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Biochemical Society Transactions (2005) Volume 33, part 4
Phenotype associated with recessively inherited
mutations in DNA mismatch repair (MMR) genes
M. de Vos*, B. Hayward*, D.T. Bonthron* and E. Sheridan†1
*Department of Molecular Medicine, University of Leeds, Leeds LS2 9JT, U.K., and †Department of Clinical Genetics, St James’s University Hospital,
Leeds LS9 7TF, U.K.
Abstract
The MMR (DNA mismatch repair) system helps to maintain the integrity of the genome. This involves
eliminating base–base mismatches and insertion/deletion loops, which can lead to microsatellite instability,
as seen in tumour cells. Hereditary non-polyposis colon cancer is the result of dominant mutations in MMR
genes, such as MLH1, MSH2 and MSH6. More recently there have been case reports of biallelic mutations in
the MMR genes MLH1, MSH2 and PMS2. These result in a distinct autosomal recessive cancer predisposition
syndrome. The syndrome is characterized by childhood haematological malignancies, brain tumours and
the presence of café au lait patches. Second primaries occur frequently in this condition, and survival into
adulthood is rare.
The integrity of the genome is maintained by a variety of
sophisticated mechanisms which repair damaged DNA. The
MMR (mismatch repair) system is one of the best characterized of these. The primary function of the MMR system is to
eliminate base–base mismatches and insertion/deletion loops,
which arise during DNA replication [1]. Insertion/deletion
loops classically result in the shortening or lengthening of
repetitive sequences in microsatellites. This is termed MSI
(microsatellite instability) and is seen in tumour cells, which
harbour biallelic MMR mutations.
MMR in humans depends on homologues of the bacterial
MutS and MutL proteins, these function as heterodimers. The
MutSα complex comprising a heterodimer of MSH2/MSH6
is the most abundant species, with lesser amounts of MSH2/
MSH3 (MutSβ) also being present. The MutS complex initiates DNA repair by mismatch recognition. Interaction between this recognition complex and downstream repair proteins is dependent upon MutL-like activity. An MLH1/PMS2
heterodimer (MutLα) is the major species providing MutLlike MMR activity in human cells [2].
Germline mutations in MLH1, MSH2 and MSH6 are
the major cause of HNPCC (hereditary non-polyposis colon
cancer), the commonest form of inherited colon cancer.
HNPCC is a dominantly inherited disorder with a high penetrance. As well as CRC (colorectal cancer), HNPCC patients
have an excess of extracolonic malignancies, principally endometrial and ovarian cancers in women, and, to a lesser extent,
other cancers such as renal, small bowel and ureter [3].
Key words: hereditary non-polyposis colon cancer (HNPCC), mismatch repair gene (MMR gene),
recessive inheritance, supratentorial primitive neuroectodermal tumour (SPNET).
Abbreviations used: CAL, café au lait patch; CML, chronic myeloid leukaemia; CRC, colorectal
cancer; HNPCC, hereditary non-polyposis colon cancer; MMR, mismatch repair; MSI, microsatellite
instability; NF-1, neurofibromatosis type 1; SPNET, supratentorial primitive neuroectodermal
tumour.
To whom correspondence should be addressed (email [email protected]).
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Recessive mutations in the PMS2 gene
Although PMS2 was originally described as a cause of classical
HNPCC [4], very few families with HNPCC due to PMS2
mutations have since been described. In fact the only clear
association has been with Turcot’s syndrome. This is a variant of HNPCC characterized by the presence of CRC and
brain tumours. We recently reported a consanguineous U.K.
family of Pakistani origin, in which two siblings developed
SPNET (supratentorial primitive neuroectodermal tumours)
and a further sibling developed a T-cell lymphoma. All three
also manifested CALs (café au lait patches). A homozygous
mutation C2482T in exon 14 of PMS2 was found in all
three affected individuals [5]. In a further case originally
reported with dominantly inherited Turcot’s syndrome [6],
we also identified a second mutation in exon 13 (2184delTC).
We have since identified another homozygous mutation in
two siblings affected by SPNET, also within a consanguineous U.K. family of Pakistani origin. Recessively inherited
mutations in PMS2 had been previously reported twice [7,8];
however, the association with SPNET had not been seen
before. SPNETs are very rare: there are less than 10 cases in the
U.K. yearly, so it is unlikely that this is a chance association.
Very little is known about molecular correlates of SPNET.
There had certainly been no previous evidence implicating
MMR genes in SPNET.
Combining the data from the families we have described
with those previously published, there is evidence of a characteristic phenotype. Haematological malignancies, particularly
of T-cell subtype and brain tumours, occur in childhood, with
survivors developing CRC in their teenage years (Table 1).
