12_Genetic_suscepgtibility_cancer_99.doc

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Annals of the ICRP,Volume 28, Issues 1-2, March 1998, Pages 1-157

Genetic susceptibility to cancer: ICRP Publication 79

Approved by the Commission in May 1997

Available online 25 May 1999.

Abstract

A as! "rou# o$ %he I&'P &ommi%%ee 1 ('a)ia%ion *$$ec%s+ has reviee) relevan% )a%a i%h %he

obec%ive o$ a)vising %he Main &ommission o$ %he I&'P on %he #ossible im#lica%ions $or ra)iological

#ro%ec%ion o$ emerging vies on gene%ic susce#%ibili%y %o cancer (&ha#%er 1+.

&ha#%er 2 consi)ers /A )amage an) i%s #rocessing0re#air a$%er ionising ra)ia%ion an) serves#rinci#ally %o )emons%ra%e %ha% a $e rare cancer-#rone, human recessive gene%ic )isor)ers sho /A

re#air )e$iciency an) #ro$oun) increases in ra)iosensi%ivi%y. ess )rama%ic changes in ra)iosensi%ivi%yare also a##aren% in a i)er range o$ such )isor)ers. he cellular mechanisms %ha% un)erly %he

associa%ion be%een /A )amage #rocessing an) %umorigenesis are )iscusse).

&ha#%er revies %he mechanisms an) gene%ics o$ soli) %umours illus%ra%ing %he ays in hich

mu%a%ions in #ro%o-oncogenes, %umour su##ressor genes %oge%her i%h %hose in /A re#air an) cell

cycle con%rol genes can con%ribu%e %o %umour )evelo#men%. 3#eci$ic e4am#les are given o$ ho germline mu%a%ion o$ such genes can #re)is#ose %o $amilial cancer. I% is u)ge) %ha% u# %o 5 o$ all soli)

%umours have a recognisable gene%ic com#onen%. 6eri%able organ-s#eci$ic e$$ec%s are mos% usual an)

cancers o$ %he breas% an) colon %en) %o sho %he mos% obvious gene%ic com#onen%s. &learly )iscernible

gene%ic e$$ec%s are seen hen rare )ominan% germ line mu%a%ions e4#ress s%rongly as $amilial cancer

(high #ene%rance mu%a%ions+, bu% %he e4is%ence o$ #erha#s less rare lo #ene%rance mu%a%ions an) genegene in%erac%ions are recognise) bu% no% ell un)ers%oo).

&ha#%er consi)ers %he mechanisms an) gene%ics o$ lym#ho-haemo#oie%ic %umours. 3#eci$icchromosomal %ransloca%ions an) #ro%o-oncogene ac%iva%ion even%s are much more $reuen% in human

leu!aemia0lym#homa %han in soli) %umours. "ene%ic #re)is#osi%ion %o leu!aemia0lym#homa is $oun) in

a number o$ non-$amilial recessive gene%ic )isor)ers o$ /A #rocessing an)0or chromosomal

ins%abili%y. :amilial mani$es%a%ion o$ susce#%ibili%y %o %hese %umours is, hoever, e4%remely rare. hegene%ic com#onen%, al%hough #oorly )e$ine), is u)ge) %o be less %han %ha% o$ soli) %umours an)

e4#resse) largely in chil)hoo).

&ha#%er 5 revies an) )iscusses limi%e) )a%a %ha% commen% u#on %umorigenic ra)iosensi%ivi%y incancer-#rone gene%ic con)i%ions. :rom !nole)ge o$ %he $un)amen%al #rocesses involve) i% is u)ge)%ha% in mos%, bu% no% all, cases gene%ic susce#%ibili%y %o s#on%aneous %umours ill be accom#anie) by a

grea%er-%han-normal ris! a$%er ra)ia%ion. A revie o$ e#i)emiological, clinical an) e4#erimen%al )a%a

relevan% %o %his issue sugges%s %ha% al%hough a i)e range o$ )i$$eren% sensi%ivi%ies may be involve), a$ac%or o$ 1; increase in sensi%ivi%y broa)ly accor)s i%h %he limi%e) human )a%a available. his in%erim

u)gemen% o$ a $ac%or o$ 1; increase in ra)ia%ion ris! in such human gene%ic )isor)ers is ma)e $or %he

#ur#oses o$ illus%ra%ive mo)elling an) calcula%ion. In a))i%ion, s#eci$ic a%%en%ion is given %o breas%

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http://www.sciencedirect.com/science/journal/01466453http://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%234965%231998%23999719998%2398738%23FLA%23&_cdi=4965&_pubType=J&view=c&_auth=y&_acct=C000000879&_version=1&_urlVersion=0&_userid=40834&md5=32e75f525adb483e9fae9681e3de340chttp://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%234965%231998%23999719998%2398738%23FLA%23&_cdi=4965&_pubType=J&view=c&_auth=y&_acct=C000000879&_version=1&_urlVersion=0&_userid=40834&md5=32e75f525adb483e9fae9681e3de340chttp://www.sciencedirect.com/science/journal/01466453


