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MUTYH-associated polyposis

Friday 5 June 2009

MAP; MYH-associated polyposis

Definition: MUTYH-associated polyposis (MAP) is a recessively inherited disorder which predisposes biallelic carriers for a high risk of polyposis and colorectal carcinoma (MAP-CRC).

This recently recognized type of adenomatous polyposis was first documented in a Welsh kindred in which three siblings had multiple colorectal adenomas and carcinomas but lacked a germline APC mutation.

MUTYH-associated polyposis (MAP) may be difficult to distinguish from classical FAP.

It was shown to account for 7.5% of classical-appearing but APC mutation-negative FAP (>100 adenomas).

MAP may present with hundreds of adenomas but not with the many thousands that characterize the more severe forms of FAP.

In view of the lower numbers of colorectal adenomas and presentation in the mid-50s, MAP may mimic attenuated FAP.

However, MAP accounted for only 6.4% of subjects with multiple colorectal adenomas (5–100).

MAP is an autosomal recessive condition and may either present as a sporadic disorder or affect two or more siblings.

Somatic G:C to T:A transversion mutations may affect KRAS as well as APC.

One might therefore expect to observe hyperplastic polyps initiated by KRAS mutation in MAP (as well as adenomas).

Such a finding would facilitate the distinction between MAP versus classical and attenuated FAP.

Small numbers of hyperplastic polyps have indeed been noted in MAP. These polyps are usually small and distally located. However, in one instance, the number of hyperplastic polyps was sufficiently great to suggest a diagnosis of hyperplastic polyposis.

Very large numbers of small rectal hyperplastic polyps in a subject with proven MAP can also be observed.

Pathologists are likely to sample only the most advanced appearing lesions in surgical specimens containing multiple polyps. However, a policy of deliberately targeting small polyps may be diagnostically rewarding given that the finding of multiple small hyperplastic polyps would be unusual in both classical and attenuated FAP.

Genetics

Somatic mutations in the colorectal neoplasms showed a higher than expected rate of G:C to T:A transversions, and this, in turn, indicated a failure to repair a pro-mutagenic product of oxidative DNA damage: 8-oxo-7,8-dihydro-2′-deoxyguanosine.

The siblings were found to have bi-allelic germline mutations in the candidate DNA repair gene MUTYH that maps to chromosome 1p32–34.

This gene was originally referred to as MYH, and the term MYH-associated polyposis is still widely used.

The three siblings in the initial report were compound heterozygotes for the missense mutations Y165C and G382D in MUTYH.

Similar findings were subsequently confirmed in other subjects of European origin and with multiple colorectal adenomas ranging from 5 to several hundreds.

While the mutations Y165C and G382D are the most common in Europeans, a Y90X mutation occurs in subjects of Pakistani origin, whereas an E466X mutation has been found in subjects of Indian origin.

An in-frame deletion nt1395-7delGGA has been described in Italian populations.

MAP-CRCs

About one third of the biallelic MAP patients in population based CRC series has no adenomas.

MAP CRCs show some similarities to micro-satellite unstable cancers, with a preferential proximal location, a high rate of mucinous histotype and increased presence of TILs.

These features should direct the practicing pathologist towards a MAP aetiology of CRC as an alternative for a mismatch repair deficient cause.

High frequent G>T transversions in APC and KRAS2 (mutated in early tumour development) but not in P53 and SMAD4 (implicated in tumour progression) might indicate a predominant MUTYH effect in early carcinogenesis. (19527492)

In one series, MAP CRCs frequently localized to the proximal colon (69%), were mucinous in 21%, and had a conspicuous Crohn’s like infiltrate reaction in 33%; all of these parameters occurred at a higher rate than reported for sporadic CRCs.

Tumour infiltrating lymphocytes (TILs) were also highly prevalent in MAP CRCs.

Somatic APC MCR mutations occurred in 14% while 64% had KRAS2 mutations (c.34G>T). G>T transversions were found in p53 and SMAD4, although the relative frequency compared to other mutations was low. (19527492)

MUTYH gene

The MUTYH gene encodes a key glycosylase of the base-excision repair system that is involved in maintaining genomic DNA stability against oxidative damage.

