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MEETING ABSTRACT Open Access Polyposis syndromeswhat to do when genotyping seems not informative F Macrae From Familial Aspects of Cancer 2011 Research and Practice: A combined meeting of kConFab, Australian Breast Cancer Family Study, Australian Colorectal Cancer Family Study, Australian Ovarian Cancer Study, Family Cancer Clinics of Australia and New Zealand and kConFab Kingscliff, Australia. 23-26 August 2011 Background In polyposis, the type and numbers of polyps, the pat- tern of inheritance, and any extraintestinal features are all important in strategic planning of the DNA muta- tional approach. But where should we go when no mutation is uncovered? This paper outlines an approach we have adopted at RMH. Multiple adenomatous polyposis As a routine, we check to see if both sequencing and MLPA has been complete for APC, and full sequencing for MYH (though the return outside the three common mutations is low in our ethnic mix). On at least one occasion, a change in the MLPA kit by Holland Inc lead to identification of an important deletion as the probes changed in the MLPA kit. So recollecting blood to run on a new kit can be informative. RNA studies may also identify expression perturbations leading to closer scru- tiny of the DNA. We then look for translocations by FISH analysis. If all this is negative, we move the patient to a research setting; Justine Marum is well into a PhD evaluating the role of AXIN mutations in this group of patients. The findings to date are being confirmed with other approaches to establishing pathogenicity of the AXIN variants identified. This work is being done also in collaboration with Dr Marie Faux at the Ludwig Insti- tute of Cancer Research and Prof Rodney Scott at Uni- versity of Newcastle. Clinically, patients with multiple adenomas even with- out a germline mutation identified, are at increased risk of colorectal cancer; indeed, multiplicity of adenomas is the highest risk factor of subsequent colorectal cancer identifiable. The new NHMRC guidelines out for public comment recommend follow up of patients: As multipli- city of adenomas is a strong determinant of risk of meta- chronous advanced and non advanced neoplasia, follow up should be at twelve months for those with five or more adenomas, and sooner in those with ten or more adenomas. The risk of colorectal cancer to relatives of patients with multiple adenomas is related to the number of ade- nomas in the proband outside FAP and MYH. There- fore, as distinct from patients with small numbers of adenomas, relatives of patients with larger numbers (10 +) should be offered colonoscopy at an age relative to the age of presentation of the proband. The interval is not well defined but I would suggest 5 yearly. Hyperplastic polyposis HPS has no defined genetic basis as yet. These patients are at high risk of colorectal cancer, either through the serrated pathway or through their concurrent adenomas. Two yearly colonoscopy is advised. Although the mode of inheritance is also poorly defined, it is thought it may be recessive. Therefore siblings are offered surveillance, though usually not expected to be found with HPS themselves. There is however, a high risk of colorectal cancer in first degree relatives (siblings or parents) so colonoscopy should be offered to these relatives 5 yearly. Low level mosaicism, gonadal mosaicism, somatic mosaicism Somatic mosaicism is now well described in FAP, with respect to the APC gene; cases of multiple adenomatous polyposis may therefore be found with no germline (lymphocytic) APC mutation. We have been searching for the same APC mutation in multiple polyps, and in Head, Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Australia Macrae Hereditary Cancer in Clinical Practice 2012, 10(Suppl 2):A2 http://www.hccpjournal.com/content/10/S2/A2 © 2012 Macrae; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Polyposis syndromes– what to do when genotyping seems not informative

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MEETING ABSTRACT Open Access

Polyposis syndromes– what to do whengenotyping seems not informativeF Macrae

From Familial Aspects of Cancer 2011 Research and Practice: A combined meeting of kConFab, AustralianBreast Cancer Family Study, Australian Colorectal Cancer Family Study, Australian Ovarian Cancer Study,Family Cancer Clinics of Australia and New Zealand and kConFabKingscliff, Australia. 23-26 August 2011

BackgroundIn polyposis, the type and numbers of polyps, the pat-tern of inheritance, and any extraintestinal features areall important in strategic planning of the DNA muta-tional approach. But where should we go when nomutation is uncovered? This paper outlines an approachwe have adopted at RMH.