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cancer ris! in he%ero )iscusses an) )evelo#s com#u%a%ional mo)elling #roce)ures %ha% aim %o )escribe %he im#ac%

o$ gene%ic $ac%ors on ra)ia%ion-%umorigenesis in human #o#ula%ions. *s%ima%es o$ %he #revalence o$!non cancer-#rone gene%ic )isor)ers are ma)e bu% breas% cancer susce#%ibili%y is use) %o illus%ra%e %he

a##lica%ion o$ %he mo)el )evelo#e). he mos% im#or%an% message %o emerge $rom %his or! is %ha%,even a% an assume) high level o$ ra)ia%ion sensi%ivi%y, %he #revalence o$ $amilial (high #ene%rance+gene%ic )isor)ers in %he #o#ula%ion is %oo lo (?1+ $or %here %o be a signi$ican% im#ac% on ris! in

%y#ical human #o#ula%ions. In #rinci#le, hoever, %here is %he #o%en%ial $or such im#ac% in a%y#ical

inbre) sub-#o#ula%ions here %hese mu%a%ions can be more common. hese mo)elling #roce)ures are

also use) %o illus%ra%e ho incom#le%e #ene%rance o$ %hese mu%a%ions ill )ilu%e any im#ac% on#o#ula%ion ris!.

In conunc%ion i%h %he Main &ommission o$ %he I&'P, in &ha#%er 7 %he as! "rou# )iscusses %he

#o%en%ial im#lica%ions o$ %he main re#or% $or ra)iological #ro%ec%ion. heir #rinci#al conclusions are@ (i+

ha% curren% es%ima%es o$ ra)ia%ion cancer ris! alrea)y inclu)e an un!non con%ribu%ion $romgene%ically ra)iosensi%ive sub-#o#ula%ions. (ii+ sing %he )a%a ci%e), %he li!ely con%ribu%ion %o ra)ia%ion

ris! $rom $amilial cancer )isor)ers is %oo lo %o genera%e an unacce#%able )is%or%ion o$ curren%

es%ima%es o$ cancer ris! in %he vas% maori%y o$ human #o#ula%ions. (iii+ here is insu$$icien% !nole)ge%o u)ge %he con%ribu%ion %o ris! $rom mu%a%ions o$ lo #ene%rance %ha% )o no% e4#ress as $amilial

cancer. (iv+ Because o$ %he high ris! o$ s#on%aneous cancer in $amilial )isor)ers, lo )oses o$ ra)ia%ion

(say 1;; m3v+ are mos% unli!ely %o im#ac% signi$ican%ly on li$e-%ime cancer ris! in an a$$ec%e)in)ivi)ual= a% high )oses, such as %hose e4#erience) in ra)io%hera#y, %his rela%ive ris! may hoever

become im#or%an%. (v+ Because organ-s#eci$ic cancer ris! is #re)ic%e) in mos% $amilial )isor)ers, %he

absolu%e increase overall in ris! %o an a$$ec%e) in)ivi)ual ill be )ilu%e), ie. com#aring normal an)a$$ec%e) in)ivi)uals. (vi+ he u%ili%y o$ gene%ic %es%ing $or cancer #re)is#osi%ion in %he con%e4% o$

ra)iological #ro%ec%ion is curren%ly limi%e) by %echnical $ac%ors an) concerns on #re)ic%ive #oer. In %he

$u%ure gene%ic %es%ing may $in) selec%e) use #rior %o cer%ain me)ical e4#osures %o ra)ia%ion, bu% %he

value o$ such #roce)ures, as a##lie) %o lo-)ose occu#a%ionally e4#ose) in)ivi)uals, is o#en %o )oub%=i% oul) also be subec% %o maor e%hical scru%iny ou%si)e %he remi% o$ %he I&'P.

he as! "rou# an) %he Main &ommission o$ %he I&'P s%ress %ha%, because o$ %he curren% lac! o$

!nole)ge, %he above u)gemen%s shoul) be regar)e) as #reliminary. he re#or% serves #rinci#ally %o

#rovi)e a $rameor! on hich %o )evelo# $ur%her vies in %his ra#i)ly a)vancing area o$ humangene%ics.

