* 172411

PHOSPHOLIPASE A2, GROUP IIA; PLA2G2A


Alternative titles; symbols

PHOSPHOLIPASE A2, SYNOVIAL; PLA2S; PLAS1
PHOSPHOLIPASE A2 POLYPEPTIDE B; PLA2B
MODIFIER OF MIN-1, MOUSE, HOMOLOG OF; MOM1


HGNC Approved Gene Symbol: PLA2G2A

Cytogenetic location: 1p36.13     Genomic coordinates (GRCh38): 1:19,975,431-19,980,434 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p36.13 {?Colorectal cancer, susceptibility to} 114500 AD, SMu 3

TEXT

Description

Phospholipases A2 (PLA2s) hydrolyze the sn-2 fatty acid acyl ester bond of phosphoglycerides, releasing free fatty acids and lysophospholipids. They play an important role in a variety of cellular processes, including digestion and metabolism of phospholipids, as well as production of precursors for inflammatory reactions. PLA2G2A belongs to PLA2 group II, which consists of extracellular enzymes with low molecular masses that require calcium ions for catalysis (Dennis, 1994).


Cloning and Expression

Elevated levels of synovial fluid and plasma phospholipase A2 correlate with the activity of inflammatory arthritis. Seilhamer et al. (1989) characterized multiple forms of phospholipase A2 in arthritic synovial fluid.

By N-terminal sequencing of peptides obtained from human synovial fluid, followed by screening a genomic library and a cDNA library prepared from peritoneal exudate cells, Seilhamer et al. (1989) obtained a full-length PLA2G2A cDNA. The deduced protein contains a 20-amino acid signal sequence, followed by a 124-amino acid mature peptide that has a calculated molecular mass of about 14 kD. The protein has characteristics of the type II class of PLA2s, including conserved catalytic residues and a Ca(2+)-binding loop. Northern blot analysis detected a 0.8-kb transcript in inflamed human synovial tissue and in peritoneal exudate cells from a peritonitis patient, but not in 2 activated human promyelocytic cell lines. Expression of Pla2g2a was not detected in pig jejunum, pancreas, and spleen, or in rat liver.

Johnson et al. (1990) purified and cloned human PLA2G2A, which encodes the major form of PLA2 expressed in rheumatoid arthritis synovial fluid. PLA2G2A is a member of the type II PLA2 family, which includes the inflammatory PLA2 found in the venom of the viperid class of snakes. Johnson et al. (1990) showed that there is diversity of phospholipase A2 in synovial fluid that is apparently related to alternative splicing of the PLA2G2A gene.


Gene Family

PLA2s constitute a diverse family of enzymes with respect to sequence, function, localization, and divalent cation requirements. In a review, Dennis (1994) stated that PLA2s can be classified into at least 5 groups based on their size, structure, and need for divalent cations. Groups I, II, and III all contain so-called secreted forms of PLA2, which are extracellular enzymes that have a low molecular masses and require calcium ions for catalysis. Groups IV and V contain cytosolic forms of PLA2 that have a high molecular masses and require calcium ions only in the case of group IV PLA2. PLA2G2A belongs to PLA2 group II.


Gene Function

Seilhamer et al. (1989) demonstrated that simian kidney cells expressing human PLA2 secreted PLA2 activity to the culture medium.

A role for PLA2G2A in the pathogenesis of ulcerative colitis (see 266600) was postulated by Haapamaki et al. (1997), who demonstrated expression of the PLA2G2A gene in metaplastic Paneth cells and columnar epithelial cells in inflamed colonic mucosa from patients with ulcerative colitis. No expression was detected in other tissues from the same patients or, by Northern blot analysis, in colonic biopsies from disease-free controls. Haapamaki et al. (1997) hypothesized that intraluminal secretion of PLA2G2A during the active phase of ulcerative colitis is a host defense mechanism.