Apart from one member of our original family, those children
who survived their initial cancers have gone on to develop
second primaries. CMLs (chronic myeloid leukaemias) are
common, often leading to an initial diagnosis of NF-1 (neurofibromatosis type 1), although none of the cases would
The Molecular Biology of Colorectal Cancer
Table 1 Recessive mutations reported in MMR genes
ALL, acute lymphatic leukaemia; AML, acute myeloid leukaemia; NHL, non-Hodgkin’s lymphoma; PNET, primitive neuroectodermal tumour; wt, wildtype; i, first malignancy; ii, second malignancy; iii, third malignancy.
Gene
Tumour(s) seen in family members
MLH1
CML
MLH1
NHL
ALL
Breast cancer
MLH1
MLH1
MLH1
MLH1
NHL
AML
Glioma
Duodenal adenocarcinoma
CRC
Healthy boy
Age of onset (years)
1
3
2
36
2
6
4
11
10
6
R226X/R226X
[11]
S44F/A441T
[12]
G67W/G67W
[13]
Del exon 16/del exon 16
[14]
R687W/R687W
[15]
P648S/P648S
[16]
[17]
[18]
p.C1129 V1130 del insL
[19]
codon 407/codon 787
[7]
1169ins20/1169ins20
[20]
4
13
11
R134X/wt
[6]
7
15
13
E705K/wt
[9]
R802X/R802X
[5]
ALL
NHL
Glioblastoma
MSH6
Oligodendroglioma
CRC
i Oligodendroglioma
10
12
14
CRC
ii Neuroblastoma
18
13
i CRC
PNET
Endometrial cancer
14
21
23
Brain tumour
ii Astrocytoma
iii ALL
24
2
4
PMS2
i Glioblastoma
CRC
ii CRC
PMS2
Astrocytoma
NHL
CRC
PMS2
Reference
1662-1 splice acceptor/1662-1 splice acceptor
Del exon 1-6/exon3 del-1 153
MSH2
MSH2
PMS2
Recessive mutations
2
1
3
PMS2
actually fulfil the NIH (National Institutes of Health) consensus criteria for NF-1.
Importantly, the phenotype is only seen in sibships in these
families, and there is no evidence in any of these families for
a dominantly inherited HNPCC phenotype. In fact, there
is little evidence in the literature for a dominant phenotype
associated with mutations in PMS2. The only remaining case
with a reported dominant mutation is that of Miyaki et al.
[9]. They reported a boy with an astrocytoma at age 7 years, a
lymphoma at 15 and CRC at 16. A single mutation at codon
705 of the PMS2 gene was identified, inherited from the boy’s
unaffected mother. The phenotype is reminiscent of that seen
in recessive PMS2 families; its presence in his mother suggests
that another unidentified mutation in the PMS2 gene was
present in this case.
Recessive MMR gene mutations
Recessive mutations have now been reported in MLH1,
MSH2 and MSH6 (Table 1). A consistent phenotype asso-
ciated with recessive MMR mutations emerges. This is similar
to that seen with mutations in PMS2. Haematological malignancies and brain tumours in childhood, with CRC in adolescence or early adult life, occur frequently. The association
with SPNET has so far only been seen with PMS2 in patients
of Pakistani origin. In the case of MLH1, MSH2 and MSH6,
the recessive phenotype occurs in the context of a family
history consistent with HNPCC. In the PMS2 families, there
is no history of HNPCC. A further key distinction between
dominant HNPCC and those cases with recessive MMR
mutations concerns MSI. This is observed in the tumour
tissue of patients with dominant MMR mutations. However,
in patients with recessive MMR mutations, germline MSI in
normal tissue is also observed at high frequency (Table 1).
Structure of the PMS2 gene
The existence of pseudogenes corresponding to the first five
exons of PMS2 has long been recognized. In the analysis
of our original family, we demonstrated homozygosity by
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descent at the PMS2 locus in the affected children. We were
therefore surprised when we identified heterozygous changes
in exons 3, 4, 5, 13 and 14. These were consistently present in
both affected and unaffected individuals. A detailed search of
the genome revealed 14 pseudogenes, many corresponding to
exons 1–5 and previously described [21]. However, in addition, we identified a novel 100 kb genomic duplicon, containing copies of exons 9 and 11–15. All of these pseudogenes
are located on chromosome 7. Mutations in PMS2 have been
reported only rarely; however, this could in part be owing
to the confounding effect of the pseudogenes. We have
published details of the reagents which distinguish gene from
pseudogene in our original manuscript [5].
Conclusions
Recessive mutations in MMR genes result in a phenotype
characterized by the development of haematological malignancies and brain tumours in childhood. Survivors have a
high risk of second primaries and often go on to develop
CRCs in adolesence or early adult life. The normal tissue of
these individuals show evidence of MSI.
Recessive mutations in PMS2 seem to be particularly common in the U.K. Pakistani population, where they are associated with a specific phenotype of SPNET. Their contribution to the overall incidence of childhood cancer in this
community remains unclear.
