title: A novel deleterious c.2656G>T MSH2 germline mutation in a Pakistani family with a phenotypic overlap of hereditary breast and ovarian cancer and Lynch syndrome.
abstract: BACKGROUND
  Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS) account for a significant proportion of inherited gynecologic malignancies, mainly caused by pathogenic germline mutations in the BRCA1 and BRCA2 genes or in mismatch repair (MMR) genes, such as MLH1 and MSH2. Women harboring deleterious mutations in these genes have increased life-time risks of developing a number of malignancies including ovarian cancer. Since there is a phenotypic overlap of HBOC and LS, timely identification of individuals at-risk of a particular syndrome is crucial in order to optimize cancer risk management.
  
  
  METHODS
  We report a novel pathogenic MSH2 mutation, c.2656G > T, which was identified in a 67-year-old female patient with breast cancer, who had previously tested negative for a deleterious mutation in the breast cancer susceptibility genes BRCA1, BRCA2, CHEK2 or RAD51C. The patient reported a personal history of endometrial cancer diagnosed at age 48, and a strong family history of breast and ovarian cancer, as well as several other malignancies within the spectrum of LS. The novel mutation was also found in the index patient's daughter and a niece, who were diagnosed with endometrial and ovarian cancer, respectively. Breast and endometrial tumors from c.2656G > T mutation carriers showed loss of MSH2 and MSH6 protein expression. The mutation was absent in the control population.
  
  
  CONCLUSIONS
  Our finding suggests that testing for MMR genes may be of benefit to BRCA1/2 negative families with overlapping HBOC and LS phenotype in Pakistan. It is clinically significant to identify individuals harboring mutations in genes linked with a particular syndrome so that they can benefit from targeted life-saving cancer surveillance and preventive strategies.
authors.affiliation: Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
authors.forename: Muhammad U
authors.initials: MU
authors.lastname: Rashid
authors.affiliation: Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
authors.forename: Humaira
authors.initials: H
authors.lastname: Naeemi
authors.affiliation: Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
authors.forename: Noor
authors.initials: N
authors.lastname: Muhammad
authors.affiliation: Department of Pathology, SKMCH & RC, Lahore, Pakistan.
authors.forename: Asif
authors.initials: A
authors.lastname: Loya
authors.affiliation: Department of Internal Medicine, SKMCH & RC, Lahore, Pakistan.
authors.forename: Muhammed A
authors.initials: MA
authors.lastname: Yusuf
authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, 70-115 Szczecin, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Lubiński
authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, 70-115 Szczecin, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Jakubowska
authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
keywords: Endometrial cancer; HNPCC; Hereditary breast and ovarian cancer; LS; MSH2; Pakistan