My note on paper: RNF43 mutations are recurrent in Chinese patients with mucinous ovarian carcinoma but absent in other subtypes of ovarian cancer

Paper: RNF43 mutations are recurrent in Chinese patients with mucinous ovarian carcinoma but absent in other subtypes of ovarian cancer
(doi: 10.1016/j.gene.2013.08.054)

Abstract:
Fact-
*Large scale sequencing identified prevalent RNF43 mutation in pancreatic and ovarian mucinous carcinomas
*Exome sequences on RNF43 in 251 Chinese patients with distinct ovarian subtypes
*2/15 (13.3%) novel heterozygous nonsynonymous mutation found in mucinous ovarian carcinoma
*the mutations is highly conserved
*No RNF43-mutated samples contain hotspot mutation in
--DICER1 (dicer 1, ribonuclease type III),
--PPP2R1A (protein phosphatase 2, regulatory subunit A, alpha),
--TRRAP (transformation/transcription domain-associated
protein)
-- DNMT3A (DNA (cytosine-5-)-methyltransferase 3 alpha)
*lack of RNF43 mutation in other subtypes suggest no functional role in that subtype

 Intro:
Ovarian CA (OVCA) -
*heterogeneity malignant
*90% of OVCA are epithelial origin
*10% of OVCA are non-epithelial

Gap:
Molecular etiology of OVCA is unk bc of heterogeneity

RNF43;
*oncoprotein
**highly express in HCC
**highly express in CRC
**promote cell growth and invasion

*Tumor suppressor
**mutation in RN43 distributed across the whole gene
**mutated samples contain RNF43 LOH

*Large scale sequencing;
**identify prevalent RNF43 somatic mutations in mucinous CA of pancreas + ovary
**functional analysis revealed the role on tumor suppressor in wnt/b-catenin signaling pw (negative regulation)

Critical concern in molecular genetics in human CA;
**specific mutations found in tumor type - common in other cancers?
**internal link among different mutated genes -- might contribute be synergistic (that is why need to do sequencing all those four genes in RNF-mutated sample and looking for the hotspots)

Method;
OVCA
1.Epithelial origin
*Serous (high and low grade)
*Clear cell
*Endometrioid
*Mucinous (Mucinous carcinoma is a type of cancer that arises from epithelial cells; these line certain internal organs and skin, and produce mucin (the main component of mucus)
*undifferentiated (not have specialized ("mature") structures or functions. Undifferentiated cancer cells often grow and spread quickly)
*unclassified
*Transitional -- cancer that begins in cells called urothelial cells that line the urethra, bladder, ureters, renal pelvis, and some other organs. Urothelial cells are also called transitional cells. These cells can change shape and stretch without breaking apart
2.Non-epithelial
*Germ cell (yolk sac, dysgerminoma,teratoma,mixed)
*Sex-cord-stromal tumor(Granulosa,sertoli-leydig)
*Krukenberg tumors

Prior studies of OVCA;
*Found high frequency in particular gene mutations in particular subtypes
*Found high frequency in genes in more than one type of cancers

RNF43 somatic mutation is found only in mucinous tumors;
*Truncating mutation (c.118delA,
p.Arg40AspfsX11)
*Missense mutation (c.142ANG, p.Ile48Val)



Evolutionary conservation analysis of missense mutation of RNF43

13 species:
Homo sapiens (RNF43, GenBank accession No. NM_017763.4),
Pan troglodytes (XM_001172611.3)
Macaca mulatta (XM_001106574.2)
Gorilla gorilla gorilla (XM_004041273.1),
Saimiri boliviensis boliviensis (XM_003929103.1),
Rattus norvegicus (NM_001135921.1),
Mus musculus (NM_172448.3),
Bos taurus (NM_001191194.1),
Canis lupus familiaris (XM_548234.3)
Ovis aries (XM_004012397.1),
Felis catus (XM_003996633.1)
Oryctolagus cuniculus (XM_002719265.1)
Gallus gallus (XM_003642379.1)