Leung et al. (2002) analyzed gene expression patterns in human gastric cancers by using cDNA microarrays representing approximately 30,300 genes. Expression of PLA2G2A was significantly correlated with patient survival. The observation was confirmed in an independent set of patient samples by using quantitative RT-PCR. Beyond its potential diagnostic and prognostic significance, this result suggests the possibility that the activity of PLA2G2A may suppress progression or metastasis of human gastric cancer.


Gene Structure

Seilhamer et al. (1989) determined that the PLA2G2A gene contains 5 exons and spans 4.6 kb. The upstream region contains a TATA-like sequence and a CCAAT box.


Mapping

Masharani et al. (1988) described RFLPs of a gene homologous to the pancreatic PLA2 gene (PLA2G1B; 172410). Seilhamer et al. (1988, 1989) assigned this gene, symbolized PLA2L by them, to chromosome 1 by hybridization to DNA from human-rodent hybrids. Johnson et al. (1990) mapped the PLA2G2A gene to chromosome 1p35.

In a large familial adenomatous polyposis (FAP; 175100) kindred in which patients harbored the same germline mutation but showed markedly different disease characteristics, Dobbie et al. (1997) investigated the region of human chromosome 1p36-p35 that is homologous to the region of murine chromosome 4 containing the Mom1 gene (see ANIMAL MODEL). They looked for linkage between each of 14 microsatellite markers and the development of extracolonic symptoms in polyposis coli patients. Depending on the mode of inheritance of the modifier locus, a maximum lod score was observed for markers D1S211 and D1S197, reaching 2.08 and 1.77, respectively. The observed values obtained within a large FAP family were considered supportive of a phenotype-modifying locus within this chromosomal region.


Molecular Genetics

To test the hypothesis of the correlation between PLA2G2A gene alterations and human tumor development of the sort demonstrated in the mouse model of FAP (see ANIMAL MODEL), Nimmrich et al. (1997) screened 14 patients with FAP and 20 patients with sporadic colorectal cancer (114500) for germline and somatic PLA2G2A gene mutations. None of the individuals with FAP showed PLA2G2A germline alterations. However, a heterozygous germline mutation (172411.0001) was observed in 1 patient with colorectal cancer; the wildtype allele was somatically lost in the tumor of this patient.


Animal Model

Modifier of Min-1 Locus

Moser et al. (1990) identified a dominant, fully penetrant mouse mutation named Min (multiple intestinal neoplasia) that causes a phenotype closely resembling familial adenomatous polyposis (FAP; 175100). Heterozygotes for the Min mutation developed numerous intestinal and colonic adenomas similar in morphology to the adenomas seen in FAP. If left untreated, the adenomas eventually become locally invasive (Moser et al., 1992). In addition, about 10% of Min/+ females on a hybrid background develop spontaneous mammary adenoacanthomas or adenocarcinomas (Moser et al., 1993). Homozygotes for Min die in utero. The Min mice carry a nonsense mutation in the mouse homolog of the FAP gene (Su et al., 1992). In the laboratory of William Dove at the University of Wisconsin, where the Min mutation was discovered and characterized, it was noted that the number of intestinal tumors in Min/+ mice was strongly affected by genetic background: C57BL/6J-Min/+ mice had an average of 29 tumors, whereas their Min/+ F1 progeny with AKR mice showed an average of only 6 tumors. This finding suggested that the AKR strain carries alleles that act in a dominant fashion to modify the tumorigenic effect of Min. Dietrich et al. (1993) mapped the postulated modifying gene, called Mom1 (modifier of Min-1), to the distal portion of mouse chromosome 4. Allelic variation in Mom1 appeared to control about 50% of the genetic variation in tumor number in 2 different intraspecific backcrosses. A cumulative lod score exceeding 14 supported the mapping. Mom1 was found to lie in a region of synteny conservation with human chromosome 1p36-p35, a region of frequent somatic loss of heterozygosity in a variety of human tumors, including colon tumors.

