Non-syndromic oral clefts and risk of cancer: a systematic review


  • Daniela Araújo Veloso Popoff State University of Montes Claros
  • Mateus Prates Coelho State University of Montes Claros
  • Daniella Reis Barbosa Martelli State University of Montes Claros
  • Rajiv Saini Rural Dental College
  • Ricardo Della Coletta University of Campinas
  • Hercílio Martelli-Júnior State University of Montes Claros



Cleft lip and palate, cancer, family studies.


Objective: To discuss the risk of cancer among relatives of individuals with cleft lip and palate (CL/P), as well as the risk of CL/P among relatives of individuals with cancer, since studies published currently have suggested  an increased risk of cancer among relatives of cleft individuals. Design: A systematic literature review was carried out in accordance with the Cochrane Collaboration Group protocol, including literature search strategy, selection of papers through the inclusion and exclusion criteria, data extraction and quality assessment. PubMed, Scopus and ISI - Web of Science databases were systematically searched using the fallowing search strings: “cleft lip and palate” AND “cancer”, “oral clefts” AND “cancer” and “orofacial clefts” AND “cancer”. Results: From 653 studies accessed, 8 comprised the final sample: 6 investigating CL/P index cases and their family history of cancer and 2 investigating individuals with cancer and their family history for CL/P. The sample sizes were not homogeneous. Oral clefts, the type of cancer and the degree of kinship family were not categorized in all studies. Leukemia, breast cancer and colon cancer were the most cited types, even as first-and-second degree relatives. Conclusions: An increased risk of cancer among relatives of cleft individuals could not be entirely confirmed. However, studies with this specific purpose suggest that first-and-second degrees relatives of cleft individuals have some types of cancer more often than unexposed families, highlighting that future studies should expand their samples to investigate possible common molecular mechanisms that allow relating oral clefts and cancer.

Author Biographies

Daniela Araújo Veloso Popoff, State University of Montes Claros

Department of Dentistry, professor

Mateus Prates Coelho, State University of Montes Claros

Department of Medicine, graduate student

Daniella Reis Barbosa Martelli, State University of Montes Claros

Department of Dentistry, professor

Rajiv Saini, Rural Dental College

Department of Periodontology and Oral Implantology, professor

Ricardo Della Coletta, University of Campinas

Department of Oral Diagnosis, professor

Hercílio Martelli-Júnior, State University of Montes Claros

Department of Dentistry


The evolution of human genetic studies of cleft lip and cleft palate.

Marazita L M.

Annu Rev Genomics Hum Genet. 2012;13:263-83. Epub 2012 Jun 6.

PMID:22703175 [PubMed - indexed for MEDLINE]

Cleft Lip and Palate in Family Members of Cancer Survivors.

Taioli E, Ragin C, Robertson L, Linkov F, Thuman LE, Vieira AR.

Cancer Invest. 2010 Nov;28(9):958-62.

PMID:20569073 [PubMed - indexed for MEDLINE]

Identifying determinants of quality of life of children with cancer and childhood cancer survivors: a systematic review.

Klassen AF, Anthony SJ, Khan A, Sung L, Klaassen R.

Support Care Cancer. 2011 Sep;19(9):1275-87. Epub 2011 May 25.

PMID:21611865 [PubMed - indexed for MEDLINE]

Parental age as a risk for non-syndromic oral clefts: a meta-analysis.

Herkrath APCQ, Herkrath FJ, Rebelo MAB, Vettore MV.

J Dent. 2012 Jan;40(1):3-14.Epub 2011 Oct 13.

PMID:22019990 [PubMed - indexed for MEDLINE]

Risk of breast cancer in females with cleft lip and palate.

Dietz A, Pedersen DA, Jacobsen R, Wehby GL, Murray JC, Christensen K.

Ann Epidemiol. 2012 Jan;22(1):37-42. Epub 2011 Oct 28.

PMID: 22037380 [PubMed - indexed for MEDLINE]

Prevalence of nonsyndromic oral clefts in a reference hospital in the state of Minas Gerais, Brazil, between 2000-2005.

Martelli-Junior H, Porto LCVP, Barbosa DR, Bonan PRF, Freitas AB, Coletta RD.

Braz Oral Res. 2007 Oct-Dec;21(4):314-7.

PMID:18060257 [PubMed - indexed for MEDLINE]

Unraveling human cleft lip and palate research.

Vieira AR.

J Dent Res. 2008 Feb;87(2):119-25.

PMID:18218836 [PubMed - indexed for MEDLINE]

The current understanding of cleft lip malformations

Wantia N, Rettinger G.

Facial Plast Surg. 2002 Aug;18(3):147-53.

PMID:12152133 [PubMed - indexed for MEDLINE]

The complex genetics of cleft lip and palate.

Cobourne MT.

Eur J Orthod. 2004 Feb;26(1):7-16.

