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Annals of Surgical Oncology 9:555-561 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

hMLH1 and hMSH2 Gene Mutation in Brazilian Families With Suspected Hereditary Nonpolyposis Colorectal Cancer

Benedito Mauro Rossi, MD, PhD, FACS, CSSO, Ademar Lopes, MD, PhD, FACS, FSSO, Fabio Oliveira Ferreira, MD, PhD, Wilson Toshihiko Nakagawa, MD, MS, Cláudia C. Napoli Ferreira, BS, José C. Casali da Rocha, MD, Catarina C. Simpson, BS and Andrew J. G. Simpson, PhD

From the Department of Pelvic Surgery (BMR, AL, FOF, WTN), the Hereditary Colorectal Cancer Registry (CCNF), the Department of Oncogenetics (JCCDR), and the Laboratory of Molecular Biology (CCS), the Hospital do Câncer A. C. Camargo, Fundação Antonio Prudente, São Paulo, Brazil; and the Laboratory of Cancer Genetics (AJGS), the Ludwig Institute for Cancer Research, São Paulo, Brazil.

Correspondence: Address correspondence and reprint requests to: Benedito Mauro Rossi, MD, PhD, Fundação Antonio Prudente, Hospital do Câncer A. C. Camargo, Departamento de Cirurgia Pélvica, Rua Prof. Antonio Prudente, 211, 01509-010, São Paulo, Brazil.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The aim of this study was to search for mutations in the human mutS homolog 2 (hMSH2) and human mutL homolog 1 (hMLH1) genes in 25 unrelated Brazilian kindreds with suspected hereditary nonpolyposis colorectal cancer (HNPCC).

Methods: The families were grouped according to the following clinical criteria: Amsterdam I or II; familial colorectal cancer (CRC); an early age of onset of CRC in the proband only; or with at least one or two relatives who had HNPCC-related cancers; CRC in the proband only. All patients were studied with direct sequencing.

Results: Ten mutations were detected (10 of 25 [40%]); of nine different mutations, seven were novel. The hMLH1 gene had a higher mutation detection rate than hMSH2 (8 of 25 [32%] vs. 2 of 25 [8%]). Only 3 of these 10 families fulfilled the Amsterdam criteria. Two different polymorphisms were detected in the hMLH1 gene and four in the hMSH2 gene.

Conclusions: The hMLH1 gene had a higher mutation detection rate than hMSH2. The physician who deals with CRC must take into consideration the heredity issue with patients who present with an early age of onset or a familial history of CRC- or HNPCC-related cancers, including gastric cancer, even if they do not fulfill the former Amsterdam criteria.

Key Words: HNPCC • Lynch syndrome • Hereditary colorectal cancer • Mutation detection • hMSH2 • hMLH1


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, is an autosomal-dominant cancer syndrome with high penetrance (80% to 85%). It is characterized by an early age of onset of colorectal carcinomas (CRCs); proximal predominance of colon cancer; multiple synchronous or metachronous CRCs; and tendency to have multiple primary tumors, including endometrial carcinoma, small-bowel carcinoma, and transitional-cell carcinoma of the ureter and the renal pelvis. Other less common extracolonic cancers can occur, such as carcinoma of the stomach and ovary and hepatobiliary carcinoma.1–6

HNPCC is a common cancer predisposition syndrome and accounts for approximately 7% of all CRCs.7 However, Salovaara et al.8 have suggested that on the basis of a population study, this incidence should be lower (2%). The diagnosis is basically clinical, made by the characteristic family history. In 1991, the Amsterdam clinical criteria were proposed by the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer9 in an attempt to provide uniformity in the clinical diagnosis of HNPCC in collaborative studies:

  1. Three or more relatives with histologically verified CRC, one of whom is a first-degree relative of the other two.
  2. CRC involving at least two successive generations.
  3. One or more CRC cases diagnosed before the age of 50 years.
  4. Exclude familial adenomatous polyposis.

These were named Amsterdam criteria I. The International Collaborative Group former criteria were widely accepted; however, they were also criticized, mainly for excluding extracolonic cancers. In 1999, the same group proposed to add to the first criteria the following extracolonic tumors:

  1. Adenocarcinoma of the endometrium.
  2. Small-bowel carcinoma.
  3. Transitional-cell carcinoma of the renal pelvis or ureter.