MacPhee et al. (1995) identified a candidate gene for Mom1 in the mouse. The gene for secretory type II phospholipase A2 (Pla2s) was shown to map to the same region as Mom1 and displayed 100% concordance between allele type and tumor susceptibility. Expression and sequence analysis revealed that Mom1-susceptible strains are most likely null for Pla2s activity. MacPhee et al. (1995) interpreted the results as indicating that Pla2s acts as a novel modifier of polyp number by altering the cellular microenvironment within the intestinal crypt. The homologous gene in the human, PLA2G2A, maps to 1p35 in a region of homology to distal mouse chromosome 4. The authors stated that it is unclear how loss of PLA2G2A in tumor cells would contribute to neoplasia in the human. One possibility is that PLA2G2A involvement is reflected by the variable numbers of adenomas identified among FAP family members inheriting the same mutation. The variation in tumor burden could be attributable to the segregation of different PLA2G2A alleles. Population surveys would be useful for determining the extent of PLA2G2A allelic variation, as well as for identifying individuals at risk for developing intestinal cancer. The identification of mouse Pla2s as a candidate for a major modifier of intestinal polyp formation may provide a missing link between high fat diets and increased incidence of colon cancer.

Cormier et al. (1997) provided further evidence on the role of PLA2G2A in resistance to intestinal tumorigenesis. They reported that a cosmid transgene overexpressing Pla2g2a in mice caused a reduction in tumor multiplicity and size, comparable to that conferred by a single copy of the resistance allele of Mom1. Thus, they concluded that this secretory phospholipase can provide active tumor resistance. The association of Pla2g2a with Mom1 thus withstood a strong functional test. The work probably represents the successful identification of a polymorphic quantitative trait locus (QTL) in mammals.

Dragani and Manenti (1997) reviewed other work in rodents defining counteractive cancer susceptibility and cancer resistance genes. This phenomenon is observed in mouse models of lung cancer, where the tumor-promoting effect of the Pas1 locus is downregulated by the presence of the Par resistance loci. In rats, tumors presumed to arise as a consequence of the hepatocarcinogen sensitivity locus, Hcs, are discouraged from growing by coincident presence of resistance (Hcr) loci.

Nadeau (2001) reviewed modifier genes in mice and humans and pointed out that the classic paper of Dietrich et al. (1993) identified a pharmacologically relevant pathway in humans.

The Mom1 locus was the first locus mapped as a modifier of a specific enhancer-inducing mutation, i.e., a modifier of the germline APC gene mutation (see 611731), which induces intestinal tumorigenesis (Dietrich et al., 1993). Dragani (2003) reviewed the progress in the following 10 years, during which more than 100 cancer modifiers had been mapped and 4 strong candidate genes had been identified, 1 of them being PLA2G2A.


ALLELIC VARIANTS ( 1 Selected Example):

.0001 COLORECTAL CANCER

PLA2G2A, 2-BP DEL, NT1119
  
RCV000014605

In the blood sample and the normal colorectal tissue of an 80-year-old female patient with colorectal cancer (114500), Nimmrich et al. (1997) identified a heterozygous 2-bp deletion at genomic position 1119 (codon 48) in exon 3 of the PLA2G2A gene. Assuming normal splicing of the gene, this frameshift deletion was predicted to result in a premature stop at codon 67 in exon 4. Somatic loss of the wildtype PLA2G2A sequence was demonstrated in the tumor of the patient. The tumor was diagnosed as being a late metastasizing carcinoma carrying a heterozygous mutation in p53 (191170) and a somatic monoallelic loss of the DCC gene (120470). The PLA2G2A germline mutation had not been transmitted to the normal 58-year-old son.


