Abstract
PurposeTo investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. MethodsOutcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3,127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial nonmucinous ovarian cancer, and 1,567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. ResultsThirty-five PALB2 and 44 CHEK2_1100delC PGVs were detected in patients (odds ratio [OR] PALB2 breast–ovarian = 5.90 [95% CI: 1.92–18.36], CHEK2 breast–ovarian = 4.46 [95% CI: 1.86–10.46], PALB2 breast = 6.16 [95% CI: 1.98–19.21], CHEK2 breast = 4.89 [95% CI: 2.01–11.34]). Grade 3 ER-positive HER2-negative, grade 3 and triple negative (TN) tumors were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service (respectively: 15/43, 254/1,843, P = 0.0005; 28/37, 562/1,381, P = 0.0001; 12/43, 204/1,639, P < 0.0001). PALB2_PGV likelihood increased with increasing Manchester score (MS) (MS < 15 = 17/1,763, MS 20–39 = 11/520, P = 0.04) but not for CHEK2_1100delC (MS < 15 = 29/1,762, MS 20–39 = 4/520). PALB2 PGVs showed perfect segregation in 20/20 first-degree relatives with breast cancer, compared with 7/13 for CHEK2_1100delC (P = 0.002). ConclusionPALB2 PGVs and CHEK2_1100delC together account for ~2.5% of familial breast/ovarian cancer risk. PALB2 PGVs are associated with grade 3, TN, and grade 3 ER-positive HER2-negative breast tumors.
Highlights
Breast cancer is the most common form of cancer in women.[1]
PALB2 pathogenic germline gene variant (PGV) are associated with grade 3, TN, and grade 3 ER-positive HER2-negative breast tumors
It has been known for over 30 years that breast cancer predisposition can be inherited in an autosomal dominant manner with around 4% of cases on a population basis being compatible with the inheritance of a high-risk pathogenic germline gene variant (PGV).[2]
Summary
Breast cancer is the most common form of cancer in women.[1]. It has been known for over 30 years that breast cancer predisposition can be inherited in an autosomal dominant manner with around 4% of cases on a population basis being compatible with the inheritance of a high-risk (circa 50–80% lifetime risk) pathogenic germline gene variant (PGV).[2]. 50–100,000 for each).[5] PALB2 was originally identified in 2007 as a moderate risk gene conferring only around a 2.3-fold relative risk;[6] this was, based on identification in 10/923 BRCA1/2 negative breast cancer cases, but 0/1,083 controls. The originally calculated relative risk was based on study of the families rather than the odds ratio (OR) generated from case–control analysis because this is usually inflated by using familial risk probands.
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