Article utline

1. In%ro)uc%ion2. /A )amage an) re#air

2.1. he /A )amage s#ec%rum a$%er ra)ia%ion

2.2. Pos%-irra)ia%ion cellular /A re#air an) mu%agenesis2.2.1. amage %o /A nucleo%i)e bases

2.2.2. 3ingle s%ran) brea!s (ssb+ in /A

2.2.. ouble s%ran) lesions in /A2.2.. /A re#air an) recombina%ional #rocesses

2.2.5. 6uman a%a4ia-%elangiec%asia

2
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2.2.>. 'a)ia%ion mu%agenesis an) i%s rela%ionshi# %o /A re#air

2.2.7. &hromosomal s%ruc%ure an) ra)ia%ion mu%agenesis

2.2.8. "enomic ins%abili%y

2.. 6uman gene%ic )isor)ers a$$ec%ing /A re#air an) genomic ins%abili%y2.. 3ummary an) conclusions

. Mechanisms an) gene%ics o$ soli) %umours

.1. Cncogenes.2. umour su##ressor genes

.2.1. umour su##ressor genes in %he cell cycle

.2.2. hep53 gene in /A )amage chec!#oin% con%rol.2.. 3oma%ic mu%a%ions o$p53 in human %umours

.. /A re#air an) re#lica%ion genes in soli) %umours

.. "ene%ic susce#%ibili%y %o soli) %umours..1. 6eri%able breas% an) ovarian cancer

..2. 6eri%able colon cancer

... 6eri%able renal cancer

... 6eri%able %umours o$ %he nervous sys%em..5. 6eri%able #ros%a%e an) %es%icular cancer

..>. 6eri%able s!in cancer

..7. 6eri%able cancers o$ %he en)ocrine sys%em..8. "enes associa%e) i%h cancer a% mul%i#le si%es

.5. he origin o$ mu%a%ions in %umour-associa%e) genes

.5.1. "ermline mu%a%ions o$ %umour-su##ressor genes.5.2. Pre$eren%ial involvemen% o$ #aren%al alleles in %umour gene mu%a%ions

.5.. *vi)ence $or mu%a%ional mosaicism

.>. he gene%ic com#onen% o$ soli) %umours

.7. 3ummary. Mechanisms an) gene%ics o$ lym#ho-haemo#oie%ic neo#lasia

.1. Mechanisms o$ in)uc%ion o$ lym#ho-haemo#oie%ic neo#lasia

.1.1. 3%ruc%ure an) $unc%ion o$ %he lym#ho-haemo#oie%ic sys%em.1.2. ym#ho-haemo#oie%ic neo#lasia

.1.. &y%ogene%ic an) molecular mechanisms o$ lym#ho-haemo#oie%ic neo#lasia

.1..1. &hromosome %ransloca%ions.1..2. &hromosome )ele%ions an) numerical changes

.1... C%her #ro%o-oncogene an) %umour su##ressor mu%a%ions

.1... "enomic ins%abili%y in haemo#oie%ic neo#lasia.2. "ene%ic susce#%ibili%y %o lym#ho-haemo#oie%ic neo#lasia

.2.1. :amily s%u)ies

.2.2. 3%u)ies i%h %ins

.2.. &ancer $amily syn)romes.2.. &hromosome ins%abili%y syn)romes

.2..1. A%a4ia-%elangiec%asia

.2..2. Bloom syn)rome.2... :anconi anaemia

.2... 6eri%able chromosomal $ragile si%es

.2.5. &hromosomal an) )evelo#men%al abnormali%ies.2.5.1. &hromosomal abnormali%ies

.2.5.2. evelo#men%al abnormali%ies

3
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5... i:raumeni syn)rome an) neuro$ibroma%osis5... C%her gene%ic con)i%ions an) $amilial associa%ions

5.. *#i)emiological as#ec%s o$ %umorigenic ra)iosensi%ivi%y

5..1. Breas% cancer ris! in a%a4ia-%elangiec%asia he%ero


5/165

>.2..1. 'a%ionale $or %he #arame%er values chosen $or a##lying %he mo)el $or breas% cancer an)

here)i%ary non-#oly#osis colon cancer

>.2..2. 'esul%s@ breas% cancer

>.2... 6ere)i%ary non-#oly#osis colon cancer>.2.5. &ancer #re)is#osi%ion an) ra)iosensi%ivi%y )ue %o recessive mu%a%ions a% an au%osomal locus

>.. 3ummary an) conclusions

7. Im#lica%ions $or ra)iological #ro%ec%ion o$ )a%a on cancer susce#%ibili%y7.1. :amilial cancer involving genes o$ high #ene%rance

7.1.1. :amilial cancer an) ris!s in a #o#ula%ion

7.1.2. :amilial cancer an) in)ivi)ual ris!7.2. &ancer involving genes o$ lo #ene%rance

7.. Areas o$ $u%ure research in ra)iological #ro%ec%ion

7.. he a##lica%ion o$ )iagnos%ic %echnologies7.5. 3ummary an) conclusions $or ra)iological #ro%ec%ion

