CASE REPORT

MUTYH Associated Polyposis Coli: One Common and One RareMutation

Heiko Ulrik De Schepper • Herbert Fierens •

Piet-Hein Steger • Luc Colemont

Received: 2 December 2011 / Accepted: 21 February 2012

� Springer Science+Business Media, LLC 2012

Keywords MUTYH � MUTYH associated polyposis �Familial adenomatous polyposis � Q377X �Colorectal cancer

Case 1

A 52-year-old Caucasian male with no significant medical

history presented at our Department of Gastroenterology

several years ago with vague complaints of abdominal

distension, fecal urgency, and occasional hematochezia.

There was no abdominal pain or weight loss. Familial

history was unremarkable. Digital rectal examination

revealed tumor at the tip of the finger, confirmed by

rectoscopy as a fragile, non-obstructive lesion surrounded

by multiple small polyps. A colonoscopy was performed

which showed approximately 100 small sessile or pedun-

culated polyps throughout the large bowel. At 9 cm from

the anal margin a concentric polypoid mass was identified,

showing central ulceration. Pathological examination con-

firmed the presence of an invasive adenocarcinoma with

strong CEA immunoreactivity. Biopsies of other polyps

disclosed tubulovillous adenomata. Endoscopic ultrasound

examination suggested penetration of the cancerous growth

into the muscular layer. No metastatic disease was identi-

fied by CT examination of the abdomen. Final staging of

the rectal tumor was T3N0M0.

Considering the numerous polyps visualized by

endoscopy, a tentative diagnosis of familial adenomatous

polyposis (FAP) was made. In this case, total colectomy is

the only curative treatment. Neo-adjuvant chemoradiation

therapy was initiated (5-fluorouracil and Mitomycin) to

downstage the lesion. Re-evaluation showed a considerable

regression of the main rectal lesion, as well as the multiple

colonic polyps. A total colectomy was performed with

ileo-anal anastomosis and J-pouch construction. The

patient is currently in regular follow-up and has no

symptoms or signs of recurrent disease.

Familial adenomatous polyposis is caused by mutations

in the APC gene (adenomatous polyposis coli) located on

chromosome 5. To our surprise, we could not identify the

most common APC mutations in our patient. Considering

the autosomal dominant inheritance of FAP, colonoscopy

was also performed in the patient’s three children and

found to be negative. In the meantime, his sister was also

diagnosed in another hospital with rectal carcinoma and

multiple colonic polyps. She was also treated by total

colectomy.

Taking into account the more recent scientific evidence,

a new DNA analysis was performed in our patient. This

showed two mutations of the MUTYH gene (Y165C and

P391L). In contrast to FAP, MAP (MUTYH associated

polyposis) is inherited in an autosomal recessive pattern,

providing a solid explanation for the pedigree of our case.

Case 2

A 41-year-old Turkish man was recently referred to our

Department for colonoscopy because of a familial history

of colonic polyposis. The patient had no abdominal com-

plaints or anal blood loss. One brother was diagnosed

H. U. De Schepper (&) � H. Fierens � P.-H. Steger �L. Colemont

Division of Gastroenterology, St-Vincentius Hospital,

St-Vincentiusstraat 20, 2018 Antwerp, Belgium

e-mail: heikodeschepper@gmail.com

123

Dig Dis Sci

DOI 10.1007/s10620-012-2107-6

2 years earlier with polyposis and colon cancer and

underwent total coloproctectomy, while two other brothers

underwent endoscopic polypectomy. Both parents were

never diagnosed with colonic polyposis or colon cancer,

suggesting autosomal recessive inheritance of the pre-

sumed polyposis syndrome.

In our patient colonoscopy revealed the presence of

about 100 polyps and one suspicious sessile lesion in the

rectosigmoid. The latter proved to contain at least intra-

mucosal adenocarcinoma (T1N0M0).

The genetic screening performed on our patient’s

brother disclosed a biallelic frame shift mutation of the

MUTYH gene (pQ377X). The same mutation was subse-

quently identified in our patient, thereby confirming the

diagnosis of MAP. A curative subtotal colectomy with

ileorectal anastomosis was performed. There was no need

for (neo)adjuvant chemotherapy.

Polyposis of the Colon and Heredity

Isolated adenomatous polyps are a common endoscopic

finding after the age of 50. A total of 5–10% of these

polyps will undergo malignant transformation, justifying

their resection when discovered.

A familial history of colorectal cancer (CRC) increases

the risk for this disease twofold to threefold. The risk

mainly depends upon the number of affected relatives, the

degree of consanguinity, and the age at diagnosis. Although

genetic predisposition is supposed to be present in up to

30% of colorectal tumors, only 3–5% of CRC can be linked

to a hereditary syndrome with high penetrance such as FAP

or hereditary non-polyposis colorectal cancer (HNPCC) [1].

The other 25–27% of hereditary CRC cases are probably

related to more prevalent low penetrance genes operating

within a polygenic framework of cancer predisposition [4].

Adenomatous polyposis coli or FAP involves the pres-

ence of 100–1,000 polyps throughout the colon and

accounts for approximately 1% of CRC. Of these cases,

50–80% can be linked to autosomal germline mutations of

the APC gene, inherited in an autosomal dominant fashion,

while 15–20% concerns de novo mutations, and 2–4%

involves mosaic APC mutations. The APC gene encodes a

tumor suppressor factor crucial for the regulation of growth

and differentiation of colon epithelium [4].

If less than 100 polyps are identified, this is described as

multiple colorectal adenoma or MRCA. A total of 5–30%

of these cases can still be linked to APC mutations and are

referred to as attenuated FAP or AFAP. Up to 30% of

MRCA cases are related to malfunctioning of a specific

DNA repair mechanism, encoded by the MUTYH gene [7].

