Beyond BRCA1 and BRCA2 – evaluation of 123 carriers of pathogenic variants in other HBOC associated genes

Objective In panel studies of familial breast and ovarian cancer, pathogenic variants in additional HBOC-associated risk genes (BARD1, BRIP1, CDH1, CHEK2, PTEN, RAD51C, RAD51D, STK11, PALB2, TP53) beyond BRCA1/2 are detected in approximately 5% of families. This evaluation examines clinicopathological data on 123 mutation carriers from this risk group.

Material and methods Data were collected retrospectively. Healthy individuals and those with breast carcinoma with evidence of a pathogenic alteration in an HBOC-associated core gene with concomitant exclusion of a BRCA1/2 mutation (observation period 4 years) were included.

Results Carriers of a pathogenic alteration in the CHEK2 (44), PALB2 (29), and ATM (19) gene were the most numerous. Of a total of 123 confirmed female mutation carriers, 47% (58/123) had developed breast carcinoma so far, 38% (47/123) unilateral and 9% (11/123) bilateral. The age of first disease from breast carcinoma varied between 23-64 years; in 36% (21/58) the date of diagnosis was before 41 years of age, and in 12% (7/58) before 31 years of age. Complete pathologic data were available for the 58 diseased individuals. 60% (35/58) had ductal subtype, 13% (8/58) pure DCIS. The tumors of 74% (43/58) were estrogen and progesterone receptor positive; the Her2 receptor was overexpressed in 13% of tumors. 12% (7/58) had a triple negative (TNBC) subtype, of which 4 were carriers of a pathogenic PALB2 variant.

Summary PALB2-associated tumors have the highest proportion of TNBC tumors in this study population. Further characterization of this heterogeneous genetic group will help optimize clinical care.

Publication History

Article published online:
21 June 2022