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Human Molecular Genetics Pages 823-829  

Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium
Introduction
Results
Discussion
Materials And Methods
   Patient accrual
   Mutation analysis
   MSI analysis
   Statistical analysis
Acknowledgements
References

Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium

Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium

Anna L. Millar1,2,4, Tuya Pal5, Lisa Madlensky3, Chris Sherman1, Larissa Temple3, Angela Mitri1, Hong Cheng1, Victoria Marcus1, Steven Gallinger2,3, Mark Redston1, Bharati Bapat1,2,4,* and Steven Narod5

1Department of Pathology and Laboratory Medicine, 2Samuel Lunenfeld Research Institute and 3Department of Surgery, Mount Sinai Hospital, Toronto, Canada and 4Department of Laboratory Medicine and Pathobiology and 5The Centre for Research in Women's Health, University of Toronto, Toronto, Canada

Received November 20, 1998; Revised and Accepted February 17, 1999

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome caused by germline defects of mismatch repair (MMR) genes. Endometrial cancer is the most common extracolonic neoplasm in HNPCC and is the primary clinical manifestation of the syndrome in some families. The cumulative incidence of endometrial cancer among HNPCC mutation carriers is high, estimated to be from 22 to 43%. We hypothesized that women with double primary cancers of the colorectum and endometrium are likely to be members of HNPCC families. In order to determine how frequently HNPCC manifests in the context of double primary cancers, we examined alterations of two MMR genes, hMSH2 and hMLH1, in 40 unrelated women affected with double primary cancers. These cases were identified using hospital-based and population-based cancer registries in Ontario, Canada. MMR gene mutations were screened by single-strand conformation polymorphism analysis and confirmed by direct sequencing. Eighteen percent (seven of 40) were found to harbor mutations of one of the two MMR genes. Analysis of colorectal and/or endometrial tumors of mutation-negative probands found microsatellite instability in seven of 20 cases. Six of seven mutation-positive probands had strong family histories suggestive of HNPCC. First degree relatives of mutation-positive probands had a very high relative risk (RR) of colorectal cancer (RR = 8.1, CI 3.5-15.9) and endometrial cancer (RR = 23.8, CI 6.4-61.0). The relative risk of mutation-negative cases was 2.8 (CI 1.7-4.5) for colorectal cancer and 5.4 (CI 2.0-11.7) for endometrial cancer. We recommend that all double primary patients with cancers at these sites should have a genetic evaluation, including molecular analysis for HNPCC where appropriate.

INTRODUCTION

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer susceptibility syndrome frequently caused by germline mutations in DNA mismatch repair (MMR) genes (1). HNPCC is characterized by an early onset of colorectal cancer (CRC) as well as cancers of the endometrium, stomach, ovary, pancreas and the hepatobiliary and urinary tracts. CRC is the most common cancer in the syndrome (~63% of all HNPCC tumors) and endometrial neoplasms are the most common extracolonic cancers (2). As with CRC, endometrial cancers occur at an early age in HNPCC (3). Women who carry HNPCC mutations have a 22-43% lifetime risk of developing endometrial cancer compared with 3% for the general population (4-6).

Recent advances in our understanding of the molecular basis of HNPCC should lead to a more accurate diagnosis of the syndrome. Defects in MMR genes have been shown to cause HNPCC [including hMSH2, hMLH1, hPMS2 and hMSH6 (GTBP)]. To date, germline mutations in hMSH2 and hMLH1 account for ~90% of all reported MMR gene mutations; hPMS2 and hMSH6 account for the remainder (7). However, the overall representation of hMSH2 and hMLH1 mutations in HNPCC families is ~50%, with equal contributions of each (8-10). The proteins encoded by MMR genes recognize and repair DNA errors created during replication. Loss of MMR gene activity leads to an accumulation of replication errors and genetic instability, also known as the mutator phenotype (11). Particularly sensitive sites for polymerase slippage errors are regions of short tandem repeat sequences, which are called microsatellites. While alterations at these sites may be benign if they occur in the non-coding regions, they create a phenotype known as microsatellite instability (MSI) indicating a defect in MMR function. Over 90% of HNPCC tumors show this MSI phenotype, whereas only 10-15% of sporadic CRC tumors are MSI positive (12-15). MMR mutations lead to an increase in the rate of somatic mutations in specific cancer-related genes, including the important growth regulatory genes BAX (16), IGFIIR (17) and TGF-[beta] type II receptor (18). This may enhance the progression of tumorigenesis, which is hypothesized to require multiple mutations (19).

