A. Tenesa

Al-Tassan

Croitoru

M. G. Dunlop

Ogunbiyi

RASHID

S. M. Farrington

Thorstensen

Zhou

English

Tenesa, Albert

Farrington, Susan M

Dunlop, Malcolm G

Edinburgh Research Explorer

     Edinburgh Research Explorer                                      ReCitation for published version:Tenesa, A, Farrington, SM & Dunlop, MG 2005, 'Re: Association between biallelic and monoallelic germlineMYH gene mutations and colorectal cancer risk' Journal of the National Cancer Institute, vol 97, no. 4, pp.320-1; author reply 321-2., 10.1093/jnci/dji051Digital Object Identifier (DOI):10.1093/jnci/dji051Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher final version (usually the publisher pdf)Published In:Journal of the National Cancer InstitutePublisher Rights Statement:Copyright ©  2005 Oxford University PressGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 20. Feb. 2015320 CORRESPONDENCE Journal of the National Cancer Institute, Vol. 97, No. 4, February 16, 2005 CORRESPONDENCE   Re: Association Between Biallelic and Monoallelic Germline MYH Gene Mutations and Colorectal Cancer Risk  We read with interest the paper by Croitoru et al.  ( 1 ) , in which they examined the role of germline MYH gene mutations in colorectal cancer and proposed an  autosomal dominant weakly penetrant mode of inheritance. Previous evidence has suggested a recessive mode of inheri-tance for colorectal polyposis  ( 2 ) . Hence, the novel proposal by Croitoru et al. would be of major clinical and scientifi c importance and must be fully justifi ed by the data. We have major concerns about their fi ndings and respectfully refute their interpretation of their data.  The authors compared case patients and control subjects with no MYH gene mutations (genotype Wt/Wt) with case patients and control subjects with either one (genotype Wt/Mut) or two (genotype Mut/Mut) MYH gene mutations. How-ever, the authors’ data do not support a dominant mode of inheritance. Individu-als with a Wt/Mut genotype had no statis-tically signifi cant excess colorectal cancer risk compared with those with a Wt/Wt genotype (odds  ratio = 1.4; 95% confi -dence interval = 0.8 to 2.5)  ( 1 ) . Therefore, the authors’ decision to pool Wt/Mut indi-viduals with homozygous Mut/Mut case patients for their analyses is not justifi ed.  Table 1 summarizes the authors’ data from  Table 1  ( 1 ) . We used these data and Fish-er’s exact test to examine associations be-tween the frequency of germline MYH gene mutations and colorectal cancer risk among case patients and control subjects with different MYH genotypes. Our re-sults — P = .25 for Wt/Wt versus Wt/Mut,  P = 2.1 × 10 − 4  for Wt/Wt versus Mut/Mut, and  P = 5.3 × 10 − 3  for Wt/Mut versus Mut/Mut — suggest that only a recessive model of inheritance is tenable. Thus, the only valid pooling strategy supported by the authors’ data is to pool individuals with Wt/Mut and Wt/Wt genotypes (i.e., assume a recessive mode of inheritance).  Croitoru et al.  ( 1 ) also compared the number of affected fi rst- and  second- degree relatives of heterozygous and ho-mozygous MYH gene mutation carriers with that of noncarriers. This approach does not test whether people who inherit one mutant allele are at equivalent risk to those who inherit two mutant alleles. The modest effects detected by the au-thors that they ascribe to a dominant  effect are no more consistent with a dominant than a recessive mode of in-heritance. In fact, the offspring of Wt/Mut case patients have an increased risk of disease compared with offspring of Wt/Wt case  patients under both fully dominant and fully recessive modes of inheritance. Thus, this evidence in itself does not support a dominant mode of  inheritance.  Croitoru et al.  ( 1 ) also presented loss of heterozygosity (LOH) data for tumors from Wt/Mut and Mut/Mut case  patients.  Table 1.  Summary of data in Table 1 of Croitoru et al.  ( 1 ) *   MYH genotype    Wt/Wt  Wt/Mut  Mut/Mut  Total  Case   1197  29  12  1238  patients Control   1234  21  0  1255  subjects  Total  2431  50  12  2493  * MYH = MutY human homologue gene; Wt = wild type; Mut = mutant.  by guest on March 10, 2014http://jnci.oxfordjournals.org/Downloaded from Journal of the National Cancer Institute, Vol. 97, No. 4, February 16, 2005 CORRESPONDENCE 321However, LOH at chromosome 1p in tu-mors is highly variable and subject to confounding. Thorstensen et al.  ( 3 ) de-tected LOH in chromosome 1p in 50% of primary carcinomas, 33% of local re-currences, and 64% of metastases from colorectal cancer patients, whereas Ogunbiyi et al.  ( 4 ) and Zhou et al.  ( 5 ) detected LOH in chromosome 1p in 26% and 22% of colorectal cancers, re-spectively. Rashid et al.  ( 6 ) found that LOH in chromosome 1p varied with the anatomic location of hyperplastic pol-yps. Given such variability and the small numbers presented by Croitoru et al. and the fact that their samples were not matched for confounding variables, the difference in LOH frequency at chromo-some 1p is best explained by chance.  ALBERT  TENESA  SUSAN M.  FARRINGTON  MALCOLM G.  DUNLOP  REFERENCES  (1)  Croitoru ME, Cleary SP, Di Nicola N, Manno M, Selander T, Aronson M, et al. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.  J Natl Cancer Inst  2004 ; 96 : 1631 – 4.  (2)  Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, et al. Inherited variants of  MYH associated with somatic G:C → T:A mutations in colorectal tumors.  Nat Genet  2002 ; 30 : 227 – 32.  (3)  Thorstensen L, Qvist H, Heim S, Liefers GJ, Nesland JM, Giercksky KE, et al. Evalua-tion of 1p losses in primary carcinomas, local recurrences and peripheral metastases from colorectal cancer patients.  Neoplasia  2000 ; 2 :  514 – 22.  (4)  Ogunbiyi OA, Goodfellow PJ, Gagliardi G, Swanson PE, Birnbaum EH, Fleshman JW, et al. Prognostic value of chromosome 1p al-lelic loss in colon cancer.  Gastroenterology  1997 ; 113 : 761 – 6.  (5)  Zhou CZ, Qiu GQ, Zhang F, He L, Peng ZH. Loss of heterozygosity on chromosome 1 in sporadic colorectal carcinoma.  World J Gastro-enterol  2004 ; 10 : 1431 – 5.  (6)  Rashid A, Houlihan PS, Booker S, Petersen GM, Giardiello FM, Hamilton SR. Pheno-typic and molecular characteristics of hyper-plastic polyposis.  Gastroenterology  2000 ; 119 :  323 – 32.  NOTES  Affi liations of authors: Colon Cancer  Genetics Group, University of Edinburgh, and MRC Human  Genetics Unit, Western General Hospital, Edinburgh.  Correspondence to: Albert Tenesa, BSc, School of Molecular and Clinical Medicine, The University of Edinburgh, Colon Cancer Genetics Group, 14th Floor, MRC Human Genetics Unit, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK (email: albert.tenesa@ed.ac.uk).  DOI: 10.1093/jnci/dji051  RE S PO N SE  ESPONSE  Dominant and recessive transmission applies to traits or phenotypes and not to genes themselves. A good example of this terminology is sickle cell disease:  homozygous carriers have the  disease and heterozygous carriers have the sickle cell  trait , a milder phenotype of the  disease  ( 1 , 2 ) . It is, of course, true that published reports to date clearly support a recessive mode of inheritance for MYH-associated polyposis, a phenotype associated with biallelic mutations in MYH  ( 3 , 4 ) . We de-cided a priori to examine the incidence of MYH gene mutations as a way to vali-date the association between biallelic MYH gene mutations and colorectal  cancer risk in a large North American population-based case – control series and to analyze the risk of colorectal cancer  associated with the heterozygous state.  Although Tenesa et al. used Fisher’s exact test to demonstrate, as have we, that biallelic mutations were more com-mon in the colorectal cancer case patients than in the control subjects, their results failed to adequately support their argu-ment that heterozygous carriers had no increased risk of colorectal cancer. We found a non – statistically signifi cant in-creased risk of colorectal cancer among MYH heterozygotes (odds ratio = 1.4; 95% confi dence interval = 0.8 to 2.5)  ( 5 ) . However, our study was inadequately powered to rule out this level of risk. Fur-thermore, by using the pooled cumulative MYH genotype data available from the literature, we demonstrated a convincing association between mild increased colorectal cancer risk and heterozygous MYH mutations, and although this ob-servation has now been corroborated by another group  ( 6 ) , the need for larger studies to address this issue is obvious.  