See Also:

REFERENCES

  1. Cormier, R. T., Hong, K. H., Halberg, R. B., Hawkins, T. L., Richardson, P., Mulherkar, R., Dove, W. F., Lander, E. S. Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis. Nature Genet. 17: 88-91, 1997. [PubMed: 9288104, related citations] [Full Text]

  2. Dennis, E. A. Diversity of group types, regulation, and function of phospholipase A2. J. Biol. Chem. 269: 13057-13060, 1994. [PubMed: 8175726, related citations]

  3. Dietrich, W. F., Lander, E. S., Smith, J. S., Moser, A. R., Gould, K. A., Luongo, C., Borenstein, N., Dove, W. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75: 631-639, 1993. [PubMed: 8242739, related citations] [Full Text]

  4. Dobbie, Z., Heinimann, K., Bishop, D. T., Muller, H., Scott, R. J. Identification of a modifier gene locus on chromosome 1p35-36 in familial adenomatous polyposis. Hum. Genet. 99: 653-657, 1997. [PubMed: 9150735, related citations] [Full Text]

  5. Dragani, T. A. 10 Years of mouse cancer modifier loci: human relevance. Cancer Res. 63: 3011-3018, 2003. [PubMed: 12810618, related citations]

  6. Dragani, T. A., Manenti, G. Mom1 leads the pack. Nature Genet. 17: 7-8, 1997. [PubMed: 9312327, related citations] [Full Text]

  7. Haapamaki, M. M., Gronroos, J. M., Nurmi, H., Alanen, K., Kallajoki, M., Nevalainen, T. J. Gene expression of group II phospholipase A2 in intestine in ulcerative colitis. Gut 40: 95-101, 1997. [PubMed: 9155583, related citations] [Full Text]

  8. Johnson, L. K., Frank, S., Vades, P., Pruzanski, W., Lusis, A. J., Seilhamer, J. J. Localization and evolution of two human phospholipase A2 genes and two related genetic elements.In: Wong, P. Y.-K.; Dennis, E. A. : Phospholipase A2. New York: Plenum Press (pub.) 1990. Pp. 17-34.

  9. Johnson, L. K., Seilhamer, J. J., Frank, S., Lusis, A., Vadas, P., Pruzanski, W. Synovial fluid phospholipase A(2): chromosomal co-localization with homologous genes may provide disease-related PLA(2) diversity. (Abstract) Arthritis Rheum. 33 (suppl.): S79, 1990.

  10. Leung, S. Y., Chen, X., Chu, K. M., Yuen, S. T., Mathy, J., Ji, J., Chan, A. S. Y., Li, R., Law, S., Troyanskaya, O. G., Tu, I.-P., Wong, J., So, S., Botstein, D., Brown, P. O. Phospholipase A2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis. Proc. Nat. Acad. Sci. 99: 16203-16208, 2002. [PubMed: 12456890, images, related citations] [Full Text]

  11. MacPhee, M., Chepenik, K. P., Liddell, R. A., Nelson, K. K., Siracusa, L. D., Buchberg, A. M. The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of Apc(Min)-induced intestinal neoplasia. Cell 81: 957-966, 1995. [PubMed: 7781071, related citations] [Full Text]

  12. Masharani, U., Coleman, R. T., Johnson, L. K., Seilhamer, J. J. EcoRI and NsiI RFLPs at a human PLA2 gene on chromosome 1. Nucleic Acids Res. 16: 9073, 1988. [PubMed: 2902574, related citations] [Full Text]

  13. Moser, A. R., Dove, W. F., Roth, K. A., Gordon, J. I. The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J. Cell Biol. 116: 1517-1526, 1992. [PubMed: 1541640, related citations] [Full Text]

  14. Moser, A. R., Mattes, E. M., Dove, W. F., Lindstrom, M. J., Haag, J. D., Gould, M. N. Apc(Min), a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias. Proc. Nat. Acad. Sci. 90: 8977-8981, 1993. [PubMed: 8415640, related citations] [Full Text]

  15. Moser, A. R., Pitot, H. C., Dove, W. F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247: 322-324, 1990. [PubMed: 2296722, related citations] [Full Text]

  16. Nadeau, J. H. Modifier genes in mice and humans. Nature Rev. Genet. 2: 165-174, 2001. [PubMed: 11256068, related citations] [Full Text]

