Double mutation of APC and BRCA1 in an Italian family

  • Maria Teresa Vietri
    Correspondence
    Corresponding author at: Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 7, 80138 Naples, Italy.
    Affiliations
    Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 7, 80138 Naples, Italy

    U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
    Search for articles by this author
  • Giovanna D'Elia
    Affiliations
    U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
    Search for articles by this author
  • Gemma Caliendo
    Affiliations
    U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
    Search for articles by this author
  • Amelia Casamassimi
    Affiliations
    Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 7, 80138 Naples, Italy
    Search for articles by this author
  • Marianna Resse
    Affiliations
    Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 7, 80138 Naples, Italy
    Search for articles by this author
  • Luana Passariello
    Affiliations
    U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
    Search for articles by this author
  • Michele Cioffi
    Affiliations
    Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 7, 80138 Naples, Italy

    U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
    Search for articles by this author
  • Anna Maria Molinari
    Affiliations
    Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 7, 80138 Naples, Italy

    U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
    Search for articles by this author

      Abstract

      Familial adenomatous polyposis (FAP) is a rare genetic disorder caused mainly by monoallelic mutations of APC gene. The hereditary breast and ovarian cancer (HBOC) syndrome is an autosomal dominantly inherited disease, which mostly predisposes to breast and ovarian cancers as a result of germline mutations in BRCA1 or BRCA2 genes. In a family, mutations in two cancer susceptibility genes are extremely rare. We studied a family with a case of a 46 years-old woman affected with FAP and ovarian cancer. The patient was affected with profuse FAP since the age of 18 years and a serous ovarian cancer was diagnosed at the age of 45 years. She reported other FAP cases and one case of breast cancer in maternal family. Initially, she was tested for FAP predisposition with mutational analysis of APC gene that revealed the presence of a frameshift mutation, c.3927_3931delAAAGA (p.Glu1309AspfsX4). The presence of ovarian cancer in the patient and of a breast cancer case in the maternal family, suggested an extended analysis to HBOC susceptibility genes that led to the detection of a frameshift mutation, c.3756_3759delGTCT (p.Ser1253Argfs), in BRCA1 gene. The genetic analysis was extended also to family members. The occurrence of the double mutation in APC and BRCA1 genes in the patient was responsible for the onset of FAP and ovarian cancer respectively.
      The genetic counselling in hereditary cancer with a careful analysis of the pedigree allows identifying the gene to be analyzed. The development of multi-gene panels testing for cancer predisposition, with next generation sequencing (NGS), may reveal mutations in genes of high and moderate penetrance for cancer, although at a low frequency and allows diagnosing a possible double heterozygosity. This enables an adjusted treatment for the affected patient and is critical as it allows initiation of early risk-reducing measures for identified mutation carriers among family members.
      To read this article in full you will need to make a payment
      Subscribe to Cancer Genetics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Njoroge S.W.
        • Burgess K.R.
        • Cobleigh M.A.
        • Alnajar H.H.
        • Gattuso P.
        • Usha L
        Hereditary diffuse gastric cancer and lynch syndromes in a BRCA1/2 negative breast cancer patient.
        Breast Cancer Res Treat. 2017; 166: 315-319
        • Khan N.
        • Lipsa A.
        • Arunachal G.
        • Ramadwar M.
        • Sarin R
        Novel mutations and phenotypic associations identified through APC, MUTYH, NTHL1, POLD1, POLE gene analysis in Indian Familial Adenomatous Polyposis cohort.
        Sci Rep. 2017; 7: 2214
        • Dinarvand P.
        • Davaro E.P.
        • Doan J.V.
        • Ising M.E.
        • Evans N.R.
        • Phillips N.J.
        • Lai J.
        • Guzman M.A
        Familial Adenomatous polyposis syndrome: an update and review of extraintestinal manifestations.
        Arch Pathol Lab Med. 2019; https://doi.org/10.5858/arpa.2018-0570-RA
        • Vietri M.T.
        • Selvaggi F.
        • De Paola M.L.
        • Sciaudone G.
        • Guadagni I.
        • Parisi M.
        • Pellino G.
        • Molinari A.M.
        • Cioffi M
        A novel frameshift mutation in exon 12 of the adenomatous polyposis coli gene in an Italian family with familial adenomatous polyposis and desmoid tumour.
        J Mol Genet Med. 2010; 4: 235-238
        • Grover S.
        • Kastrinos F.
        • Steyerberg E.W.
        • Cook E.F.
        • Dewanwala A.
        • Burbidge L.A.
        • Wenstrup R.J.
        • Syngal S
        Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas.