Our results suggested a statistically signifi cant increased risk of colorectal cancer in fi rst- and second-degree family members of both monoallelic MYH  mutation carriers and in all mutation  carriers. We disagree with Tenesa et al., who suggest that a purely recessive model is the only possible explanation for this result and continue to assert that the re-sult we obtained by Poisson regression (relative risk = 1.57, 95% confi dence in-terval = 1.05 to 2.36) provides additional  evidence for increased colorectal cancer risk in monoallelic carriers. Given the frequency of MYH mutations in the  general population and in the absence of consanguinity, we feel we can safely as-sume that the observed increased risk in family members is due to monoallelic carriers of the mutation present in the proband. Similarly, for biallelic carriers, 25% of siblings of the proband would be expected to carry biallelic mutations, whereas 50% of siblings as well as other fi rst-degree relatives would be expected to carry monoallelic mutations. Thus, the magnitude of this association is too strong to be fully explained by a purely recessive model, and the increased risk must be due to monoallelic carriers.  The purpose of our loss of heterozy-gosity (LOH) experiments was to exam-ine whether the modest increased risk of colorectal cancer in heterozygous MYH mutation carriers was consistent with Knudson’s  “ two-hit ” tumorigenesis  model  ( 7 ) . We agree with Tenesa et al. about the variability of published allelotype data, not only for chromosome 1p, but for many chromosomal loci in many  tumor types. We confi rmed our microsatellite marker LOH results by analyzing the autoradio-graphic densities corresponding to wild-type and mutant nucleotides (data not shown) and found no  internal variability in our results.  The critical difference between dif-ferent modes of inheritance relies on  whether a phenotype is present in hetero-zygous carriers. In conclusion, our MYH gene mutation case – control frequency data, results of Poisson regression analy-ses, and LOH data and phenotypic ob-servations, as well as results of pooled analyses by us and by Peterlongo et al.  ( 6 ) , suggest that an increased risk of colorectal cancer conferred by the het-erozygous state cannot be ruled out.  Homozygous MYH gene mutation carri-ers are obviously at much greater risk for colorectal cancer than heterozygotes and, as we state in our article, studies with larger sample sizes are  clearly nec-essary to accurately quantify risk of colorectal cancer in heterozygotes.  SEAN P.  CLEARY  MARINA E.  CROITORU  ROBERT  GRYFE  MICHAEL  MANNO  MICHELLE  COTTERCHIO  JULIA  KNIGHT  STEVEN  GALLINGER  by guest on March 10, 2014http://jnci.oxfordjournals.org/Downloaded from 322 CORRESPONDENCE Journal of the National Cancer Institute, Vol. 97, No. 4, February 16, 2005 REFERENCES  (1)  Strachan T, Read AP. Human Molecular Genet-ics 2. New York (NY): John Wiley;  1999 .  (2)  Wilkie AO. The molecular basis of genetic dominance.  J Med Genet  1994 ; 31 : 89 – 98.  (3)  Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.  N Engl J Med  2003 ; 348 : 791 – 9.  (4)  Sampson JR, Dolwani S, Jones S, Eccles D, Ellis A, Evans DG, et al. Autosomal recessive co-lorectal adenomatous polyposis due to inherited  mutations of MYH.  Lancet  2003 ; 362 : 39 – 41.  (5)  Croitoru ME, Cleary SP, Di Nicola N, Manno M, Selander T, Aronson M, et al. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.  J Natl Cancer Inst  2004 ; 96 : 1631 – 4.  (6)  Peterlongo P, Mitra N, Chuai S, Kirchhoff T, Palmer C, Huang H, et al. Colorectal cancer risk in individuals with biallelic or monoal-lelic mutations of MYH. Int J Cancer. 2004 Dec 1; [Epub ahead of print]; DOI 10.1002/ijc.20767.  (7)  Knudson AG Jr. Mutation and cancer: statisti-cal study of retinoblastoma.  Proc Natl Acad Sci U S A  1971 ; 68 : 820 – 3.  NOTES  Affi liations of authors: Samuel Lunenfeld Re-search Institute (MEC, SPC, MM, JK, RG, SG) and Department of Surgery (RG, SG), Mount Sinai Hospital, Toronto, ON, Canada; Ontario Familial Colorectal Cancer Registry, Cancer Care Ontario, Toronto, ON, Canada (MM, MC, JK, SG).  Correspondence to: Steven Gallinger, MD, MSc, FRCS, Rm. 1225, Mount S inai Hospital, 600 University Ave., Toronto, ON, Canada M5G 1X5 (e-mail:  sgallinger@mtsinai.on.ca ).  DOI: 10.1093/jnci/dji052  by guest on March 10, 2014http://jnci.oxfordjournals.org/Downloaded from 

Re:Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk

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Re: Association Between Biallelic and Monoallelic Germline MYH Gene Mutations and Colorectal Cancer Risk

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