7.5.1. *s%ima%ion o$ ris!s in hole #o#ula%ions

7.5.2. 'is!s in in)ivi)uals i%h $amilial cancer

7.5.. "ene%ic %es%ing $or cancer susce#%ibili%y in %he con%e4% o$ ra)iological #ro%ec%ion7.5.. &onclu)ing remar!s

'e$erences

1! Introduction

he las% %o )eca)es have i%nesse) a s#ec%acular increase in our $un)amen%al un)ers%an)ing o$ %he

cancer #rocess. his has come abou% largely %hrough %he )evelo#men% o$ #oer$ul molecular gene%ic

%echniues %ha% have alloe) cancer-associa%e) genes %o be i)en%i$ie), isola%e), $unc%ionallycharac%erise), an) ma##e) %o s#eci$ic regions o$ %he human genome. hese same %echniues, %oge%her

i%h a)vances in e#i)emiology an) clinical s%u)ies, have revolu%ionise) human gene%ics an) cou#le)

i%h a)vances in cancer biology have alloe) %he charac%erisa%ion o$ a signi$ican% number o$ heri%able

)isor)ers associa%e) i%h a $amilial #re)is#osi%ion %o neo#lasia.

In a))i%ion %o %he bene$i%s accruing %o clinical an) me)ical gene%ic u)gemen%s %his a)vance in

!nole)ge also has #o%en%ially im#or%an% socio-economic im#lica%ions. Inclu)e) in %his la%%er ca%egory

is %he ues%ion as %o he%her germ line gene mu%a%ions %ha% #re)is#ose %o s#on%aneously arising humancancer also im#ose an increase) cancer ris! a$%er e4#osure %o environmen%al geno%o4ic agen%s such as

ionising ra)ia%ion.

&urren% I&'P recommen)a%ions on ra)iological #ro%ec%ion #rovi)e) inPublication 60(I&'P, 1991+ are

base) essen%ially on %he es%ima%ion o$ e4cess cancer ris! a$%er e4#osure o$ hole #o#ula%ions. 3incehoever all such #o#ula%ions ill be gene%ically he%erogeneous, %here is a s%rong e4#ec%a%ion %ha%, even

%a!ing accoun% o$ all o%her e4ogenous $ac%ors, %he e4cess cancer ris! #er uni% o$ )ose $olloing

ra)ia%ion e4#osure ill be non-uni$orm because o$ s#eci$ic )i$$erences in gene%ic ma!e-u# be%eenin)ivi)uals.

Cn %he above basis, %his re#or% see!s %o revie $un)amen%al, clinical, an) e#i)emiological )a%a relevan%

%o a heri%able cancer #re)is#osi%ion an) $rom %his %o ma!e in%erim u)gemen%s on %umorigenic

ra)iosensi%ivi%y in %he gene%ic )isor)ers o$ %his %y#e an) also on %he li!ely con%ribu%ion %ha% gene%ic$ac%ors may ma!e %o ra)ia%ion-in)uce) cancer in %he human #o#ula%ion.

5
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%o a cancer #re)is#osi%ion, i% is im#or%an% %o brie$ly consi)er )a%a rela%ing %o ra)ia%ion-in)uce) cellular

)amage, /A re#air mechanisms, an) mu%agenic #rocesses.

Assessmen% o$ %he na%ure an) e4%en% o$ ra)ia%ion-in)uce) cellular )amage has #reoccu#ie) ra)ia%ion

biology $or many )eca)es. Al%hough enumera%ion o$ such in)uce) lesions is un)oub%e)ly a##ro#ria%e,

evalua%ion o$ %he $orms o$ cellular )amage %ha% are mos% relevan% %o neo#las%ic )evelo#men% is o$#rinci#al im#or%ance $or %he #ur#ose o$ %his re#or%. In or)er %o achieve such meaning$ul evalua%ions, i%

is necessary %o %a!e $ull accoun% o$ %he na%ure o$ %he cellular lesions %ha% #rinci#ally charac%erise %he

neo#las%ic s%a%e i%sel$. In %his ay i% becomes #ossible %o correla%e s#eci$ic ra)ia%ion-in)uce) cellular

even%s i)en%i$ie) in mo)el e4#erimen%al sys%ems i%h %he in vivo in)uc%ion o$ %umours. I% is $or%una%e%ha%, $rom %he revies o$ %he mechanisms o$ neo#las%ic )evelo#men% #rovi)e) in3ec%ion an) 3ec%ion

o$ %his re#or%, i% is #ossible %o i)en%i$y gene mu%a%ions an) chromosomal even%s inclu)ing loss o$

he%ero


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)imensions because o$ en)ogenous scavenging ca#aci%y. As a conseuence, ra)ia%ion ac%ion on /A is

essen%ially a local #rocess.