These were named Amsterdam criteria II. Adenocarcinomas of the stomach and ovary were excluded because of their low incidence.10

Occasionally, a family does not have a history of hereditary CRC, or a family history is not available. In such cases, if the proband has a suspect tumor presentation (right sided, young age, synchronous or metachronous CRC, or extracolonic tumors related to HNPCC), a de novo germ-line mutation should be considered.11,12

The only known cause of HNPCC is the occurrence of an inherited mutation in one of the following mismatch-repair (MMR) genes: hMSH2 (human mutS homolog 2), in chromosome band 2p1613,14; hMLH1 (human mutL homolog 1), in 3p2115,16; hPMS1 (human postmeiotic segregation 1), in 2q31 to 2q3317; hPMS2 (human postmeiotic homolog 2), in 7p2217; and hMSH6 (human mutS homolog 6; also known as GTBP), in 2p16, within .5 megabases of hMSH2.18,19 Among these genes, hMSH2 and hMLH1 account for the majority of mutations currently known in HNPCC families worldwide, reaching 90% in some series.20 The involvement of the other DNA MMR genes is rare.21 However, some familial clusterings of CRC- and HNPCC-related tumors do not reveal mutations in these genes. A recent study suggested that germ-line mutations in the exonuclease 1 gene may be associated with atypical HNPCC families.22

An important point to be considered is that most of the mutation analysis approaches are polymerase chain reaction (PCR) based and do not allow the detection of genomic deletions or gross rearrangements. Although the mutation spectrum at the MMR genes is mainly composed by single nucleotide insertions, deletions, or substitutions, there are as many as 32% missed exon deletions in hMSH2 if Southern blot is not performed.23

Microsatellite instability (MSI), the widespread and frequent mutation of short repetitive regions within the genome, occurs in 85% to 95% of HNPCC tumors.24 Mainly since 1997, MSI and clinical phenotypes have been proposed to be used for the identification of potential HNPCC families, even when the Amsterdam criteria I or II are not fulfilled.12,25 The aim of this study was to identify mutations in hMSH2 and hMLH1 in 25 Brazilian kindreds with suspected HNPCC, by means of direct sequencing of the coding regions of the hMLH1 and hMSH2 genes.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Twenty-five different Brazilian families with suspected hereditary CRC were consecutively enrolled from January 1995 to July 1999 at the Hospital do Câncer A. C. Camargo, Pelvic Surgery Department, and grouped according to the following criteria:

  1. Five families that fulfilled the former Amsterdam criteria I or II.
  2. One family that fulfilled the former Amsterdam criteria II.
  3. Seven families were classified as having familial CRC without fulfilling Amsterdam criteria I or II. Although the Amsterdam criteria were not fulfilled, the patients had at least one relative with CRC or with an HNPCC-related cancer.
  4. Eight families were included because the probands presented at an early age (<50 years), although they did not have affected relatives with CRC- or HNPCC-related cancers.
  5. Three families were included because the probands presented at an early age (<50 years) and had at least one relative with CRC or with an HNPCC-related cancer, without fulfilling Amsterdam criteria I or II.
  6. One family was included because the proband presented with rectal cancer, multiple metachronous colon adenomas, and renal cell carcinoma, without affected relatives.

All kindreds that did not fulfill the Amsterdam criteria had at least three generations studied and were huge, a common fact in Brazilian families. All families were registered at the Department of Pelvic Surgery Familial CRC Registry. Genetic counseling was given to all families. The study was approved by the Hospital Ethics Committee. Blood samples were drawn for genetic tests only after signed informed consent was obtained.

All patients were studied by PCR amplification and sequencing of the complete hMSH2 and hMLH1 MMR genes. MSI was not considered as a standard preliminary test in this study. Family enrollment began in 1995; however, only in 1998, after the Bethesda criteria,26 were MSI tests indicated before sequencing for families suspected of having HNPCC.

Genetic Sequencing
DNA was obtained from peripheral blood leukocytes by phenol-chloroform extraction. PCR amplification of each exon of the hMSH2 and hMLH1 genes was undertaken and included all splice donor and acceptor sites (exon/intron boundaries). Sequences, reaction conditions, and specific primers are available from the authors on request.