        JAMA. 2012; 308: 485-492
        • D'Elia G.
        • Caliendo G.
        • Casamassimi A.
        • Cioffi M.
        • Molinari A.M.
        • Vietri M.T
        APC and MUTYH analysis in FAP patients: a novel mutation in APC gene and genotype-phenotype correlation.
        Genes (Basel). 2018; 9
        • Kobayashi H.
        • Ohno S.
        • Sasaki Y.
        • Matsuura M
        Hereditary breast and ovarian cancer susceptibility genes (review).
        Oncol Rep. 2013; 30: 1019-1029https://doi.org/10.3892/or.2013.2541
        • Alemar B.
        • Gregório C.
        • Herzog J.
        • Matzenbacher Bittar C.
        • Brinckmann Oliveira Netto C.
        • Artigalas O.
        • Schwartz I.V.D.
        • Coffa J.
        • Alves Camey S.
        • Weitzel J.
        • Ashton-Prolla P
        BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: are international testing criteria appropriate for this specific population.
        PLoS One. 2017; 12e0187630
        • Vietri M.T.
        • Molinari A.M.
        • Caliendo G.
        • De Paola M.L.
        • D'Elia G.
        • Gambardella A.L.
        • Petronella P.
        • Cioffi M
        Double heterozygosity in the BRCA1 and BRCA2 genes in Italian family.
        Clin Chem Lab Med. 2013; 51: 2319-2324https://doi.org/10.1515/cclm-2013-0263
        • Ripperger T.
        • Gadzicki D.
        • Meindl A.
        • Schlegelberger B
        Breast cancer susceptibility: current knowledge and implications for genetic counselling.
        Eur J Hum Genet EJHG. 2009; 17: 722-731
        • Nallamilli B.R.
        • Hegde M.
        Detecting APC gene mutations in familial adenomatous polyposis (FAP).
        Curr Protoc Hum Genet. 2017; 92: 10.8.1-10.8.16https://doi.org/10.1002/cphg.29
        • Armstrong D.K.
        • Alvarez R.D.
        • Bakkum-Gamez J.N.
        • Barroilhet L.
        • Behbakht K.
        • Berchuck A.
        • Berek J.S.
        • Chen L.M.
        • Cristea M.
        • DeRosa M.
        • ElNaggar A.C.
        • Gershenson D.M.
        • Gray H.J.
        • Hakam A.
        • Jain A.
        • Johnston C.
        • Leath III, C.A.
        • Liu J.
        • Mahdi H.
        • Matei D.
        • McHale M.
        • McLean K.
        • O'Malley D.M.
        • Penson R.T.
        • Percac-Lima S.
        • Ratner E.
        • Remmenga S.W.
        • Sabbatini P.
        • Werner T.L.
        • Zsiros E.
        • Burns J.L.
        • Engh A.M
        NCCN guidelines insights: ovarian cancer, version 1.2019.
        J Natl Compr Canc Netw. 2019; 17: 896-909https://doi.org/10.6004/jnccn.2019.0039
        • Wallace A.J.
        New challenges for BRCA testing: a view from the diagnostic laboratory.
        Eur J Hum Genet. 2016; 24: S10-S18
        • Hu P.J.
        • Knoepp S.M.
        • Wu R.
        • Cho K.R
        Ovarian steroid cell tumor with biallelic adenomatous polyposis coli inactivation in a patient with familial adenomatous polyposis.
        Genes Chromosomes Cancer. 2012; 51: 283-289https://doi.org/10.1002/gcc.20953
        • Lee S.H.
        • Koh Y.W.
        • Roh H.J.
        • Cha H.J.
        • Kwon Y.S
        Ovarian microcystic stromal tumor: a novel extracolonic tumor in familial adenomatouspolyposis.
        Genes Chromosomes Cancer. 2015; 54: 353-360https://doi.org/10.1002/gcc.22233
        • Easton D.F.
        • Pharoah P.D.
        • Antoniou A.C.
        • Tischkowitz M.
        • Tavtigian S.V.
        • Nathanson K.L.
        • Devilee P.
        • Meindl A.
        • Couch F.J.
        • Southey M.
        • Goldgar D.E.
        • Evans D.G.
        • Chenevix-Trench G.
        • Rahman N.
        • Robson M.
        • Domchek S.M.
        • Foulkes W.D
        Gene-panel sequencing and the prediction of breast-cancer risk.
        N Engl J Med. 2015; 372: 2243-2257
        • Desmond A.
        • Kurian A.W.
        • Gabree M.
        • Mills M.A.
        • Anderson M.J.
        • Kobayashi Y.
        • Horick N.
        • Yang S.
        • Shannon K.M.
        • N4 Tung
        • Ford J.M.
        • Lincoln S.E.
        • Ellisen L.W
        Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment.
        JAMA Oncol. 2015; 1: 943-951
        • Plon S.E.
        • Pirics M.L.
        • Nuchtern J.
        • et al.
        Multiple tumors in a child with germ-line mutations in TP53 and PTEN.
        N Engl J Med. 2008; 359 (537–5)
        • Goehringer C.
        • Sutter C.
        • Kloor M.
        • Gebert J.
        • Slater E.P.
        • Keller M.
        • Treiber I.
        • Ganschow P.
        • Kadmon M.
        • Moog U
        Double germline mutations in APC and BRCA2 in an individual with a pancreatic tumor.
        Fam Cancer. 2017; 16: 303-309
        • Andrés R.
        • Menao S.
        • Arruebo M.
        • Quílez E.
        • Cardiel M.J
        Double heterozygous mutation in the BRCA1 and ATM genes involved in development of primary metachronous tumours: a case report.
        Breast Cancer Res Treat. 2019; 177: 767-770
        • Sokolenko A.P.
        • Bogdanova N.
        • Kluzniak W.
        • et al.
        Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations.
        Breast Cancer Res Treat. 2014; 145: 553-562