The genomic architecture of PMS2 is complex. Analysis
at this locus in the past has not taken this complexity into
account, so the precise role of this gene in carcinogenesis
remains poorly defined. Two reports document the occurrence of CRC in PMS heterozygotes [4,10]. In the case
of recessive mutations, a distinctive phenotype is becoming
apparent; however, there are no simple markers for the
disorder, which must be recognized by careful clinical history
and examination.
3 Peltomaki, P. and Vasen, H. (2004) Dis. Markers 20, 269–276
4 Nicolaides, N.C., Papadopoulos, N., Liu, B., Wei, Y.F., Carter, K.C., Ruben,
S.M., Rosen, C.A., Haseltine, W.A., Fleischmann, R.D. and Fraser, C.M.
(1994) Nature (London) 371, 75–80
5 De Vos, M., Hayward, B.E., Picton, S., Sheridan, E. and Bonthron, D.T.
(2004) Am. J. Hum. Genet. 74, 954–964
6 Hamilton, S.R., Liu, B., Parsons, R.E., Papadopoulos, N., Jen, J., Powell,
S.M., Krush, A.J., Berk, T., Cohen, Z. and Tetu, B. (1995) N. Engl. J. Med.
332, 839–847
7 De Rosa, M., Fasano, C., Panariello, L., Scarano, M.I., Belli, G., Iannelli, A.,
Ciciliano, F. and Izzo, P. (2000) Oncogene 19, 1719–1723
8 Wang, Q., Lasset, C., Desseigne, F., Frappaz, D., Bergeron, C., Navarro, C.,
Ruano, E. and Puisieux, A. (1999) Cancer Res. 59, 294–297
9 Miyaki, M., Konishi, M., Tanaka, K., Kikuchi-Yanoshita, R., Muraoka, M.,
Yasuno, M., Igari, T., Koike, M., Chiba, M. and Mori, T. (1997) Nat. Genet.
17, 271–272
10 Nakagawa, H., Lockman, J.C., Frankel, W.L., Hampel, H., Steenblock, K.,
Burgart, L.J., Thibodeau, S.N. and de la Chapelle, A. (2004) Cancer Res.
64, 4721–4727
11 Ricciardone, M.D., Ozcelik, T., Cevher, B., Ozdag, H., Tuncer, M.,
Gurgey, A., Uzunalimoglu, O., Cetinkaya, H., Tanyeli, A., Erken, E. and
Ozturk, M. (1999) Cancer Res. 59, 290–293
12 Hackman, P., Tannergard, P., Osei-Mensa, S., Chen, J., Kane, M.F.,
Kolodner, R., Lambert, B., Hellgren, D. and Lindblom, A. (1997)
Nat. Genet. 17, 135–136
13 Wang, Q., Montmain, G., Ruano, E., Upadhyaya, M., Dudley, S., Liskay,
R.M., Thibodeau, S.N. and Puisieux, A. (2003) Hum. Genet. 112,
117–123
14 Vilkki, S., Tsao, J.L., Loukola, A., Poyhonen, M., Vierimaa, O., Herva, R.,
Aaltonen, L.A. and Shibata, D. (2001) Cancer Res. 61,
4541–4544
15 Gallinger, S., Aronson, M., Shayan, K., Ratcliffe, E.M., Gerstle, J.T., Parkin,
P.C., Rothenmund, H., Croitoru, M., Baumann, E., Durie, P.R. et al. (2004)
Gastroenterology 126, 576–585
16 Raevaara, T.E., Gerdes, A.M., Lonnqvist, K.E., Tybjaerg-Hansen, A.,
Abdel-Rahman, W.M., Kariola, R., Peltomaki, P. and Nystrom-Lahti, M.
(2004) Genes Chromosomes Cancer 40, 261–265
17 Whiteside, D., McLeod, R., Graham, G., Steckley, J.L., Booth, K.,
Somerville, M.J. and Andrew, S.E. (2002) Cancer Res. 62, 359–362
18 Bougeard, G., Charbonnier, F., Moerman, A., Martin, C., Ruchoux,
M.M., Drouot, N. and Frebourg, T. (2003) Am. J. Hum. Genet. 72,
213–216
19 Menko, F.H., Kaspers, G.L., Meijer, G.A., Claes, K., Van Hagen, J.M. and
Gille, J.J. (2004) Fam. Cancer 3, 123–127
20 Trimbath, J.D., Petersen, G.M., Erdman, S.H., Ferre, M., Luce, M.C. and
and Giardiello, F.M. (2001) Fam. Cancer 1, 101–105
21 Nicolaides, N.C., Carter, K.C., Shell, B.K., Papadopoulos, N. and
Kinzler, K.W. (1995) Genomics 30, 195–206
References
1 Peltomaki, P. (2001) Hum. Mol. Genet. 10, 735–740
2 Harfe, B.D. and Jinks-Robertson, S. (2000) Annu. Rev. Genet. 34, 359–399
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Received 22 March 2005