The PCR products were directly sequenced on an ABI 377TM sequencer (Perkin Elmer/Applied Biosystems, Foster City, CA) by using Big DyeTM terminator chemistry on both strands with reagents obtained from Perkin Elmer/Applied Biosystems, according to the manufacturer’s specifications.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Table 1 shows the main characteristics of each family, including age at diagnosis, sex, synchronous or metachronous tumors, family history, staging, and the sequencing results of the hMLH1 and hMSH2 MMR genes.


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  		TABLE 1. TABLE 1. hMLH1 and hMSH2 mutations in Brazilian families with suspected HNPCC
 
Ten mutations were detected among the 25 families examined, with a detection rate of 40%. Of nine different mutations, seven were novel. Families 7 and 8 presented the same missense mutation in hMLH1, exon 19, codon 718, with a change at nucleotide 2152 (C -> T, His -> Tyr). Two other novel missense mutations in hMLH1 were found in families 1 and 4: exon 11, codon 338, with a change at nucleotide 1013 (A -> G, Asn -> Ser); and exon 16, codon 603, with a change at nucleotide 1808 (C -> G, Pro -> Arg), respectively. The missense mutation detected in family 5 has been previously described (Table 1). It consists of a change at nucleotide 1853 (A -> C, Lys -> Thr), codon 618, exon 16, also in the hMLH1 gene. A novel nonsense mutation of the hMLH1 was found in proband 6, who belonged to the only family that fulfilled the Amsterdam criteria II, in exon 18, codon 666, with a change at nucleotide 1998 (G -> A, Trp -> Stop; Fig. 1). Family 2 presented a novel in-frame mutation of the hMLH1 gene, exon 13, codons 500 and 501 (deletion of TCA at nucleotides 1499–1501). Another new hMLH1 mutation was found in intron 13, generating a splice defect (G -> T at nucleotide 1558 + 1). Two new hMSH2 protein-truncating mutations were found in families 9 and 10: exon 7, codon 417 (deletion of G at nucleotide 1249), causing a stop at codon 437; and exon 11, codon 556 (insertion of A at nucleotide 1667), resulting in a stop at codon 561, respectively. Both families fulfilled Amsterdam criteria I. The mutations found were distributed throughout the coding regions of the hMLH1 and hMSH2 genes.



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  		FIG. 1. Heredogram of an Amsterdam II family presenting a nonsense mutation in the hMLH1 gene: exon 18, codon 666, G -> A at nucleotide 1998 (Trp -> Stop).

 
The genetic characteristics of the CRC kindreds fulfilling the different criteria were analyzed, and some noteworthy points emerged. For example, among the 10 germ-line mutations (nine different) found in the 25 families, a higher frequency of mutations was detected in hMSH1 than in hMSH2 (8 of 25 [32%] vs. 2 of 25 [8%], respectively); among the 10 kindreds with germ-line mutations detected, only three (30%) fulfilled the Amsterdam criteria I or II. No mutations were detected in the hMLH1 or hMSH2 MMR genes in the other three families that fulfilled the Amsterdam criteria I. Furthermore, we found no significant difference between the mean age of the CRC diagnosis in the groups with and without detected mutations (45.7 vs. 46.5 years). Among the group with detected mutations, 50% of the probands were diagnosed with rectal cancer, all of them with an hMLH1 mutation, and 50% were diagnosed with a right-sided colon tumor. Among the group without a detected mutation, the tumor was located in the rectum in six cases, in the left colon in five cases, and in the right colon in four cases.

Table 2 shows the polymorphisms identified. Two polymorphisms were detected in hMLH1; one of them was found in seven different probands (7 of 25 [28%]). Four different alterations were detected in hMSH2 (frequency of 1 in 25 each).


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  		TABLE 2. TABLE 2. hMLH1 and hMSH2 polymorphisms in Brazilian families with suspected HNPCC
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In Brazil, in contrast to Europe, it is very difficult to determine the exact origin of individual families. There is heterogeneous racial miscegenation because of Portuguese Italian migration, as well as blacks from Africa and native Brazilian Indians. There are no previous studies of mutations of the hMLH1 and hMSH2 genes in Brazil. This work, therefore, represents the first record of such mutations in Brazilian patients with HNPCC.