'a)ical in)uce) )amage as a conseuence o$ a ra)ia%ion %rac! in%ersec%ion o$ /A may occur i%hin

all %he chemical moie%ies o$ /A an), since i% is local in na%ure, *-)e#en)en% clus%ering o$ /Alesions is %o be e4#ec%e). 3#on%aneous chemical reversal o$ such /A lesions may occur bu%, i$ no%, %he

)amage) si%e becomes %he #o%en%ial subs%ra%e $or en


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"!"!,! #ouble strand lesions in #$A

/A )ouble s%ran) lesions inclu)ing $ran! brea!s are believe) %o be %he lesion %y#e o$ grea%es%

im#or%ance in %he in)uc%ion by ra)ia%ion o$ cell le%hal even%s, chromosomal abnormali%ies, an) gene

mu%a%ions ("oo)hea), 199+. :or %he #ur#oses o$ sim#lici%y %he use o$ %he %erm /A )ouble s%ran)brea! ()sb+ ill be use) in %he %e4% %o )escribe collec%ively all $orms o$ /A )ouble s%ran) lesion.

Misre#air or non-re#air o$ a #ro#or%ion o$ coinci)en% lesions in /A is %o be e4#ec%e) %hrough /A

)isloca%ion an)0or %he non-availabili%y o$ an un)amage) com#lemen%ary seuence $or #olymerase

ac%ion. 3uch misre#air may inclu)e %he in%erac%ion o$ /A )sb %hrough some $orm o$ illegi%ima%erecombina%ion in or)er %o $orm %he chromosomal e4changes an) in%ers%i%ial )ele%ions %ha% are

charac%eris%ic o$ ra)ia%ion an) hich are im#lica%e) in neo#las%ic )evelo#men% (3ec%ion an)3ec%ion

+. he biological im#or%ance o$ /A )sb in ra)ia%ion res#onse is mos% clearly evi)en% $rom s%u)ies o$mu%an% ro)en% cell lines %ha% are )e$ec%ive in %he re#air o$ ra)ia%ion in)uce) )amage (able 2.1=

hac!er, 1992,&ollins, 199, Deggo, 199=G)


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are a% leas% seven human genes involve) in %he re#air o$ /A )amage in)uce) by ionising ra)ia%ion,

i.e.XRCC1XRCC7, o$ hich $ive are involve) in /A )sb re#air. A $ur%her gene%ic a##roach hich

e4#loi%s %he evolu%ionary conserva%ion o$ /A re#air genes has ma)e i% #ossible %o clone a $ur%her $our

human homologues o$ %he yeas% ra>, 51, 52, an) 5 genes= %hese la%%er %hree genes are also involve)in /A )sb re#air (able 2.2+. he $irs% )irec% evi)ence %ha% recombina%ion as im#or%an% in %he re#air

o$ /A )sb in)uce) by ionising ra)ia%ion )erive) $rom s%u)ies on %he ra)ia%ion res#onse o$ a severe

combine) immune )e$iciency (sci+ mu%an% o$ %he labora%ory mouse (Bie)ermann e% al., 1991=6en)ric!son e% al., 1991+. In %his au%osomal recessive )isor)er hole animal ra)iosensi%ivi%y is

re$lec%e) a% %he cellular level an) is accom#anie) by )e$ec%s in %he re#air o$ /A )sb an) im#aire)

recombina%ion o$ !"#$%immune seuences hich in %urn genera%es %he immuno)e$iciency #heno%y#eo$ %hese animals. !"#$%recombina%ion reuires several /A brea!age an) reoining s%e#s, an) is

)irec%e) %oar)s conserve) recombina%ion signal seuences %ha% $lan! each o$ %he germline V, , an) D

genomic segmen%s (see also 3ec%ion +. his recombina%ion #rocess u%ilises an array o$ cellularcom#onen%s an) %he evi)ence available sugges%s %ha% %he /A )sb re#air machinery hich is use)

rou%inely %o han)le /A )amage is recrui%e) %o #ar%ici#a%e in %he /A )sb reoining s%e#s o$ !"#$%

recombina%ion. he rela%ionshi# be%een com#e%en% !"#$%recombina%ion an) )sb re#air is $ur%her

evi)ence) by %he observa%ion %ha% %hose ra)iosensi%ive mu%an%s hich are com#e%en% %o carry ou% /A)sb re#air have normal !"#$%reoining (Pergola e% al., 199= accioli e% al., 199= hac!er, 199+.

able 2.2. 6uman homologues o$ yeas% genes involve) in ra)ia%ion res#onse

he /A )sb re#air )e$ec%ivexrsmu%an%s are )e$ec%ive in %he /A en)-bin)ing ac%ivi%y o$ a

he%ero)imeric #ro%ein !non as Fu ()e Vries e% al., 1989= 'a%hmell an) &hu, 199+ an) a geneenco)ing %he Fu 8; ! subuni% an) %heXRCC5gene ma# %o %he same loca%ion a% human chromosome