Diagnosis of HNPCC is based on the presentation of multiple CRCs in several generations and the early onset of CRC (<50 years). These criteria, known as the Amsterdam criteria, are useful in identifying HNPCC in large families (20) and reflect the presence of underlying germline hMLH1 and hMSH2 mutations (21,22). However, these criteria may be too stringent for smaller families or when complete pedigree information is not available. In addition, the Amsterdam criteria do not account for extracolonic cancers. Since endometrial cancer is the second most common cancer associated with HNPCC, strict adherence to the Amsterdam criteria may also lead to a missed diagnosis of HNPCC. Newer guidelines, such as the Bethesda criteria (23), have been proposed in order to address these possible limitations. These criteria include HNPCC-related extracolonic cancers as well as histopathologic features of colorectal tumors for clinical diagnosis.

Hereditary predisposition to cancer often manifests in several ways, including two or more tumors arising in a single individual, the presence of many cancers in a family and cancer diagnosis at an early age. Therefore, double primary cancers of the two principal HNPCC-associated sites, the colorectum and endometrium, suggest the possibility of a diagnosis of HNPCC.

The overall aim of our study was to estimate the proportion of double primary cancers of the colorectum and endometrium that is due to HNPCC. To accomplish this we have obtained family histories on a series of women with double primary cancers of these sites, identified through hospital- and population-based registries. The results of our previous pedigree analysis demonstrated an elevated relative risk (RR) for developing cancer at these sites in first degree relatives of double primary probands when compared with that for first degree relatives of probands with cancer at a single site, in particular for women affected at a young age (24).

Our current objective is to extend these earlier clinical observations. In the present study, we have conducted molecular genetic analysis of the hMLH1 and hMSH2 genes and microsatellite instability in this series for 40 unrelated patients affected with double primary cancers of the colorectum and endometrium.

RESULTS

Of the 40 cases examined, seven were found to carry mutations in hMLH1 or hMSH2 (17.5%) (Table 1). The majority of these (six of seven) were hMSH2 mutations and all resulted in a truncated protein. One missense mutation was detected (DP1; Table 1), containing a germline A->T substitution at nt 1358 in exon 8 of hMSH2, which creates a novel splice site consensus sequence. By reverse transcriptase (RT)-PCR and protein truncation test (PTT) analysis, this mutation was shown to cause a 30 bp deletion spanning codons 453-462, leading to a truncated protein.

Overall, mutation-positive probands had stronger family histories and an earlier age at diagnosis (Table 2). Five of these seven patients with hMLH1/hMSH2 gene mutations had strong family histories (71%) and three of these seven families met the Amsterdam criteria (Fig. 1, cases 1-7). This compares with seven of 33 cases (21%) having strong cancer family histories among the 33 mutation-negative cases (odds ratio = 9.3, P = 0.02).

Table 1. Summary of mutational analysis
Case Family history Gene Exon Codon Nucleotide change Mutation status
DP1 Amsterdam criteria hMSH2 8 453 A1358->T Creates a novel splice site -> 30 bp del
DP2 Amsterdam criteria hMSH2 15 878 Del AG at 2633 Frameshift
DP3 Strongly familial hMSH2 15 878 Del AG at 2633 Frameshift
DP4 Strongly familial hMSH2 12 SD of exon 12 Del 11 bases at 2005+2 Splice defect
DP5 Amsterdam criteria hMSH2 1 45 Del 29 bases at 134 Frameshift
DP6 Possibly familial hMLH1 12 397 Del T1190 Frameshift
DP7 Non-familial hMSH2 7 389 C1165->T Arg->Stop
Del, deletion; SD, splice donor site.