Twenty-five unrelated families were studied, and germ-line mutations were detected in 10 cases (40%)—8 mutations were found in hMLH1 (4 missense [1 in 2 distinct families], 1 in-frame, 1 splice defect [intron], and 1 nonsense) and two in hMSH2 (2 frameshifts). Lynch et al.33 identified germ-line mutations in hMLH1 or hMSH2 in 18 of 56 families (32.1%) clinically characterized as having HNPCC; this is slightly less than the proportion in this study. Pensotti et al.34 identified germ-line mutations in hMLH1 or hMSH2 in 8 of 16 (50%) families of Italian descent with a clinical diagnosis of HNPCC.

Among the nine mutations detected in the 10 families in this study, two have been previously described (families 3 and 5): one by Han et al.27 and the other in Italy (International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer, unpublished data, date unavailable). However, we detected the remaining seven for the first time, although we already described the mutation found in family 9.28 Although families 7 and 8 were unrelated, they presented the same missense alteration (His -> Tyr, at nucleotide 2152; hMLH1). Indeed, three of the new missense mutations (in families 1, 4, 7, and 8) should be studied in other family members to determine whether they segregate with cancer, because missense mutations cannot be distinguished with precision from rare polymorphisms. Furthermore, the frequency of occurrence must be evaluated in normal Brazilian individuals. The fourth missense mutation has been previously described by Han et al.27

With regard to the proportion of mutations in hMLH1 and hMSH2, Han et al.35 reported similar results in Korean families. Of 13 mutations identified, only one was in hMSH2, whereas 12 were in hMLH1. Among Japanese families, however, Bai et al.12 showed an inverse proportion, with a greater number of germ-line mutations in hMSH2 than in hMLH1 (11 vs. 1, respectively). All the families studied by Bai et al. fulfilled the Amsterdam criteria or the Japanese criteria, and mutations were found in 12 of 37 (32.4%)—close to the results of this study. Peltomäki and Vasen24 also found a greater number of mutations in hMLH1, as well as a higher proportion of frameshift mutations in hMSH2. In this study, both mutations found in hMSH2 resulted in protein truncation.

In the study described here, only 20% (5 of 25) of the families fulfilled the Amsterdam criteria I9; of these, 40% (2 of 5) showed germ-line mutations, both in hMSH2 (families 9 and 10). Only family 6 was characterized as Amsterdam II,10 with a germ-line mutation found in hMLH1 (nonsense). Seven of the 10 mutations (70%) found were in patients from families that did not fulfill the Amsterdam criteria I or II. These findings indicate that physicians attending patients who have CRC should not restrict themselves to the Amsterdam criteria when considering a heredity diagnosis. However, we also insist on the clinical characteristics of HNPCC that follow the Amsterdam criteria I or II. Therefore, if there is risk of a hereditary diagnosis in a family, but the family does not fulfill the Amsterdam criteria, the physician must be cautious when diagnosing heredity clinically until the molecular confirmation of the syndrome through genetic tests to identify the specific germ-line mutation. In 1997, the Bethesda criteria26 were published, not to represent a clinical diagnosis, but rather to indicate those individuals eligible for genetic testing (MSI) because of the risk of HNPCC.

Of the eight probands indicated for genetic testing because of early CRC only, three (37.5%) presented mutations in hMLH1 or hMSH2, a result similar to what was obtained in patients of families that fulfilled the Amsterdam criteria I or II. Therefore, a young age at CRC diagnosis must alert the physician, mainly in small families or those difficult to characterize, that HNPCC is a possibility.34 Our results did not show meaningful differences in the age of diagnosis between the group with detected germ-line mutations and that without (45.7 vs. 46.5 years). Fitzgibbons et al.36 found that the mean age of the CRC diagnosis in patients with HNPCC was 45.6 years. We cannot rule out the possibility of de novo germ-line mutations—i.e., the first mutation occurrence within a family—which could explain isolated cases of CRC in young patients, with no previous occurrence in the family but with positive genetic tests. In such isolated cases with identified germ-line mutations, the same mutation should be searched for in the parents (if negative, de novo mutation is confirmed) and in the family members for the diagnosis of carriers.

