Prevalence of PALB2 Germline Mutations in Early-onset and Familial Breast/Ovarian Cancer Patients from Pakistan.
PURPOSE
Partner and localizer of BRCA2 (PALB2) is a breast cancer susceptibility gene that plays an important role in DNA repair. This is the first study assessing the prevalence of PALB2 mutations in early-onset and familial breast/ovarian cancer patients from Pakistan.


MATERIALS AND METHODS
PALB2 mutation screening was performed in 370 Pakistani patients with early-onset and familial breast/ovarian cancer, who were negative for BRCA1, BRCA2, TP53, CHEK2, and RAD51C mutations, using denaturing high-performance liquid chromatography analysis. Mutations were confirmed by DNA sequencing. Novel PALB2 alterations were analyzed for their potential effect on protein function or splicing using various in silico prediction tools. Three-hundred and seventy-two healthy controls were screened for the presence of the identified (potentially) functional mutations.


RESULTS
A novel nonsense mutation, p.Y743*, was identified in one familial breast cancer patient (1/127, 0.8%). Besides, four in silico-predicted potentially functional mutations including three missense mutations and one 5' untranslated region mutation were identified: p.D498Y, novel p.G644R, novel p.E744K, and novel c.-134_-133delTCinsGGGT. The mutations p.Y743* and p.D498Y were identified in two familial patients diagnosed with unilateral or synchronous bilateral breast cancer at the ages of 29 and 39, respectively. The other mutations were identified in an early-onset (≤ 30 years of age) breast cancer patient each. All five mutations were absent in 372 healthy controls suggesting that they are disease associated.


CONCLUSION
Our findings show that PALB2 mutations account for a small proportion of early-onset and hereditary breast/ovarian cancer cases in Pakistan.
['Rashid|Muhammad Usman|MU|', 'Khan|Faiz Ali|FA|', 'Muhammad|Noor|N|', 'Loya|Asif|A|', 'Hamann|Ute|U|']
D000328:Adult D017668:Age of Onset D000368:Aged D001943:Breast Neoplasms D018567:Breast Neoplasms, Male D016022:Case-Control Studies D002851:Chromatography, High Pressure Liquid D018389:Codon, Nonsense D000076164:Fanconi Anemia Complementation Group N Protein D005260:Female D018095:Germ-Line Mutation D006801:Humans D008297:Male D008875:Middle Aged D020125:Mutation, Missense D010051:Ovarian Neoplasms D010154:Pakistan D015995:Prevalence D017422:Sequence Analysis, DNA
PALB2 Pakistan Familial breast cancer Germ-line mutation