PALB2 loss-of-function (Lof) mutation strongly suggests it as a tumor suppressor in familial breast cancer (BC). In Knudson’s hypothesis, mutation in both alleles is required for a single functional tumor suppressor to sufficiently cause malignant phenotype. But, some reports suggest the inhibition of one copy of PALB2 can lead to malignant phenotype (haploinsufficiency).
143 familial BC patients were enrolled. All the cases were assessed by Familial Cancer specialists and determined to be eligible for clinical genetic testing. Tumors and blood specimens were obtained and subjected to the whole-exome or big-panel gene sequencing. Both germline and somatic mutations were analyzed. Somatic mutation of PALB2 in local and public cancer database were analyzed, too.
In both the public and our local database, the somatic PALB2 mutation rate is 0.8%∼1.6% , much less than the germline mutation rate of 4.03%∼4.8%, in sporadic BC samples. In recruited 143 familial BC patients, ten (6.99%) had mono-allelic PALB2 germline mutations. The hotspots were c.1057A[3>2] and c.3114-1G>A. Other mutations included c.389delA, c.2068C>T, c.2167_2168delAT, c.2629delT and c.2968G>T. All were high risk stop gain, frameshift or splicing mutations, leading to truncated protein. Out of the ten patients, only one had accompanied somatic PALB2 mutation, one had accompanied germline BRCA1 heterozygous mutation, and three patients had other accompanied somatic gene mutations (eg. TP53, PIK3CA, etc). For the rest four patients, the germline PALB2 mutation was the only DNA hit, conforming to the haploinsufficient hypothesis; their germline PALB2 mutations concentrated in EX5 to EX9 regions, which were the key functional regions to binding to MRG15 and RAD51. The mono-allelic mutation caused a low expression level and severely functional damages, explaining their dominant pathological clinical phenotypes.
Many familial breast cancer patients with mono-allelic germline PALB2 mutations had the single DNA hit, suggesting a haploinsufficiency theory. The mutations concentrated in EX5-EX9, the MRG15 and RAD51-binding region, resulting in severe functional defects and breast cancer phenotype.
Hunan Provincial Cancer Hospital and Geneplus Beijing Institute.
Hunan Provincial Key Research Prokect (2018SK2124, Quchang Ouyang).
All authors have declared no conflicts of interest.