Three synchronous primary carcinomas in a patient with HNPCC associated with a novel germline mutation in MLH1: Case report

Abstract

Background: MLH1 is one of six known genes responsible for DNA mismatch repair (MMR), whose inactivation leads to HNPCC. It is important to develop genotype-phenotype correlations for HNPCC, as is being done for other hereditary cancer syndromes, in order to guide surveillance and treatment strategies in the future.

Case presentation: We report a 47 year-old male with hereditary nonpolyposis colorectal cancer (HNPCC) associated with a novel germline mutation in MLH1. This patient expressed a rare and severe phenotype characterized by three synchronous primary carcinomas: ascending and splenic flexure colon adenocarcinomas, and ureteral carcinoma. Ureteral neoplasms in HNPCC are most often associated with mutations in MSH2 and rarely with mutations in MLH1. The reported mutation is a two base pair insertion into exon 10 (c.866_867insCA), which results in a premature stop codon.

Conclusion: Our case demonstrates that HNPCC patients with MLH1 mutations are also at risk for ureteral neoplasms, and therefore urological surveillance is essential. This case adds to the growing list of disease-causing MMR mutations, and contributes to the development of genotype-phenotype correlations essential for assessing individual cancer risk and tailoring of optimal surveillance strategies. Additionally, our case draws attention to limitations of the Amsterdam Criteria and the need to maintain a high index of suspicion when newly diagnosed colorectal cancer meets the Bethesda Criteria. Establishment of the diagnosis is the crucial first step in initiating appropriate surveillance for colorectal cancer and other HNPCC-associated tumors in at-risk individuals.

Figure 1

(a) CT scan with PO/IV contrast suggested a large tumor of the ascending colon (arrow). Enlarged pericolic lymph nodes are suggestive of metastases. Also shown is right-sided hydroureteronephrosis caused by the mid-ureteral tumor (arrowhead). (b) The colon tumor at the splenic flexure tumor is visible on a different cut (arrow).

Figure 2

The patient (proband) is indicated by an arrow. Age of diagnosis or death is indicated if known. Diamonds indicate a group of siblings of unknown sex. Solid boxes indicate a diagnosis of colon cancer, and crosshatched boxes indicate cancer of non-colorectal origin. A diagonal strikethrough indicates a deceased individual. Unconfirmed diagnoses of individuals with extracolonic cancer are noted. Unaffected members of the extended family have been omitted for conciseness. One family member died in childhood from acute lymphoblastic leukemia (ALL).

Figure 3

Three immunohistochemical stains (40×) from the patient's ureteral tumor and a selected colon tumor. The colon and ureteral cancers stained negative for MLH1 and positive for MSH2. Both colon tumors stained negative for cytokeratin 7 and positive for cytokeratin 20, whereas the ureteral tumor stained positive for both cytokeratins, demonstrating a distinct organ of origin for each tumor type and thus discounting the possibility that either tumor type is a metastasis of the other. Data not shown for positive controls.

Figure 4

Sequence data pertaining to the novel MLH1 mutation found in the proband. A two-nucleotide 5'-CA-3' insertion (box) between base pair positions 866 and 867 leads to nonsense coding of amino acid residues and predicted truncation of the protein product (c.866_867insCA). Note: due to the palindromic nature of the insertion site, the insertion may also be classified as a 5'-AC-3' insertion between base pairs 867 and 868.