This is then referred to as MUTYH-associated polyposis or

MAP, which is inherited in an autosomal recessive manner.

For screening purposes, the distinction between MAP

and (A)FAP is very important, as the siblings rather than

the offspring of MAP cases are most likely to require

further investigation.

The MAP Genotype

MAP is an autosomal recessive hereditary colorectal cancer

syndrome. Biallelic MUTYH mutations are identified in

about 1% of CRC in a Western population. The exact

prevalence is not clear and most probably underestimated,

considering the relatively novel nature of this entity.

MAP is characterized by an increased rate of somatic

mutations of the APC gene. These mutations involve trans-

versions of a guanine-cytosine base pair to a thymine-adenine

base pair (G:T transversion). This type of mutation is pri-

marily induced by oxidative stress—oxidation produces the

stable guanine derivative 8-oxo-7,8-dihydroxy-20-deoxygua-

nosine which preferentially (mis)matches with adenine and

thus results in transversion. Mispairing is normally corrected

by base excision repair enzymes, the most relevant being

MTH, OGG1, and MUTYH. Defects of these enzymes lead to

an increased cancer risk. The colorectal predisposition is

probably related to the high degree of oxidative stress inherent

to the colonic environment due to the presence of the

microbiome and to dietary components. Siber et al. [7]

showed that both alleles of the MUTYH gene are mutated in

28.6% of patients with MRCA (15–100 polyps) and in 7.5%

of patients suspected for APC (100–1,000 polyps) but without

APC gene mutation. Familial history in these cases was often

suggestive for a recessive mode of inheritance.

Monoallelic MUTYH mutations increase CRC risk to a

lesser extent, more so in combination with mutations of

other DNA repair genes [3].

At present, around 80 mutations of the MUTYH gene

(located on chromosome 1 between p32.1 and p344.3) have

been described in MAP families. The missense mutations

Y179C and G396D are the most common variants in the

Caucasian population [2], representing 73% of mutant alleles

in MAP. In case 1, the responsible mutation was indeed

identified as Y179C. In case 2 the mutation was found to be

Q377X, a much less common frameshift MUTYH mutation.

Remarkably, and as is the case in our patient, this mutation

seems to be especially associated with Turkish descent [5],

although this remains to be confirmed in larger series.

The MAP Phenotype

Most patients with a biallelic MUTYH mutation will

develop 10–100 adenomata and CRC before the sixth

decade of life. Median age at diagnosis is 56 years [6].

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At the time of diagnosis 63% of MAP patients has

10–99 polyps, 23% has 100–1,000 polyps and 7% has ten

polyps. Duodenal adenomata are also more prevalent in

MAP (17%). A recent Dutch cohort study even reported a

lifetime risk of duodenal cancer of approximately 4% [8].

The same study found that the incidence of other extrain-

testinal malignancies (ovarian, bladder, and skin) in MAP

was almost twice that of the general population. An asso-

ciation with gastrointestinal carcinoid tumors was sug-

gested but the evidence is rather sporadic.

The MAP Approach

When colonoscopy shows more than 100 polyps and/or the

pedigree suggests an autosomal dominant hereditary pat-

tern, it should be common practice to screen for APC

mutations first and to include MUTYH screening if the

latter is negative. If there are less than 100 adenomata

during colonoscopy or if the pedigree suggests autosomal

recessive heredity, MUTYH screening should be the first

step. One should keep in mind however that heterozygous

carriers of MUTYH mutations are relatively frequent,

enabling MAP in successive generations (pseudo-dominant

heredity).

Although there are no official guidelines available, it is

suggested that all first-degree relatives should equally be

screened for MUTYH mutations. In siblings with biallelic

mutations a colonoscopy should be performed every

1–2 years starting at age 18–20. Total colonoscopy is

superior to sigmoidoscopy considering most CRC in MAP

are situated in the right hemicolon. A duodenoscopy should

be associated with this screening strategy every 2–3 years

from age 25 onwards.

If colorectal cancer is detected or if the polyp burden

becomes uncontrollable endoscopically, total colectomy

with ileorectal anastomosis is the only curative intervention.

Conflict of interest The authors declare no conflict of interest.

References

1. Castells A, Castellvi-Bel S, Balaguer F. Concepts in familial

colorectal cancer: where do we stand and what is the future?

Gastroenterology. 2009;137:404–409.

2. Cheadle JP, Sampson JR. MUTYH-associated polyposis—from

defect in base excision repair to clinical genetic testing. DNARepair. 2007;6:274–279.

3. Jones N, Vogt S, Nielsen M, et al. Increased colorectal cancer

incidence in obligate carriers of heterozygous mutations in

MUTYH. Gastroenterology. 2009;137:489–494.

4. Markowitz SD, Bertagnolli MM. Molecular origins of cancer:

Molecular basis of colorectal cancer. N Engl J Med. 2009;361:

2449–2460.

5. Nielsen M, Franken PF, Reinards TH, et al. Multiplicity in polyp

count and extracolonic manifestations in 40 Dutch patients with

MUTYH associated polyposis coli (MAP). J Med Genet. 2005;42:

e54.

6. Nielsen M, Joerink-van de Beld MC, Jones N, et al. Analysis of

MUTYH genotypes and colorectal phenotypes in patients with

MUTYH-associated polyposis. Gastroenterology. 2009;136:471–

476.

7. Siber OM, Lipton L, Crabtree M, et al. Multiple colorectal

adenomas, classic adenomatous polyposis and germ-line mutations

in MUTYH. N Engl J Med. 2003;348:791–799.

8. Vogt S, Jones N, Christian D, et al. Expanded extracolonic tumor

spectrum in MUTYH-associated polyposis. Gastroenterology.

2009;137:1976–1985.

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