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. 2017 Nov;54(11):732-741.
doi: 10.1136/jmedgenet-2017-104588. Epub 2017 Aug 4.

Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks

Brennan Decker  1   2 , Jamie Allen  1 , Craig Luccarini  3 , Karen A Pooley  1 , Mitul Shah  3 , Manjeet K Bolla  1 , Qin Wang  1 , Shahana Ahmed  3 , Caroline Baynes  1 , Don M Conroy  1 , Judith Brown  1 , Robert Luben  1 , Elaine A Ostrander  2 , Paul Dp Pharoah  1   3 , Alison M Dunning  3 , Douglas F Easton  1   3
Affiliations

Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks

Brennan Decker et al. J Med Genet. 2017 Nov.

Abstract

Background: Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK.

Methods: Gene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four in silico algorithms.

Results: Truncating variants in PALB2 (OR=4.69, 95% CI 2.27 to 9.68), ATM (OR=3.26; 95% CI 1.82 to 6.46) and CHEK2 (OR=3.11; 95% CI 2.15 to 4.69), but not XRCC2 (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in ATM and CHEK2 were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in PALB2 were associated with similar risks for both subtypes. There was also some evidence that missense variants in ATM, CHEK2 and PALB2 may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect.

Conclusions: Truncating variants in PALB2 are associated with a higher risk of BC than those in ATM or CHEK2. A substantial risk of BC due to truncating XRCC2 variants can be excluded.

Keywords: Cancer: breast; Evidence Based Practice; Genetic Epidemiology; Geneticscreening/counselling.

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Conflict of interest statement

Competing interests: No, there are no competing interests.

Figures

Figure 1
Figure 1
Spectrum of ATM, CHEK2, PALB2 and XRCC2 variation in ExAC populations and East Anglian cases and controls. (A) Nearly all variants were very rare or private. (B) The absolute number of variants per gene was highly divergent due to the difference in gene size. (C) However, when corrected for gene size, the genes had similar per-kB rates of total, truncating, singleton and novel variants not previously reported in the dbSNP, ExAC or COSMIC. (D) The carrier frequency for truncating variants in the study controls was near the mean of the ExAC populations. Notably, the ExAC Finnish population was an outlier for CHEK2 and PALB2 due to well-studied founder effects. (E) OR point estimates were similar using the study controls versus ExAC populations as controls. ExAC, Exome Aggregation Consortium.
Figure 2
Figure 2
Position and frequency of protein-truncating variants in (A) ATM, (B) CHEK2, (C) PALB2 and (D) XRCC2.
Figure 3
Figure 3
Position and frequency for rare missense variants in (A) ATM (B) CHEK2 and (C) PALB2. ORs were calculated for all Pfam (ATM and CHEK2) and UniProt (PALB2) domains (table 2).
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