Multiple adenomatous polyposisAs a routine, we check to see if both sequencing andMLPA has been complete for APC, and full sequencingfor MYH (though the return outside the three commonmutations is low in our ethnic mix). On at least oneoccasion, a change in the MLPA kit by Holland Inc leadto identification of an important deletion as the probeschanged in the MLPA kit. So recollecting blood to runon a new kit can be informative. RNA studies may alsoidentify expression perturbations leading to closer scru-tiny of the DNA. We then look for translocations byFISH analysis. If all this is negative, we move the patientto a research setting; Justine Marum is well into a PhDevaluating the role of AXIN mutations in this group ofpatients. The findings to date are being confirmed withother approaches to establishing pathogenicity of theAXIN variants identified. This work is being done alsoin collaboration with Dr Marie Faux at the Ludwig Insti-tute of Cancer Research and Prof Rodney Scott at Uni-versity of Newcastle.Clinically, patients with multiple adenomas even with-

out a germline mutation identified, are at increased riskof colorectal cancer; indeed, multiplicity of adenomas isthe highest risk factor of subsequent colorectal cancer

identifiable. The new NHMRC guidelines out for publiccomment recommend follow up of patients: As multipli-city of adenomas is a strong determinant of risk of meta-chronous advanced and non advanced neoplasia, followup should be at twelve months for those with five ormore adenomas, and sooner in those with ten or moreadenomas.The risk of colorectal cancer to relatives of patients

with multiple adenomas is related to the number of ade-nomas in the proband – outside FAP and MYH. There-fore, as distinct from patients with small numbers ofadenomas, relatives of patients with larger numbers (10+) should be offered colonoscopy at an age relative tothe age of presentation of the proband. The interval isnot well defined but I would suggest 5 yearly.

Hyperplastic polyposisHPS has no defined genetic basis as yet. These patientsare at high risk of colorectal cancer, either through theserrated pathway or through their concurrent adenomas.Two yearly colonoscopy is advised. Although the modeof inheritance is also poorly defined, it is thought it maybe recessive. Therefore siblings are offered surveillance,though usually not expected to be found with HPSthemselves. There is however, a high risk of colorectalcancer in first degree relatives (siblings or parents) socolonoscopy should be offered to these relatives 5 yearly.

Low level mosaicism, gonadal mosaicism, somaticmosaicismSomatic mosaicism is now well described in FAP, withrespect to the APC gene; cases of multiple adenomatouspolyposis may therefore be found with no germline(lymphocytic) APC mutation. We have been searchingfor the same APC mutation in multiple polyps, and inHead, Colorectal Medicine and Genetics, The Royal Melbourne Hospital,

Australia

Macrae Hereditary Cancer in Clinical Practice 2012, 10(Suppl 2):A2http://www.hccpjournal.com/content/10/S2/A2

© 2012 Macrae; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.

background mucosa, in these patients without definitiveprogress, but others have reported this phenomenon.Some of this can be traced to low level mosaicismincluding even in the germline (lymphocytes) but notdetected with standard approaches to APC mutationalanalysis. We have also been interested to seek evidenceof gonadal mosaicism in the parents of apparent denovo cases, and are still pursuing this possibility. Thisrequires predictive DNA testing of all siblings of appar-ent de novo cases, and their parents. Gonadal mosaicismin FAP has been reported in Utah. Recently we havehad occasion to consider whether mosaicism mayinvolve both the gonads and the colon – through arequest to colonoscope parents who tested negative foran apparent de novo APC mutation in their only child.This has lead to a range of opinions and experiencesdescribed from colleagues around the world which willbe of interest to the FCC counsellors.

Published: 12 April 2012

doi:10.1186/1897-4287-10-S2-A2Cite this article as: Macrae: Polyposis syndromes– what to do whengenotyping seems not informative. Hereditary Cancer in Clinical Practice2012 10(Suppl 2):A2.

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