  17. Nimmrich, I., Friedl, W., Kruse, R., Pietsch, S., Hentsch, S., Deuter, R., Winde, G., Muller, O. Loss of the PLA2G2A gene in a sporadic colorectal tumor of a patient with a PLA2G2A germline mutation and absence of PLA2G2A germline alterations in patients with FAP. Hum. Genet. 100: 345-349, 1997. [PubMed: 9272153, related citations] [Full Text]

  18. Seilhamer, J. J., Plant, S., Pruzanski, W., Schilling, J., Stefanski, E., Vadas, P., Johnson, L. K. Multiple forms of phospholipase A(2) in arthritic synovial fluid. J. Biochem. 106: 38-42, 1989. [PubMed: 2777750, related citations] [Full Text]

  19. Seilhamer, J. J., Pruzanski, W., Vadas, P., Plant, S., Miller, J. A., Kloss, J., Johnson, L. K. Cloning and recombinant expression of phospholipase A(2) present in rheumatoid arthritic synovial fluid. J. Biol. Chem. 264: 5335-5338, 1989. [PubMed: 2925608, related citations]

  20. Seilhamer, J. J., Randall, T. L., Johnson, L. K., Heinzmann, C., Klisak, I., Sparkes, R. S., Lusis, A. J. Novel gene exon homologous to pancreatic phospholipase A(2): sequence and chromosomal mapping of both human genes. J. Cell. Biochem. 39: 327-337, 1989. [PubMed: 2708461, related citations] [Full Text]

  21. Seilhamer, J. J., Randall, T. L., Johnson, L. K., Lusis, A., Sparkes, R. S., Heinzman, C. Chromosomal mapping of human pancreatic PLA2 and a homologous PLA2 exon. (Abstract) J. Cell. Biochem. (Suppl. 12E): 55 only, 1988.

  22. Su, L.-K., Kinzler, K. W., Vogelstein, B., Preisinger, A. C., Moser, A. R., Luongo, C., Gould, K. A., Dove, W. F. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256: 668-670, 1992. Note: Erratum: Science 256: 1114 only, 1992. [PubMed: 1350108, related citations] [Full Text]


Patricia A. Hartz - updated : 10/29/2008
Victor A. McKusick - updated : 9/8/2003
Victor A. McKusick - updated : 9/8/2003
Victor A. McKusick - updated : 9/8/2003
Victor A. McKusick - updated : 1/15/2003
Victor A. McKusick - updated : 6/3/2002
Paul Brennan - updated : 11/14/1997
Victor A. McKusick - updated : 9/10/1997
Victor A. McKusick - updated : 9/2/1997
Victor A. McKusick - updated : 5/16/1997
Creation Date:
Victor A. McKusick : 10/12/1990
carol : 10/01/2013
terry : 3/14/2013
carol : 3/19/2010
terry : 6/3/2009
mgross : 11/4/2008
mgross : 11/4/2008
terry : 10/29/2008
carol : 8/14/2008
ckniffin : 2/5/2008
cwells : 9/9/2003
terry : 9/8/2003
terry : 9/8/2003
terry : 9/8/2003
cwells : 1/16/2003
terry : 1/15/2003
cwells : 6/18/2002
terry : 6/3/2002
alopez : 8/9/1999
terry : 7/13/1998
terry : 7/10/1998
alopez : 12/5/1997
alopez : 11/26/1997
alopez : 11/17/1997
alopez : 11/14/1997
terry : 9/16/1997
terry : 9/10/1997
jenny : 9/3/1997
terry : 9/2/1997
terry : 7/10/1997
mark : 5/20/1997
terry : 5/16/1997
mark : 2/5/1997
jenny : 2/4/1997
mark : 3/14/1996
mark : 3/14/1996
terry : 3/5/1996
terry : 7/28/1995
mark : 6/30/1995
mimadm : 1/14/1995
carol : 9/23/1993
supermim : 3/16/1992
carol : 11/8/1991

* 172411

PHOSPHOLIPASE A2, GROUP IIA; PLA2G2A


Alternative titles; symbols

PHOSPHOLIPASE A2, SYNOVIAL; PLA2S; PLAS1
PHOSPHOLIPASE A2 POLYPEPTIDE B; PLA2B
MODIFIER OF MIN-1, MOUSE, HOMOLOG OF; MOM1


