Coexisting germline mutations in APC and BRCA2 in a patient with colon cancer

BRCA2-deficient cells are unable to repair DNA damage and accumulate genetic alterations, often in genes important for cell cycle checkpoint. Cells with genetic alterations are able to continue with cell cycle and progress to neoplasia.10–12 In females, while both BRCA1 and 2 mutations are associated with cancer of breast, ovary, fallopian tubes, and peritoneum, BRCA1 confers a greater risk. On the other hand, in males, BRCA2 confers greater risk of breast, prostate, and pancreatic cancer. BRCA mutations have been associated with melanoma, gastric, and hematological malignancies. Currently, there are no well-established guidelines for managing male BRCA2 patients.11,12 It is recommended that the patient be counseled regarding risk of various malignancies and that surveillance be conducted of the various cancers as for a high-risk patient.12

Conclusion: To our knowledge this is the only reported case of coexistence of APC and BRCA2 pathogenic mutation.

Based on the KRAS mutational status, our patient would not have benefited from anti-EGFR therapies and thus he was spared the expense and side effects associated with this therapy. Seven months after his initial presentation, his CEA rose and MRI revealed three new liver lesions as well as recurrence at the site of anastomosis. He underwent total colectomy. Two liver lesions were biopsied and the third was ablated. The two biopsied lesions were negative for metastatic carcinoma. He was started on adjuvant 5-FU and bevacizumab (Avastin). The patient’s liver lesion will be followed with serial CEA levels.

Although our patient did not have children, the germline mutation in the APC gene indicates the need for further evaluation of his sibling and the maternal side of the family. This should include genetic counseling and testing so that earlier and more frequent endoscopic screenings can be performed as appropriate. The patient himself will be screened by esophagogastroduodenoscopy.

Because of the germline mutation in the BRCA2 gene, the patient underwent mammogram. He will be surveyed for breast, skin, and prostate cancer. Based on the pedigree, it can be postulated that this germline mutation might be of paternal origin and may have played a role in the father’s pancreatic cancer. We have encouraged the patient to discuss conformational testing of the BRCA2 and APC mutations with his mother.

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8. Soravia C, Berk T, Madlensky L, et al. Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet. 1998;62(6):1290–1301.
9. NM_000059.3(BRCA2):c.8297delC (p.Thr2766Asnfs) AND Breast-ovarian cancer, familial 2. http://www.ncbi.nlm.nih.gov/clinvar/RCV000031732.
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12. Mohamad HB, Apffelstaedt JP. Counseling for male BRCA mutation carriers: a review. Breast. 2008;17(5):441–450.

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Test yourself

Here are three questions taken from the case report. Answers are online now at www.amp.org/casereviews and will be published next month in CAP TODAY.

1. Mutations in KRAS are associated with:

a) resistance to EGFR tyrosine kinase inhibitors and monoclonal antibodies

b) enhanced response to EGFR tyrosine kinase inhibitors and monoclonal antibodies

c) no impact on response to EGFR tyrosine kinase inhibitors and monoclonal antibodies

2. Mutations in the APC gene result in:

a) FAP

b) AFAP

c) Lynch syndrome

d) a & b

3. Patients with AFAP phenotype have:

a) alternatively spliced sequence in exon 9

b) mutations in 5′ to codon 168

c) mutations in 3′ to codon 1580

d) all of the above
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Dr. Dolkar (PGY3 resident) and Dr. Siddiqui are in the Department of Pathology and Laboratory Medicine, Dr. Zikria is in the Department of Oncology, Dr. Bussell is in the Department of Surgery, and Morrill-Cornelius is a genetic counselor in the Hereditary Cancer Program—all at Danbury Hospital, Western Connecticut Health Network.