Spectrum of PALB2 germline mutations and characteristics of PALB2‐related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next‐generation sequencing

Abstract

Background Partner and localizer BRCA2 ( PALB2 ) is a breast cancer predisposition gene, but the clinical relevance of PALB2 germline mutations in Chinese patients with breast cancer remains unknown. This study attempted to investigate the full prevalence and spectrum of PALB2 germline mutations in China and the associations between PALB2 germline mutations and breast cancer risk. Methods A total of 21,216 unselected patients with breast cancer were enrolled from 10 provinces in China, and 5890 Chinese women without cancer were enrolled as healthy controls. PALB2 screening was based on next‐generation sequencing. Results A total of 16,501 BRCA1/2 ‐negative patients with breast cancer were analyzed. Deleterious PALB2 mutation carriers accounted for 0.97% (n = 160) in the breast cancer cohort and for 0.19% (n = 11) in the healthy control cohort. Forty‐one novel PALB2 germline mutations were identified. A high frequency of PALB2 c.751C>T was detected, and it accounted for 10.63% of the PALB2 germline mutations detected (17 of 160). PALB2 mutations were significantly associated with increased breast cancer risk (odds ratio [OR], 5.23; 95% confidence interval [CI], 2.84‐9.65; P < .0001), especially among women 30 years old or younger (OR, 10.09; 95% CI, 3.95‐25.79; P < .0001). Clinical characteristics, including a family history, bigger tumor size, triple‐negative breast cancer, positive lymph nodes, and bilateral breast cancer, were closely related to PALB2 mutations. Conclusions This study revealed a comprehensive spectrum of PALB2 germline mutations and characteristics of PALB2 ‐related breast cancer in China. PALB2 germline mutations confer a moderately increased risk for breast cancer but profoundly increase breast cancer risk for those 30 years old or younger in the Chinese population.

Frequency and molecular characteristics of PALB2‐associated cancers in Russian patients

“…Our study revealed that PALB2 pathogenic variants are detected in approximately 1% of Russian high‐risk BC patients, while their frequency in consecutive BC patients is approximately 1.5 times lower. These estimates are similar to the data obtained in North American, European and Asian studies 11‐15 . We also identified five OC patients carrying PALB2 pathogenic alleles; however, despite analyzing more than 1800 women with OC, our data on PALB2 contribution in OC risk are not conclusive.…”

“…European and Asian studies. [11][12][13][14][15] We also identified five OC patients carrying PALB2 pathogenic alleles; however, despite analyzing more These PALB2 pathogenic variants were described in our previous reports. 22,23 b These PALB2 mutation carriers were identified by whole exome sequencing within another study.…”

“…Only a few studies analyzed PALB2 gene status in healthy population, and these reports produced similar results. [39][40][41] The mere fact of occurrence of cancer-predisposing alleles in cancer-free subjects is not surprising, given that even carriers of highly penetrant tumor-predisposing mutations are characterized by huge variations with regard to the age at cancer onset. However, it…”

“…Presence of heterozygous pathogenic PALB2 variant in the genome increases the risk of breast cancer (BC) and is likely to be associated with predisposition to other tumor types 5‐11 . Multiple studies performed in various countries and ethnic groups confirmed the contribution of PALB2 to BC morbidity 11‐15 . However, PALB2 ‐related cancers are relatively rare, therefore their systematic analysis is complicated.…”

“…[5][6][7][8][9][10][11] Multiple studies performed in various countries and ethnic groups confirmed the contribution of PALB2 to BC morbidity. [11][12][13][14][15] However, PALB2-related cancers are relatively rare, therefore their systematic analysis is complicated.…”