PMID:14994877 [PubMed - indexed for MEDLINE]

Cleft lip and palate: synthesizing genetic and environmental influences.

Dixon M, ML, Beaty TH,Murray JC.

Nat Rev Genet. 2011 March; 12(3): 167–178.

PMID:21331089 [PubMed - indexed for MEDLINE]

Zeiger JS, Beaty TH (2002) Gene–environment interaction and risk to oral clefts. In: Wyszynski DF editors. Cleft lip and palate: from origin to treatment. New York: Oxford University Press; pp. 283–289.

Frequency of congenital craniofacial malformations in a Brazilian Reference Center. Paranaiba LMR, Miranda RT, Ribeiro LA, Barros LM, Martelli-Júnior H.

Rev Bras Epidemiol. 2011;14:151-160.

Risk of cancer in relatives of children born with isolated cleft lip and palate.

Vieira AR, Khaliq S, Lace B.

Am J Med Genet A. 2012 Jun;158A(6):1503-4. Epub 2012 May 14.

PMID:22585460 [PubMed - indexed for MEDLINE]

AXIS inhibition protein 2, orofacial clefts and a family history of cancer.

Menezes R, Marazita ML, Goldstein McHenry T, Cooper ME, Bardi K, Brandon C, Letra A, Martin RA, Vieira AR.

J Am Dent Assoc. 2009 Jan;140(1):80-4.

PMID:19119171 [PubMed - indexed for MEDLINE]

Do parents of children with congenital malformations have a higher cancer risk? A nationwide study in Denmark.

Zhu JL, Basso O, Hasle H, Winther JF, Olsen JH, Olsen J.

Br J Cancer. 2002 Aug 27;87(5):524-8.

PMID:12189550 [PubMed - indexed for MEDLINE]

Cleft lip/palate and CDH1/E-cadherin mutation in families with hereditary diffuse gastric cancer.

Frebourg T, Oliveira C, Hochain P, Karam R, Manouvrier S, Graziadio C, Vekemans M, Hartmann A, Baert-Desurmont S, Alexandre C, Lejeune Dumoulin S,Marroni C, Martin C, Castedo S, Lovett M, Winston J, Machado JC, Attié T, Jabs EW, Cai J, Pellerin P, Triboulet JP, Scotte M, Le Pessot F, Hedouin A, Carneiro F, Blayau M, Seruca R.

J Med Genet. 2006 Feb;43(2):138-42. Epub 2005 Apr 14.

PMID: 15831593 [PubMed - indexed for MEDLINE]

Defining predictors of cleft lip and palate risk.

Yildirim, Seymen F, Deeley K, Cooper ME, Vieira AR.

J Dent Res. 2012 Jun;91(6):556-61. Epub 2012 Apr 10.

PMID:22496123 [PubMed - indexed for MEDLINE]

Family history of cleft lip and palate in subjects diagnosed with leukemia.

Jindal A, Vieira AR.

Am J Med Genet A. 2012 Mar;158A(3):678-9.Epub 2012 Feb 2.

PMID:22302642 [PubMed - indexed for MEDLINE]

Alderson P, Green S, Higgins JPT, editors. Cochrane Reviewers’ Handbook 4.2.2

[updated March 2004]. In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John

Wiley & Sons, Ltd.

The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies.

von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzche PC, Vanderbroucke JP.

BMJ. 2007 Oct 20;335(7624):806-8.

PMID:17947786 [PubMed - indexed for MEDLINE]

Nonsyndromic cleft lip and palate is not associated with cancer or other birth defects.

Steinwachs EF, Amos C, Johnston D, Mulliken J, Stal S, Hecht JT

Am J Med Genet. 2000 Jan 3;90(1):17-24

PMID:10602112 [PubMed - indexed for MEDLINE]

Major hematological diseases associated with cleft lip and palate.

Lin CH, Lo LJ, Wang ML, Chen YR, Noordhoff MS.

Cleft Palate Craniofac J. 2000 Sep;37(5):512-5.

PMID:11034036 [PubMed - indexed for MEDLINE]

Mossey P, Little J (2002) Epidemiology of oral clefts: an international perspective. In: Wyszynski DF, editors. Cleft lip and palate: from origin to treatment. New York: Oxford University Press.pp 127-158.

Maternal use of antibiotics and the risk of orofacial clefts: a nationwide cohort study. Mølgaard-Nielsen, Hviid A.

Pharmacoepidemiol Drug Saf. 2012 Mar;21(3):246-53. Epub 2011 Nov 28.

PMID: 22125260 [PubMed - indexed for MEDLINE]

Cancer risk in persons with oral cleft - a population-based study of 8,093 cases.

Bille C, Winther JF, Bautz A, Murray JC, Olsen J, Christensen K.

Am J Epidemiol. 2005 Jun 1;161(11):1047-55.