Table 2. Summary of clinical features for mutation-positive versus mutation-negative probands
Clinical features Mutation-positive (n = 7) Mutation-negative (n = 33)
Age at diagnosis of colorectal cancer (years) 44.9 54.8
Age at diagnosis of endometrial cancer (years) 49.7 56.8
Amsterdam criteria 3 1
Strongly familial 2 6
Possibly familial 1 10
Non-familial 1 16


Figure 1. Pedigrees for mutation-positive cases 1-7. Case 2 is an HNPCC/Muir-Torre kindred. Case 8 is a mutation-negative family that met the Amsterdam criteria. Blood samples were obtained from probands for each family and analyzed for germline hMSH2 and hMLH1 mutations. Probands are indicated by an arrow. Affected and unaffected members are shown as solid and open symbols, respectively. Cancer site(s) and age at diagnosis are indicated. bl, bladder; bn, brain; bo, bowel; br, breast; co, colorectum; en, endometrium; es, esophagus; lu, lung; ov, ovary; pa, pancreas; pr, prostate; psu, primary site unspecified; st, stomach; th, throat; ur, ureter; wt, Wilm's tumor.

Also, six of the seven patients with known germline mutations had been diagnosed with both colorectal and endometrial cancer by the age of 55. The other case was diagnosed with colorectal cancer at age 48, but endometrial cancer at age 65. Of the 33 mutation-negative probands, eight were diagnosed with both of these cancers by age 55. Overall, mutations were found for six of 14 (43%) women who had both cancers before the age of 55 years (odds ratio = 18.8, P = 0.004). No difference was seen between the average age at diagnosis in the living cases of our study and the deceased cases (with pedigrees), which were excluded from mutation analysis.

Tissue was available from three of the seven mutation-positive probands and all three were MSI+ (Fig. 1, cases 3-5). Of the 20 mutation-negative probands analyzed, seven had MSI+ tumors. Strong family histories were seen in two of these patients, three were possibly familial and two were non-familial. Among 11 non-familial probands analyzed, nine were MSI- (Table 3). Finally, one proband, whose pedigree met the Amsterdam criteria, did not carry an hMLH1 or hMSH2 mutation and had an MSI- tumor (Fig. 1, case 8).

Cancer risk estimates for first degree relatives of double primary probands are presented in Table 4. A marked increase in RR is seen for cancer of the colorectum and endometrium in relatives of probands carrying hMSH2 or hMLH1 mutations. This increased risk in relatives is diminished after the age of 55. The RR of colorectal and endometrial cancer remains high for the mutation-negative patients, specifically those diagnosed before the age of 55 years (Table 4). This increased risk is not seen in patients diagnosed over the age of 55 years.

Risks were similar for relatives of the 40 women who consented to genetic testing, compared with the total 46 women for whom pedigrees were available and consent for genetic testing was requested (Table 5).

Table 3. Summary of microsatellite instability status versus clinical features for mutation-positive and -negative probands (n = 23)
Clinical features Case Mut+/- MSI+/-
Amsterdam criteria DP3 hMSH2 +
  DP5 hMSH2 +
  DP33 - -
Strongly familial DP4 hMSH2 +
  DP26 - +
  DP31 - +
  DP36 - -
Possibly familial DP9 - +
  DP13 - +
  DP35 - +
  DP17 - -
  DP16 - -
Non-familial DP10 - +
  DP29 - +
  DP14 - -
  DP15 - -
  DP20 - -
  DP21 - -
  DP24 - -
  DP27 - -
  DP8 - -
  DP32 - -
  DP34 - -