HGNC Approved Gene Symbol: PLA2G2A

Cytogenetic location: 1p36.13     Genomic coordinates (GRCh38): 1:19,975,431-19,980,434 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p36.13 {?Colorectal cancer, susceptibility to} 114500 Autosomal dominant; Somatic mutation 3

TEXT

Description

Phospholipases A2 (PLA2s) hydrolyze the sn-2 fatty acid acyl ester bond of phosphoglycerides, releasing free fatty acids and lysophospholipids. They play an important role in a variety of cellular processes, including digestion and metabolism of phospholipids, as well as production of precursors for inflammatory reactions. PLA2G2A belongs to PLA2 group II, which consists of extracellular enzymes with low molecular masses that require calcium ions for catalysis (Dennis, 1994).


Cloning and Expression

Elevated levels of synovial fluid and plasma phospholipase A2 correlate with the activity of inflammatory arthritis. Seilhamer et al. (1989) characterized multiple forms of phospholipase A2 in arthritic synovial fluid.

By N-terminal sequencing of peptides obtained from human synovial fluid, followed by screening a genomic library and a cDNA library prepared from peritoneal exudate cells, Seilhamer et al. (1989) obtained a full-length PLA2G2A cDNA. The deduced protein contains a 20-amino acid signal sequence, followed by a 124-amino acid mature peptide that has a calculated molecular mass of about 14 kD. The protein has characteristics of the type II class of PLA2s, including conserved catalytic residues and a Ca(2+)-binding loop. Northern blot analysis detected a 0.8-kb transcript in inflamed human synovial tissue and in peritoneal exudate cells from a peritonitis patient, but not in 2 activated human promyelocytic cell lines. Expression of Pla2g2a was not detected in pig jejunum, pancreas, and spleen, or in rat liver.

Johnson et al. (1990) purified and cloned human PLA2G2A, which encodes the major form of PLA2 expressed in rheumatoid arthritis synovial fluid. PLA2G2A is a member of the type II PLA2 family, which includes the inflammatory PLA2 found in the venom of the viperid class of snakes. Johnson et al. (1990) showed that there is diversity of phospholipase A2 in synovial fluid that is apparently related to alternative splicing of the PLA2G2A gene.


Gene Family

PLA2s constitute a diverse family of enzymes with respect to sequence, function, localization, and divalent cation requirements. In a review, Dennis (1994) stated that PLA2s can be classified into at least 5 groups based on their size, structure, and need for divalent cations. Groups I, II, and III all contain so-called secreted forms of PLA2, which are extracellular enzymes that have a low molecular masses and require calcium ions for catalysis. Groups IV and V contain cytosolic forms of PLA2 that have a high molecular masses and require calcium ions only in the case of group IV PLA2. PLA2G2A belongs to PLA2 group II.


Gene Function

Seilhamer et al. (1989) demonstrated that simian kidney cells expressing human PLA2 secreted PLA2 activity to the culture medium.

A role for PLA2G2A in the pathogenesis of ulcerative colitis (see 266600) was postulated by Haapamaki et al. (1997), who demonstrated expression of the PLA2G2A gene in metaplastic Paneth cells and columnar epithelial cells in inflamed colonic mucosa from patients with ulcerative colitis. No expression was detected in other tissues from the same patients or, by Northern blot analysis, in colonic biopsies from disease-free controls. Haapamaki et al. (1997) hypothesized that intraluminal secretion of PLA2G2A during the active phase of ulcerative colitis is a host defense mechanism.

Leung et al. (2002) analyzed gene expression patterns in human gastric cancers by using cDNA microarrays representing approximately 30,300 genes. Expression of PLA2G2A was significantly correlated with patient survival. The observation was confirmed in an independent set of patient samples by using quantitative RT-PCR. Beyond its potential diagnostic and prognostic significance, this result suggests the possibility that the activity of PLA2G2A may suppress progression or metastasis of human gastric cancer.