25 (6a$e


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"!"!.! /uman ata0ia'telan%iectasia

he im#or%ance o$ /A )sb re#air has been reveale) by %he s%u)y o$ %he human au%osomal recessive

cancer #rone syn)rome a%a4ia-%elangiec%asia (A-+ (3e)gic! an) Bo)er, 1991=aylor, 1992=Bun)ey,

199+. he syn)rome is charac%erise) by cerebellar a%a4ia as a conseuence o$ #rogressiveneuro)egenera%ion %oge%her i%h #ermanen%ly )ila%e) bloo) vessels, !non as %elangiec%ases,

#ar%icularly in %he eye bu% hich may occur on %he ears or nose. I%s $reuency in %he #o#ula%ion is

aroun) one in ;;,;;; (Eoo)s e% al., 199;+. Bo%h cellular an) humoral immune )e$iciencies are

common an) %here is a consi)erably eleva%e) inci)ence o$ %umours. A##ro4ima%ely 1; o$ A-#a%ien%s )evelo# cancer in %he $irs% %o )eca)es o$ li$e, %he maori%y o$ %hese %umours are o$

haemo#oie%ic origin (see 3ec%ion + an) some may ell be associa%e) i%h %he a##earance o$

s#on%aneous chromosome %ransloca%ions be%een chromosomes 7 an) 1 hich can e4#an) %o $ormlarge clones in %he circula%ing -cell #o#ula%ions o$ some #a%ien%s (aylor, 1982+. he high $reuency o$

chromosome aberra%ions in bloo) )erive) cells has le) %o %his syn)rome being )e$ine) as a

Hchromosome brea!age or chromosome ins%abili%y syn)rome. he syn)rome became %he $ocus o$ra)iobiological in%eres% $olloing %he )emons%ra%ion %ha% a )rama%ic clinical ra)iosensi%ivi%y (&unli$$e e%

al., 1975+ as re$lec%e) a% %he cellular level by hy#ersensi%ivi%y %o bo%h %he le%hal an) chromosome

brea!age ac%ion o$ ionising ra)ia%ion (aylor e% al., 1975=aylor, 1982+. 6y#ersensi%ivi%y %o %he le%hale$$ec%s o$ ra)ia%ion has been seen in all cell %y#es %es%e) %o )a%e (&ole e% al., 1988+ an) %here is some

evi)ence im#lica%ing %he misre#air o$ /A )sb in %he )isor)er (&o4 e% al., 198>= hac!er, 1992+, a

$ea%ure %ha% may be consis%en% i%h %he immunological )e$ec%s in %he )isor)er. :ormal inves%iga%ions on

%he re#air o$ )sb in A- cells have genera%e) con$lic%ing resul%s. he mos% recen% o$ %hese (see :oray e%al., 1995+ inclu)e) lo )ose-ra%e irra)ia%ion an) e4%en)e) re#air %imes an) are consis%en% in shoing

higher levels o$ resi)ual )sb %han in normal cells. In a))i%ion %here is evi)ence %ha%, )uring > h #os%-

irra)ia%ion, re#air in A- is $as%er %han normal (:oray e% al., 1995+. 6oever, %he search $or abiochemically )e$ine) )e$ec% in %he re#air o$ ionising ra)ia%ion )amage in A- has #rove) )i$$icul%.

3everal labora%ories have #ro)uce) convincing evi)ence $or an abnormal cellular res#onse o$ /A

syn%hesis $olloing %rea%men% i%h ionising ra)ia%ion hich may rela%e %o %he $as%er early re#air in A-cells. hus, in normal cells %here is a mar!e) inhibi%ion o$ /A syn%hesis $olloing ra)ia%ion hich is

no% observe) in A- cells (6oul)sor%h an) avin, 198;= Pain%er an) Joung, 198;+. his cellular#heno%y#e, %erme) ra)ioresis%an% /A syn%hesis, has been use) %o carry ou% gene%ic com#lemen%a%ion

%es%s hich sugges%e) %ha% A- coul) be sub)ivi)e) in%o $our com#lemen%a%ion grou#s (Das#ers e% al.,1988, bu% see #aragra#h 2+. he relevance o$ a )e$ec% giving ra)ioresis%an% /A syn%hesis is no%

hoever obvious. In %he HA- li!e ra)ia%ion-sensi%ive hams%er cell mu%an%s (able 2.1+ %rans$ec%ion

i%h a human gene $rom chromosome correc%s %he /A syn%hesis )e$ec% bu% )oes no% ameliora%e %hele%hal or clas%ogenic e$$ec%s o$ ra)ia%ion (Verhaegh e% al., 1995+. In a))i%ion %o %he abnormali%y in

ra)ia%ion resis%an% /A syn%hesis A- cells also sho o%her #er%urba%ions in #rogression %hrough %he

cell cycle (hac!er, 199+. 3ince A- cells remain hy#ersensi%ive un)er con)i%ions here %hey are no%#roli$era%ing an) here, by )e$ini%ion, %he cell cycle abnormali%ies canno% be o#era%ing, %here mus% be

a))i%ional mechanisms o$ )e$ec%ive /A re#air (hac!er, 199+.

