Download Case Study: Recessive MUTYH Colorectal Cancer

Case Study:
Recessive MUTYH Colorectal Cancer
Clinical Overview:
A 60-year old male was referred for genetic counseling and cancer risk assessment due to a personal history of polyposis and personal/
family history of colorectal cancer. The Lynch/Colorectal High Risk Panel was ordered at GeneDx due to suspicion for an inherited colon
cancer predisposition syndrome. Two pathogenic variants were detected in MUTYH, confirming a diagnosis of MUTYH-Associated
Polyposis (MAP) syndrome in the patient.
Biallelic MUTYH pathogenic variants (present on both copies of the gene) are diagnostic of MAP, an autosomal recessive condition
characterized by an increased risk of colorectal polyps and colorectal cancer. The risk for colon cancer is estimated at 43% by age 60
and 80% by age 70.1,2 Most individuals with MAP develop between 10-100 polyps, but individuals can develop hundreds of polyps.
Clinical presentation is variable and up to one third of cases develops colorectal cancer in the absence of polyposis.3-7 Adenomas are
the most common polyp type in MAP, but serrated polyps are observed as well.3,8 Duodenal polyps and gastric fundic gland polyps have
been observed in a minority of individuals with MAP conferring a 4% lifetime risk of developing duodenal cancer. Risks for extraintestinal
cancers including endometrial, ovarian, bladder, breast, and skin may be increased.9,10 There are conflicting data about the increased risk
for colon cancer, endometrial cancer, and breast cancer in carriers of a single MUTYH mutation.1,11,12,13,14
Figure 1: Family history
Patient Information:
Age: 60
Specimen: Blood
Referral diagnosis: The patient had a personal
history of >50 colorectal polyps and colorectal
cancer diagnosed at age 42.
Family history: Significant for a sister with colorectal
cancer diagnosed at age 60 and a maternal cousin
with colorectal cancer diagnosed at age 50. A
paternal aunt was diagnosed with breast cancer at
age 75.
Breast cancer
Dx at 75
Diagnostic Summary:
POSITIVE. Two pathogenic variants in MUTYH
were detected: c.391T>A (p.Trp131Arg) and
c.1187G>A (p.Gly396Asp).
Lynch/Colorectal High Risk Panel: This panel
analyzed seven genes implicated in hereditary
colorectal cancer predisposition including APC,
MLH1, MSH2, MSH6, PMS2, EPCAM and
MUTYH. The pathogenic variants detected in
MUTYH are consistent with the patient’s personal
history of colorectal polyposis/cancer and family
history of colorectal cancer. In addition, the
c.1187G>A (p.Gly396Asp) pathogenic variant
is a common founder mutation in the European
population.
Colorectal cancer
Dx at 42
>50 Colorectal polyps
Patient
Age 60y
Colorectal cancer
Dx at 60
Colorectal cancer
Dx at 50
Age 30y
Diagnostic Implications:
MAP is among the few inherited cancer predisposition syndromes with an autosomal recessive pattern. As with other autosomal recessive
syndromes, patients must inherit pathogenic variants in both copies of the MUTYH genes to confirm the MAP diagnosis. This inheritance
pattern is different from most other inherited cancer predisposition syndromes. Each child and parent of an individual with MAP is an
obligate carrier. MAP risk for children is dependent on the MUTYH status of their other parent. Siblings of patients with MAP have a 25%
chance to inherit biallelic pathogenic variants. Targeted familial testing is available for relatives of patients with MAP. Given the conflicting
data about cancer risks in individuals with a single MUTYH pathogenic variant, risk assessment for family members who are only carriers is
limited.
Management guidelines are available for patients with MAP. The National Comprehensive Cancer Network provides treatment and
surveillance guidelines for patients with a personal history of MAP. Guidelines are dependent on patient age and polyp burden. Surveillance
includes colonoscopy and upper endoscopy. Please refer to NCCN for additional details on management at
http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
References:
1. Jenkins, MA et al. Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study.
Cancer Epidemiol Biomarkers Prev. 2006 Feb;15(2):312-4.
2. Lubbe SJ et al. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol. 2009 Aug
20;27(24):3975-80.
3. Sieber OM et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.N Engl J Med. 2003
Feb 27;348(9):791-9.
4. Croitoru ME et al. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.J Natl Cancer
Inst. 2004 Nov 3;96(21):1631-4.
5. Farrington SM et al. Re: Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl
Cancer Inst. 2005 Feb 16;97(4):320-1; author reply 321-2.
6. Balaguer F et al. Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study. Clin
Gastroenterol Hepatol. 2007 Mar;5(3):379-87.
7. Cleary SP et al. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology.
2009 Apr;136(4):1251-60.
8. Boparai KS et al. Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis.
Gastroenterology. 2008 Dec;135(6):2014-8.
9. Barnetson RA et al. Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer. Clin Genet.
2007 Dec;72(6):551-5. Epub 2007 Oct 22.
10.Vogt S et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10.
11.Rennert G et al. MutYH mutation carriers have increased breast cancer risk. Cancer. 2012 Apr;118(8):1989-93.
12.Win AK et al. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int J Cancer. 2011 Nov
1;129(9):2256-62.
13.Out AA et al. MUTYH gene variants and breast cancer in a Dutch case-control study. Breast Cancer Res Treat. 2012 Jul;134(1):219-27.
14.Santonocito C et al. Common genetic variants of MUTYH are not associated with cutaneous malignant melanoma: application of
molecular screening by means of high-resolution melting technique in a pilot case-control study. Int J Biol Markers. 2011 Jan-Mar;26.
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