Table 4. Relative risks (RR) and confidence intervals (CI) for mutation-positive versus mutation-negative probands
Cancer site Age at diagnosis Mutation-positive (n = 7) Mutation-negative (n = 33)
    RR CI RR CI
Any cancer <55 5.4 2.9-9.3 2.1 1.4-3.2
  [ge]55 1.3 0.5-2.7 0.7 0.5-1.1
  Any age 2.7 1.6-4.1 1.1 0.8-1.5
Colorectal <55 24.5 7.9-57.2 8.3 3.6-16.4
  [ge]55 3.8 0.8-11.1 1.8 0.9-3.4
  Any age 8.1 3.5-15.9 2.8 1.7-4.5
Endometrial <55 62.8 12.6-183.4 15.1 4.1-38.7
  [ge]55 8.3 0.1-46.3 2.4 0.3-8.5
  Any age 23.8 6.4-61.0 5.4 2.0-11.7

Table 5. Relative risks (RR) and confidence intervals (CI) for genetically tested versus total living probands
Cancer site Age at diagnosis Genetically tested probands (n = 40) Total living probands studied (n = 46)
    RR CI RR CI
Any cancer <55 2.7 1.9-3.7 2.5 1.8-3.4
  [ge]55 0.8 0.5-1.1 0.7 0.5-1.0
  Any age 1.3 1.0-1.7 1.2 0.9-1.5
Colorectal <55 11.2 5.9-19.1 10.9 6.0-18.3
  [ge]55 2.1 1.1-3.6 1.9 1.0-3.2
  Any age 3.5 2.3-5.2 3.2 2.1-4.7
Endometrial <55 22.4 4.0-46.1 20.2 8.1-41.6
  [ge]55 3.1 0.6-9.1 2.8 0.6-8.1
  Any age 7.8 3.7-14.4 7.0 3.4-12.9

DISCUSSION

The development of multiple primary cancers in the same individual is uncommon and suggestive of genetic predisposition to cancer (25). Relatives of women with double primary cancers of the colorectum and endometrium are at an increased risk for these cancers, compared with relatives of patients with cancer at only one of these sites. This association is particularly strong for patients diagnosed at an early age. In our study, mutations were found in six of 14 patients when both cancers were diagnosed by age 55.

The majority of women found to carry MMR mutations in our study had strong family histories. Three of the four families inour study that met the Amsterdam criteria had germline hMLH1/hMSH2 mutations and, as expected, had MSI+ tumors. No mutation was found in the fourth family and MSI analysis was negative. However, we have identified four additional patients with MMR gene mutations based on the presence of double primary cancers who would not have been identified using the Amsterdam criteria alone. It is possible that by using patient ascertainment based on colorectal and endometrial double primary cancers, we have selected for HNPCC kindreds with a strong history of extracolonic cancers (Fig. 1, cases 2 and 4). This may also contribute to the high proportion of hMSH2 mutations (six of seven) observed in our series of patients, as hMSH2 mutation carriers have been shown to have an increased risk for extracolonic cancers (26). Wijnen et al. (27) recently showed that the presence of both colorectal cancer (with an early age at diagnosis) and endometrial cancer, in a patient from a family meeting the Amsterdam criteria, is a strong predictive factor for germline hMSH2 and hMLH1 mutations. In their study, the mutation detection rate increased from 45% for a kindred meeting the Amsterdam criteria to 90% if the kindred also included one member with both colorectal and endometrial cancer (27).

First degree relatives of the double primary cancer patients in our study have an increased RR for colorectal and endometrial cancer. We found this risk to be greater for first degree relatives of the women with MMR mutations, compared with those for whom no mutation is found. However, it is important to note that the risk for relatives of patients for whom no mutations were found remains significantly elevated. This observation is in accordance with our MSI analysis findings, which show a high rate of MSI+ (seven of 20) tumors in our mutation-negative families. These families, in particular those with strong family histories of cancer, may contain mutations in other MMR genes, such as hMSH6, hPMS2 or as yet unidentified genes. Some families with weaker histories of cancer may be sporadic, having somatic hMLH1 or hMSH2 mutations. Therefore, it is likely that the actual proportion of double primary endometrial and colorectal cancers due to HNPCC is higher than that observed in the present study. A similar observation has recently been reported by Simpkins et al. (28), who found that 12 of 15 apparently sporadic MSI+ endometrial cancers were due to hMLH1 promoter hypermethylation (28).