3ubseuen% gene%ic lin!age s%u)ies shoe) $irs% %ha% %he A- gene(s+ ma##e) %o chromosome 1122.2

("a%%i e% al., 1988+ an) %ha% %hree o$ %he com#lemen%a%ion grou#s ma##e) %o %he same region. :inally,3avi%s!y e% al. (1995+succee)e) in cloning a c/A covering a signi$ican% #ar% o$ %he gene inclu)ing

%he im#or%an% $unc%ional )omains. he si%e o$ %he mu%a%ion in %heA)*gene as ne4% i)en%i$ie) in a

number o$ A- #a%ien%s, some #rove) %o be homo


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com#lemen%a%ion grou#s. he maori%y o$ %he mu%a%ions i)en%i$ie) %o )a%e are $rame shi$%s resul%ing in a

%o%al loss o$ $unc%ion o$ %he gene #ro)uc%, a resul% hich migh% be consi)ere) sur#rising in %he ligh% o$

%he mul%i-sys%em na%ure o$ %he )isease. A##ro4ima%ely 2; o$ A- #a%ien%s $rom i%hin %he ni%e)

Fing)om are recognise) as having in%erme)ia%e ra)ia%ion sensi%ivi%y an) %o e4hibi% mil)er clinicalsym#%oms (aylor e% al., 199>+. hey also sho a common ha#lo%y#e an) are com#oun) he%ero05 in one allele hich lea)s %o a $rameshi$% an)

%ermina%ion o$ %he message. he secon) mu%a%ion in %his grou# varies $rom #a%ien% %o #a%ien% an) i% is#robably %his secon), less severe, mu%a%ion hich )e%ermines %he #heno%y#e. n#ublishe) in$orma%ion

on %he )is%ribu%ion o$ mu%a%ions, again $rom i%hin %he ni%e) Fing)om, sugges%s %ha% %hey are almos%

all com#oun) he%ero


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!ine%ics o$ %he mu%a%ion in)uc%ion curves ere linear $or F> an) linear ua)ra%ic $or EI-2-/3. EI-

2-/3 cells #rove) hoever %o be 5;-$ol) more mu%able a% %he he%ero cells.

Previous s%u)ies by %he grou# shoe) %ha% in F> cells one allele (tkK0L+ as u# %o 1;-$ol) more

mu%able by 4 rays %han %he al%erna%ive allele (tkL0L+ an) %ha% %his as e4#laine) by %he lac! o$ recovery o$tkmu%an%s i%h associa%e) loss o$ he%ero


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)ele%ion mechanism %ha% #re)omina%es a$%er ra)ia%ion an) %he %olerance o$ genomic regions %o /A loss

even%s. In a))i%ion %o %he )a%a ci%e) in 3ec%ion 2.2.> %his $ea%ure is clearly illus%ra%e) by s%u)ies on

mu%a%ion in)uc%ion a% %he aprtlocus (see Meu%h an) Bha%%acharyya, 199+.

he aprtgene is au%osomally enco)e) an), %hus, normally #resen% as %o co#ies in %he genome. Inor)er %o s%u)y in)uce) mu%agenesis i% is %here$ore necessary %o use cell lines having one allele carrying

a #oin% mu%a%ion (he%ero


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"!"!2! Genomic instability

he curren% consensus is %ha% %he )evelo#men% o$ neo#lasia is a mul%is%age #rocess (:earon an)

Vogels%ein, 199;= see also 3ec%ion +. he assum#%ion o$ in)e#en)ence $or $ive or more s%e#s in %his

#rocess, each i%h a s#on%aneous ra%e o$ say 1;L7#er cell genera%ion is no% biologically $easible an)several lines o$ evi)ence #oin% %oar)s %he acuisi%ion o$ inheren% genomic ins%abili%y a% a rela%ively

early s%age o$ neo#las%ic )evelo#men% in or)er %o accelera%e %he neo#las%ic #rocess (see 3ec%ion +.