Gene Structure

Seilhamer et al. (1989) determined that the PLA2G2A gene contains 5 exons and spans 4.6 kb. The upstream region contains a TATA-like sequence and a CCAAT box.


Mapping

Masharani et al. (1988) described RFLPs of a gene homologous to the pancreatic PLA2 gene (PLA2G1B; 172410). Seilhamer et al. (1988, 1989) assigned this gene, symbolized PLA2L by them, to chromosome 1 by hybridization to DNA from human-rodent hybrids. Johnson et al. (1990) mapped the PLA2G2A gene to chromosome 1p35.

In a large familial adenomatous polyposis (FAP; 175100) kindred in which patients harbored the same germline mutation but showed markedly different disease characteristics, Dobbie et al. (1997) investigated the region of human chromosome 1p36-p35 that is homologous to the region of murine chromosome 4 containing the Mom1 gene (see ANIMAL MODEL). They looked for linkage between each of 14 microsatellite markers and the development of extracolonic symptoms in polyposis coli patients. Depending on the mode of inheritance of the modifier locus, a maximum lod score was observed for markers D1S211 and D1S197, reaching 2.08 and 1.77, respectively. The observed values obtained within a large FAP family were considered supportive of a phenotype-modifying locus within this chromosomal region.


Molecular Genetics

To test the hypothesis of the correlation between PLA2G2A gene alterations and human tumor development of the sort demonstrated in the mouse model of FAP (see ANIMAL MODEL), Nimmrich et al. (1997) screened 14 patients with FAP and 20 patients with sporadic colorectal cancer (114500) for germline and somatic PLA2G2A gene mutations. None of the individuals with FAP showed PLA2G2A germline alterations. However, a heterozygous germline mutation (172411.0001) was observed in 1 patient with colorectal cancer; the wildtype allele was somatically lost in the tumor of this patient.


Animal Model

Modifier of Min-1 Locus

Moser et al. (1990) identified a dominant, fully penetrant mouse mutation named Min (multiple intestinal neoplasia) that causes a phenotype closely resembling familial adenomatous polyposis (FAP; 175100). Heterozygotes for the Min mutation developed numerous intestinal and colonic adenomas similar in morphology to the adenomas seen in FAP. If left untreated, the adenomas eventually become locally invasive (Moser et al., 1992). In addition, about 10% of Min/+ females on a hybrid background develop spontaneous mammary adenoacanthomas or adenocarcinomas (Moser et al., 1993). Homozygotes for Min die in utero. The Min mice carry a nonsense mutation in the mouse homolog of the FAP gene (Su et al., 1992). In the laboratory of William Dove at the University of Wisconsin, where the Min mutation was discovered and characterized, it was noted that the number of intestinal tumors in Min/+ mice was strongly affected by genetic background: C57BL/6J-Min/+ mice had an average of 29 tumors, whereas their Min/+ F1 progeny with AKR mice showed an average of only 6 tumors. This finding suggested that the AKR strain carries alleles that act in a dominant fashion to modify the tumorigenic effect of Min. Dietrich et al. (1993) mapped the postulated modifying gene, called Mom1 (modifier of Min-1), to the distal portion of mouse chromosome 4. Allelic variation in Mom1 appeared to control about 50% of the genetic variation in tumor number in 2 different intraspecific backcrosses. A cumulative lod score exceeding 14 supported the mapping. Mom1 was found to lie in a region of synteny conservation with human chromosome 1p36-p35, a region of frequent somatic loss of heterozygosity in a variety of human tumors, including colon tumors.