The exclusion of deceased cases from our study raises the possibility of bias because HNPCC-related cancers may have a better prognosis compared with sporadic cancer patients (29). However, there was no significant difference seen between the average age at diagnosis of the living cases and the deceased cases for which pedigrees were available (data not shown).

Based on our study we conclude that a diagnosis of double primary cancers of the colorectum and endometrium in a patient is a strong indicator of HNPCC, in particular for those diagnosed with both cancers before 55 years of age. Physicians are advised to consider the possibility of HNPCC when a patient presents with both colorectal and endometrial cancers before the age of 55 years or has a strong family history of HNPCC-associated cancers and to perform a comprehensive genetic evaluation.

MATERIALS AND METHODS

Patient accrual

The population-based Ontario Cancer Registry (OCR) at Cancer Care Ontario and the hospital-based tumor registry at Princess Margaret Hospital (Toronto) contain information on patients diagnosed with cancer of all sites. Identification and ascertainment of patients for this study was based primarily on these registries. Study subjects were women diagnosed with both colorectal and endometrial cancer by the age of 70 years during the period 1971-1996.

In total, 109 women were identified and confirmed. Eighty-four patients were identified by the OCR and 51 were identified through Princess Margaret Hospital. Twenty-six patients were recorded in both provincial and hospital registries. This includes 44 deceased and 65 living cases. We were able to contact 53 of the living patients. Of these, 46 agreed to provide their family histories and 40 agreed to give blood samples for molecular testing. Pedigree information was available for 10 of the deceased women. Tumor specimens were obtained for 23 of the 40 probands for whom germline mutation analysis was performed. Both endometrial and colorectal tissue was available for 15 of these cases and at least one tissue was available for the remaining eight cases (four endometrium and four colorectum).

Interviews were conducted with the 46 living probands and with the first degree relatives of the 10 deceased probands. The interviews were conducted in person or by telephone. The family history included current age or age of death, age at diagnosis of cancer and site of cancer in all first degree relatives of the proband. Pathology confirmation was obtained for 39 of the 67 reported cases of cancer (58%) in first degree relatives. The cancer diagnosis was taken as reported by the first degree relatives when pathological confirmation was not available. The diagnosis of cancer reported by first degree relatives is very likely to be accurate (30,31).

Clinical data, family histories and blood samples were obtained according to the protocol approved by the University of Toronto Human Ethics Committee. Families were classified as Amsterdam criteria, strongly familial, possibly familial and non-familial (Table 6) as previously described (24). Genetic counseling was offered to all probands and their families before and after molecular testing.

Mutation analysis

Single-stranded conformation polymorphism (SSCP) analysis was used to detect putative germline hMSH2 and hMLH1 mutations in 37 of the 40 probands. Three remaining patients overlapped with the Mount Sinai Hospital Familial Gastrointestinal Cancer Registry and had been assessed and reported independently using the PTT according to methods described elsewhere (32). Patient samples showing aberrant electrophoretic patterns were further analyzed by sequencing to confirm and characterize putative mutations.

Sixteen exons of hMSH2 and 19 exons of hMLH1 were amplified individually using intronic primer sequences (33,34). Genomic DNA was extracted from blood lymphocytes using the NH4Cl-Tris/salt precipitation method and 100-200 ng DNA was amplified in a PCR reaction volume of 15 µl with 1 µCi of [[alpha]-33P]dCTP, 1.0-2.0 mM MgCl2 and 50 ng each of the forward and reverse primer. PCR conditions included 1 min cycling at 95, 52-62 and 72°C for 35 cycles. An equal volume of denaturing formamide dye was added and the products were heat denatured at 95°C for 5 min, followed by rapid cooling on ice. The denatured products were analyzed by electrophoresis through a 5% polyacrylamide gel containing 10% glycerol at 4°C (7-10 W) for 17-20 h. The samples showing unique electrophoretic patterns were reamplified from genomic DNA in an independent PCR and sequenced using the Thermosequenase kit (Amersham Pharmacia Biotech, Cleveland, OH).