Pathology

- biallelic mutations of MUTYH in:

  • MUTYH-associated polyposis (autosomal recessive colorectal adenomatous polyposis) (MIM.608456)
  • MUTYH-associated gastric carcinoma (sporadic gastric carcinoma) (MIM.137215)
  • MUTYH-associated association pilomatrixoma/colorectal adenomatous polyposis

- MUTYH-associated polyposis (autosomal recessive colorectal adenomatous polyposis) (MIM.608456)

  • Biallelic germline MUTYH mutations have been proved to greatly predispose to non-familial adenomatous polyposis (FAP) and non-hereditary non-polyposis colorectal cancer (HNPCC) familial recessive forms of colorectal cancer with multiple adenomas.
  • To date, there is still much debate over the impact of monoallelic germline MUTYH mutations on colorectal carcinogenesis. Heterozygous MUTYH mutations do not play a major role in sporadic colorectal carcinogenesis although a modest effect on this process cannot be ruled out. (17931073)

See also

- MUTYH
- association pilomatrixoma/colorectal adenomatous polyposis

- DNA glycosylases

  • OGG1
  • NUDT1

- base excision repair

  • base-excision repair diseases

- DNA glycosylases

  • OGG1
  • NUDT1

- base excision repair (BER system)

  • base-excision repair diseases

References

- High frequency of copy-neutral LOH in MUTYH-associated polyposis carcinomas. Middeldorp A, van Puijenbroek M, Nielsen M, Corver WE, Jordanova ES, ter Haar N, Tops CM, Vasen HF, Lips EH, van Eijk R, Hes FJ, Oosting J, Wijnen J, van Wezel T, Morreau H. J Pathol. 2008 Sep;216(1):25-31. PMID: 18506705

- Colorectal carcinomas in MUTYH-associated polyposis display histopathological similarities to microsatellite unstable carcinomas. Nielsen M, de Miranda NF, van Puijenbroek M, Jordanova ES, Middeldorp A, van Wezel T, van Eijk R, Tops CM, Vasen HF, Hes FJ, Morreau H. BMC Cancer. 2009 Jun 15;9:184. PMID: 19527492 [Free]

- MUTYH-associated polyposis carcinomas frequently lose HLA class I expression - a common event amongst DNA-repair-deficient colorectal cancers. de Miranda NF, Nielsen M, Pereira D, van Puijenbroek M, Vasen HF, Hes FJ, van Wezel T, Morreau H. J Pathol. 2009 Sep;219(1):69-76. PMID: 19462419 [Free]

- The thorough screening of the MUTYH gene in a large French cohort of sporadic colorectal cancers. Küry S, Buecher B, Robiou-du-Pont S, Scoul C, Colman H, Lelièvre B, Olschwang S, Le Houérou C, Le Neel T, Faroux R, Ollivry J, Lafraise B, Chupin LD, Bézieau S. Genet Test. 2007 Winter;11(4):373-9. PMID: 17931073

- MUTYH-associated polyposis carcinomas frequently lose HLA class I expression-a common event amongst DNA-repair-deficient colorectal cancers. de Miranda NF, Nielsen M, Pereira D, van Puijenbroek M, Vasen HF, Hes FJ, van Wezel T, Morreau H. J Pathol. 2009 Apr 17. PMID: 19462419

- Cheadle JP, Sampson JR. Exposing the MYtH about base excision repair and human inherited disease. Hum Mol Genet. 2003 Oct 15 ;12 Spec No 2 :R159-65. Epub 2003 Aug 05. PMID : 12915454

- Hereditary colorectal cancer: MYH-associated polyposis and other newly identified disorders. Lindor NM. Best Pract Res Clin Gastroenterol. 2009;23(1):75-87. PMID: 19258188

- MUTYH-associated polyposis carcinomas frequently lose HLA class I expression-a common event amongst DNA-repair-deficient colorectal cancers. de Miranda NF, Nielsen M, Pereira D, van Puijenbroek M, Vasen HF, Hes FJ, van Wezel T, Morreau H. J Pathol. 2009 Apr 17. PMID: 19462419

- Cheadle JP, Sampson JR. Exposing the MYtH about base excision repair and human inherited disease. Hum Mol Genet. 2003 Oct 15 ;12 Spec No 2 :R159-65. Epub 2003 Aug 05. PMID : 12915454