C$ #ossible relevance %o %his is %he in)uc%ion o$ genomic ins%abili%y by ionising ra)ia%ion. *arlier

s%u)ies on %he !ine%ics o$ %he in)uc%ion o$ malignan% %rans$orma%ion o$ mouse 1;102 cells (Fenne)y e%al., 198;an) Fenne)y e% al., 198+ sugges%e) %ha% ra)ia%ion in)uces a %y#e o$ genomic ins%abili%y in a

large $rac%ion o$ %he cell #o#ula%ion lea)ing %o %he occurrence o$ %he ac%ual %rans$orming even% amongs%

%he #rogeny o$ %he original irra)ia%e) cells a$%er many genera%ions o$ cell re#lica%ion. &hang an) i%%le(1992+an) &hang an) i%%le (199+e4amine) %he $reuency o$ mu%a%ions in clonal #o#ula%ions )erive)

$rom single cells surviving ra)ia%ion e4#osure. hey shoe) %ha% %he ra%e o$ mu%a%ion a% %he hprtlocus

o$ a cul%ure) hams%er cell line as #ersis%en%ly eleva%e) $or u# %o 5; #o#ula%ion )oublings $olloing

ra)ia%ion e4#osure. he s#ec%rum o$ /A s%ruc%ural changes $or %hese la%e-arising mu%a%ions )i$$ere)signi$ican%ly $rom %ha% o$ )irec% ra)ia%ion-in)uce) mu%an%s in %ha% %hey ere #rimarily %he resul% o$

small scale even%s (#oin% mu%a%ions+ ra%her %han )ele%ions (i%%le, 199+. A #ersis%en%ly enhance)

mu%a%ion ra%e $olloing irra)ia%ion has also been )escribe) by 3imons an) /ieric!er (199+in a mouselym#homa cell line by use o$ a $luc%ua%ion analysis o$ hprtmu%agenesis.i e% al. (199+re#or%e)

$in)ing eleva%e) $reuency o$ microsa%elli%e mu%a%ions in human lym#hoblas%oi) cell clones selec%e) $or

in)uce) mu%a%ion a% %he )&locus. oge%her %hese )a%a on mul%i#le mu%a%ional even%s im#ly %ha% in somecellular sys%ems %here is in)uc%ion o$ some $orm o$ %rans-ac%ing mu%agenic #rocess, bu% %he na%ure o$

%his #rocess an) i%s gene%ic con%rol remain unresolve).

A% %he chromosomal level, #ersis%en% al#ha-#ar%icle in)uce) genomic ins%abili%y has been re#or%e) in

some bu% no% all bone marro sam#les $rom mouse s%rains an) human )onors (Fa)him e% al., 199+ an)Mar)er an) Morgan (199+have re#or%e) on %he in)uc%ion o$ )elaye) chromosomal ins%abili%y in

hams%er cells irra)ia%e) in vi%ro. Pam#$er an) 3%re$$er (1989+irra)ia%e) mouse embryos in %he single-cell


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%ermini o$ mammalian chromosomes (Blac!burn, 1991an) Blac!burn, 199+. elomere leng%h shor%ens

by aroun) 5;15; base #airs #er cell )ivision an) is believe) %o limi% %he #roli$era%ive ca#aci%y o$

normal human )i#loi) cells. I% has been #ro#ose) %ha% hen %elomeric leng%h shor%ens %o a cri%ical level,

su##ression o$ cell senescence is rela4e) such %ha% cells #rogressively lose #roli$era%ive ca#aci%y= such%elomeric shor%ening is also believe) %o )es%abilise chromosomes such %ha% %hey are more #rone %o

#ar%ici#a%e s#on%aneously in brea!age$usion cycles resul%ing in %he increase in chromosomal

abnormali%ies %ha% charac%erises %he senescence #rocess. *sca#e $rom such senescence an) subseuen%cell immor%alisa%ion via %he re-s%abilisa%ion o$ %elomeres is no believe) %o involve %he reac%iva%ion o$

%he en


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able 2.. 'a)iosensi%ivi%y o$ $ibroblas%s an) lym#hocy%es $rom se%s o$ normal human )onorsa

16


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&ell inac%iva%ion %en)s hoever %o be a ra%her cru)e measure o$ cellular ra)iosensi%ivi%y an) %here are)a%a shoing %ha% a number o$ cancer-#rone gene%ic con)i%ions are associa%e) i%h chromosomal

ra)iosensi%ivi%y. able 2.5lis%s %hose )isor)ers in hich chromosomal ra)iosensi%ivi%y is u)ge) %o be

increase), albei% mo)era%ely in mos% cases. In a))i%ion %o A- an) /B3 hich sho mar!e) increases,cer%ain )isor)ers associa%e) i%h %umour su##ressor gene mu%a%ion are also someha% increase) in

sensi%ivi%y, e.g. i:raumeni syn)rome, re%inoblas%oma an) nevoi) basal cell carcinoma syn)rome.

Al%hough s%ill uncer%ain i% may be %ha%, in %hese )isor)ers, %he conseuences o$ mu%a%ion o$ cer%ain

%umour su##ressor genes $or cell cycle con%rol may #rovi)e an e4#lana%ion $or %he e$$ec% (see 3ec%ion+.

able 2.5. 6uman gene%ic )isor)ers shoing evi)ence o$ chromosomal ra)iosensi%ivi%y

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