Table 6. Classification criteria
Familial: Amsterdam criteria (i) At least three relatives should have histologically verified colorectal cancer, one of whom should be a first degree relative of the other two
  (ii) At least two successive generations should be affected
  (iii) In one of the relatives colorectal cancer should be diagnosed under 50 years of age
  (iv) Familial adenomatous polyposis should be excluded
Familial: strongly familial (i) Two or more first degree relatives of proband with: colorectal cancer or endometrial cancer diagnosed at <55 years of age; kidney, ureteral, esophageal, stomach, small intestinal, pancreatic or ovarian cancer diagnosed at any age
  (ii) Two or more first degree relatives of proband with at least one colorectal cancer diagnosed at <55 years of age with another diagnosed at any age
  (iii) Two or more first degree relatives of proband with at least one endometrial cancer diagnosed at <55 years of age with another diagnosed at any age
  (iv) Two or more first-degree relatives of proband with colorectal cancer or endometrial cancer diagnosed at <55 years of age with another colorectal cancer or endometrial cancer diagnosed at any age
Possibly familial (i) One first degree relative of proband with: colorectal or endometrial cancer diagnosed at <55 years of age; kidney, ureteral, esophageal, stomach, small intestinal, pancreatic or ovarian cancer diagnosed at any age
  (ii) Two or more first degree relatives of proband with colorectal or endometrial cancer diagnosed at >55 years of age
Non-familial None of the above

MSI analysis

DNA for MSI analysis was obtained from paraffin-embedded blocks of colorectal and endometrial tissues. All blocks were examined by a gastrointestinal pathologist (C.S. or M.R.) to identify areas enriched in normal and tumor cell populations (>70% cellularity) for microdissection. Samples were deparaffinized at 95°C for 10 min, cooled to room temperature and incubated at 65°C for 12 h with a digestion buffer (100 µl) containing proteinase-K (20 mg/µl), 10 mM Tris-HCl (pH 8.0), 100 mM KCl, 2.5 mM MgCl2 and 0.45% Tween 20. Samples were then heat denatured and stored at -20°C.

Matched normal and tumor DNA was analyzed using five microsatellite loci including three dinucleotide repeats (D2S123, D5S346 and D17S250) and two poly(A) repeats (BAT25 and BAT26) (23). MSI was defined by the presence of altered/additional alleles in the PCR-amplified product of tumor DNA as compared with matched normal DNA samples. Tumors were designated MSI+ if alterations were observed in at least 40% of loci (two of five) analyzed.

Statistical analysis

The observed number of cases (O) in the first degree relatives of the probands was determined by review of family pedigrees. The expected number of cases (E) for each cancer was calculated from the product of the person-years and the Ontario provincial cancer rate for each age range (35). Patients were considered to be at risk of cancer until death or 1996. The expected number of cases was calculated for each of the age ranges selected. The RR of cancer in the first degree relatives of probands was estimated by comparing observed with expected numbers. The confidence intervals (CI) were calculated assuming a Poisson distribution, CI = OL/E - OU/E, where OL and OU are the lower and upper bounds, respectively (36).

ACKNOWLEDGEMENTS

We are grateful to the patients who agreed to participate in our study and the Cancer Registry at Cancer Care Ontario for making this study possible. We thank Ms Margot Mitchell-Lehman for her excellent efforts in the initial ascertainment and recruitment of patients. This work was supported in part by NCIC grant 8034 (S.G. and B.B.) and a University of Toronto Open Fellowship (to A.M.).

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*To whom correspondence should be addressed at: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. Tel: +1 416 586 5175; Fax: +1 416 586 8628; Email: bapat@mshri.on.ca

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