Of three probands with early CRC, but without a typical HNPCC family history, mutations were found in one (33.3%), which reinforces the possibility of heredity in cases of early CRC. Likewise, of seven probands whose family background did not fulfill the Amsterdam criteria and whose CRC diagnosis was after 50 years of age, three (42.9%) showed mutations in hMLH1 or hMSH2. Even in these situations, HNPCC should be taken into consideration.

Although the diagnosis of gastric cancer is not in the Amsterdam criteria, it is part of the syndrome. Of the 10 families that had germ-line mutations, two (20%) presented with individuals with gastric tumors. One family presented with an in-frame–type deletion, and the other presented with a missense mutation.

Rectal cancer was diagnosed in 5 of 10 probands (50%) who had germ-line mutations, all of them in hMLH1 (5 of 8 [62.5%] of the hMLH1 mutations). There is no precedent for this finding in the literature, so it could be a population feature, to be confirmed through gene segregation with the rectal tumor in the other members of the families that have this disease. The other five patients with detected germ-line mutations presented with right-sided colon tumors (5 of 10 [50%]).

Of 10 patients with germ-line mutations, six presented with CRC stage I or II (T1–3N0M0), and only one presented with stage III (N1–2).37 In three cases, staging could not be defined because of previous surgeries. Early CRC stage could be associated with HNPCC and carries the better prognosis.

One way of screening CRC patients who might have HNPCC is to research the MSI in the tumor tissue,38 on the basis of the Bethesda criteria.26 Most cases of CRC with germ-line mutations present MSI (85% to 95%).25 However, MSI also occurs in patients who have sporadic CRC. Nevertheless, the use of simple approaches, such as testing for mutations, in patients who have suspected HNPCC (e.g., MSI-BAT 26) is clearly now indicated as a standard procedure. Patients with MSI should be considered as candidates for mutation detection. If a patient with CRC belongs to a typical HNPCC family according to the Amsterdam criteria, the sequencing of hMLH1 and hMSH2 should be considered as a first option for the molecular diagnosis. In those cases, when hMLH1 and hMSH2 are normal, mutation research into hMSH6 (also called GTBP) must be taken into consideration.20 Some mutations in hMSH6 are related to cancer accumulation (CRC, gastric, endometrial, and pancreatic).39–41

The polymorphism I1e -> Val, exon 8, codon 219 of hMLH1 is reported with a frequency of 13% to 34%.29,30 We found 28% (7 of 25) of our samples with this alteration, showing that it is common in Brazilian families. A polymorphism in hMSH1 intron 13 was previously described by Tannergard et al.,30 but we require a population study to define its frequency in Brazil. In the hMSH2 gene, four polymorphisms were found—1 described by Borresen et al.,32 another by Liu et al.,31 and two new ones—each showing an incidence of 1 in 25 in our samples.

Genetic tests are only one part of the process of our management of patients and families with hereditary CRC. After clinical suspicion of hereditary CRC, the patient is questioned as to a detailed family history, preferably together with other older family members, who may provide supplementary information about distant members of the family or about those who may have already died. As many data as possible are collected, including names, dates of birth and death, causes of death, associated diseases, and surgeries. In this first consultation, the pedigree background is established and recorded in the Institutional Data Bank. After this consultation, genetic testing consisting of MSI or the sequencing of hMLH1 and hMSH2 can be indicated after written, informed consent. After the results of the tests are released, they are handed to the patient confidentially, and a process of family orientation, clinical attendance, and psychological support is provided. Lynch et al.33 and other authors42,43 propose similar support for these families. It is important to call to attention that the risk of cancer predisposition is based on clinical data and family history, and the absence of a mutation detected in a family clinically featured as HNPCC by the Amsterdam criteria does not reduce or eliminate the risk of having the disease. However, the germ-line mutation detection helps the support of the carriers.

In summary, we found a greater prevalence of germ-line mutations detected in the hMLH1 gene than in hMSH2 in Brazilian families. In addition to the Amsterdam criteria I and II, which define the clinical diagnosis of HNPCC, the physician in Brazil should also consider HNPCC when a patient is young and has CRC or when a patient has CRC and a family history of HNPCC, even if it is nontypical, with specific attention being given to gastric tumors.


   Acknowledgments
 
Supported by the Federal Research Council and the São Paulo State Research Foundation.

Received for publication June 18, 2001. Accepted for publication April 10, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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