibitors as a candidate for drug prevention in high-risk women.…”

Risk of metachronous contralateral breast cancer in patients with primary invasive lobular breast cancer: Results from a nationwide cohort

“…hormone replacement therapy use) and germline pathogenic variants such as in the CDH1 gene are also associated with the development of multiple lobular breast cancers. 16 , 17 , 18 …”

“…hormone replacement therapy use) and germline pathogenic variants such as in the CDH1 gene are also associated with the development of multiple lobular breast cancers. 16,1718 This study used a large and comprehensive populationbased dataset to evaluate metachronous CBC risk in lobular and lobular-mixed PBC patients. In addition, complete information on second breast cancer occurrence was present.…”

Impact of DNA damage response defects in cancer cells on response to immunotherapy and radiotherapy

“…Pathogenic mutations in high penetrance genes (BRCA1, BRCA2, TP53, PTEN, SKT11 and CDH1) account for perhaps 25% of familial breast cancer cases 72 . Chief among these are mutations in BRCA1 and BRCA2, key regulators of the HR pathway, accounting for 20% of all breast cancers in total 72–76 . A recent study looking at 925 breast cancer patients found BRCA1 and BRCA2 mutations in 171 and 95, respectively 73 .…”

“…72 Chief among these are mutations in BRCA1 and BRCA2, key regulators of the HR pathway, accounting for 20% of all breast cancers in total. [72][73][74][75][76] A recent study looking at 925 breast cancer patients found BRCA1 and BRCA2 mutations in 171 and 95, respectively. 73 Another investigation of a larger cohort of 1824 patients with triple-negative breast cancer reported the presence of BRCA1 and BRCA2 mutations in 155 and 49, respectively.…”