PMID:15901625 [PubMed - indexed for MEDLINE]

Nevoid basal cell carcionoma syndrome with cleft lip and palate associated with the novel PTCH gene mutations.

Sasaki R, Saito K, Watanabe Y, Yoshinaga T, Fujii K, Agawa K, Miyashita T, Ando T, Akizuki T.

J Hum Genet. 2009 Jul;54(7):398-402. Epub 2009 Jun 12.

PMID: 19521425 [PubMed - indexed for MEDLINE]

Cleft lip and palate in Puerto Rico: A Thirty-three year study.

Oliver-Padilla G, Martínez-González V.

Cleft Palate J. 1986 Jan;23(1):48-57.

PMID:3455903 [PubMed - indexed for MEDLINE]

Incidence of cleft lip, cleft palate, and cleft lip and palate among races: a review. Vanderas AP.

Cleft Palate J. 1987 Jul;24(3):216-25.

PMID:3308178 [PubMed - indexed for MEDLINE]

The genetics of isolated orofacial clefts: from genotypes to subphenotypes.

Jugessur A, Farlie PG, Kilpatrick N.

Oral Dis. 2009 Oct;15(7):437-53. Epub 2009 Jul 2.

PMID:19583827 [PubMed - indexed for MEDLINE]

Hereditary cleft lip/palate and Will Tumor: A rare association.

Yu CC, Wong FH, Lo LJ, Chen YR.

Cleft Palate Craniofac J. 2002 May;39(3):376-9.

PMID:12019017 [PubMed - indexed for MEDLINE]

Gene/environment causes of cleft lip and/or palate.

Murray JC.

Clin Genet. 2002 Apr;61(4):248-56.

PMID:12030886 [PubMed - indexed for MEDLINE]

A population-based study of cancer incidence in twins and in children with congenital malformations or low birth weight, Norway, 1967-1980.

Windham GC, Bjerkedal T, Langmark F.

Am J Epidemiol. 1985 Jan;121(1):49-56.

PMID:3155484 [PubMed - indexed for MEDLINE]

Increased prevalence of minor anomalies in childhood malignancy.

Mehes K, Signer E, Pluss HJ, Müller HJ, Stalder G.

Eur J Pediatr. 1985 Sep;144(3):243-54.

PMID:4054163 [PubMed - indexed for MEDLINE]

Excess of mild errors of morphogenesis in childhood lymphoblastic leukemia.

Mehes K, Kajtar P, Sandor G, Scheel-Walter M, Niethammer D.

Am J Med Genet. 1998 Jan 6;75(1):22-7.

PMID:9450852 [PubMed - indexed for MEDLINE]

Maternal and perinatal risk factors for childhood leukemia.

Zack M, Adami HO, Ericson A.

Cancer Res. 1991 Jul 15;51(14):3696-701.

PMID: 2065325 [PubMed - indexed for MEDLINE]

Risk of childhood cancer for infants with birth defects, part I: a record-linkage study, Atlanta, Georgia, 1968-1988.

Mili F, Khoury MJ, Flanders WD, Greenberg RS.

Am J Epidemiol. 1993 Mar 15;137(6):629-38.

PMID:8470664 [PubMed - indexed for MEDLINE]

Congenital malformations and childhood cancer.

Nishi M, Miyake H, Takeda T, Hatae Y.

Med Pediatr Oncol. 2000;34:250–254.

Increased prevalence of minor anomalies in children with hematologic malignancies. Roganovic J, Radojcic-Badovinac A, Ahel V.

Med Pediatr Oncol. 2002 Feb;38(2):128-30.

PMID:11813182 [PubMed - indexed for MEDLINE].

Infant leukemia and congenital abnormalities: a children’s oncology group study. Johnson KJ, Roesler MA, Linabery AM, Hilden JA, Davies SM, Ross JA.

Pediatr Blood Cancer. 2010 Jul 15;55(1):95-9.

PMID:20486175 [PubMed - indexed for MEDLINE]

Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip.

Rahimov F, Marazita M, Visel A, Cooper M, Hitchler M, Rubini M, Domann FE, Govil M, Christensen K, Bille C, Melbye M, Jugessur A, Lie RT, Wilcox AJ,Fitzpatrick DR, Green ED, Mossey PA, Little J, Steegers-Theunissen RP, Pennacchio LA, Schutte BC, Murray JC.

Nat Genet. 2008 Nov;40(11):1341-7. Epub 2008 Oct 5.

PMID:18836445 [PubMed - indexed for MEDLINE].

A cohort study of recurrence patterns among more than 54,000 relatives of oral cleft cases in Denmark: Support for the multifactorial threshold model of inheritance.

Grosen D, Chevrier C, Skytthe A, Bille C, Mølsted K, Sivertsen A, Murray JC, Christensen K.

J Med Genet. 2010 Mar;47(3):162-8.Epub 2009 Sep 14.

PMID:19752161 [PubMed - indexed for MEDLINE]






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