MacPhee et al. (1995) identified a candidate gene for Mom1 in the mouse. The gene for secretory type II phospholipase A2 (Pla2s) was shown to map to the same region as Mom1 and displayed 100% concordance between allele type and tumor susceptibility. Expression and sequence analysis revealed that Mom1-susceptible strains are most likely null for Pla2s activity. MacPhee et al. (1995) interpreted the results as indicating that Pla2s acts as a novel modifier of polyp number by altering the cellular microenvironment within the intestinal crypt. The homologous gene in the human, PLA2G2A, maps to 1p35 in a region of homology to distal mouse chromosome 4. The authors stated that it is unclear how loss of PLA2G2A in tumor cells would contribute to neoplasia in the human. One possibility is that PLA2G2A involvement is reflected by the variable numbers of adenomas identified among FAP family members inheriting the same mutation. The variation in tumor burden could be attributable to the segregation of different PLA2G2A alleles. Population surveys would be useful for determining the extent of PLA2G2A allelic variation, as well as for identifying individuals at risk for developing intestinal cancer. The identification of mouse Pla2s as a candidate for a major modifier of intestinal polyp formation may provide a missing link between high fat diets and increased incidence of colon cancer.

Cormier et al. (1997) provided further evidence on the role of PLA2G2A in resistance to intestinal tumorigenesis. They reported that a cosmid transgene overexpressing Pla2g2a in mice caused a reduction in tumor multiplicity and size, comparable to that conferred by a single copy of the resistance allele of Mom1. Thus, they concluded that this secretory phospholipase can provide active tumor resistance. The association of Pla2g2a with Mom1 thus withstood a strong functional test. The work probably represents the successful identification of a polymorphic quantitative trait locus (QTL) in mammals.

Dragani and Manenti (1997) reviewed other work in rodents defining counteractive cancer susceptibility and cancer resistance genes. This phenomenon is observed in mouse models of lung cancer, where the tumor-promoting effect of the Pas1 locus is downregulated by the presence of the Par resistance loci. In rats, tumors presumed to arise as a consequence of the hepatocarcinogen sensitivity locus, Hcs, are discouraged from growing by coincident presence of resistance (Hcr) loci.

Nadeau (2001) reviewed modifier genes in mice and humans and pointed out that the classic paper of Dietrich et al. (1993) identified a pharmacologically relevant pathway in humans.

The Mom1 locus was the first locus mapped as a modifier of a specific enhancer-inducing mutation, i.e., a modifier of the germline APC gene mutation (see 611731), which induces intestinal tumorigenesis (Dietrich et al., 1993). Dragani (2003) reviewed the progress in the following 10 years, during which more than 100 cancer modifiers had been mapped and 4 strong candidate genes had been identified, 1 of them being PLA2G2A.


ALLELIC VARIANTS 1 Selected Example):

.0001   COLORECTAL CANCER

PLA2G2A, 2-BP DEL, NT1119
SNP: rs587776800, gnomAD: rs587776800, ClinVar: RCV000014605

In the blood sample and the normal colorectal tissue of an 80-year-old female patient with colorectal cancer (114500), Nimmrich et al. (1997) identified a heterozygous 2-bp deletion at genomic position 1119 (codon 48) in exon 3 of the PLA2G2A gene. Assuming normal splicing of the gene, this frameshift deletion was predicted to result in a premature stop at codon 67 in exon 4. Somatic loss of the wildtype PLA2G2A sequence was demonstrated in the tumor of the patient. The tumor was diagnosed as being a late metastasizing carcinoma carrying a heterozygous mutation in p53 (191170) and a somatic monoallelic loss of the DCC gene (120470). The PLA2G2A germline mutation had not been transmitted to the normal 58-year-old son.


See Also:

Johnson et al. (1990)

REFERENCES

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Contributors:
Patricia A. Hartz - updated : 10/29/2008
Victor A. McKusick - updated : 9/8/2003
Victor A. McKusick - updated : 9/8/2003
Victor A. McKusick - updated : 9/8/2003
Victor A. McKusick - updated : 1/15/2003
Victor A. McKusick - updated : 6/3/2002
Paul Brennan - updated : 11/14/1997
Victor A. McKusick - updated : 9/10/1997
Victor A. McKusick - updated : 9/2/1997
Victor A. McKusick - updated : 5/16/1997

Creation Date:
Victor A. McKusick : 10/12/1990

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