Study: Most cancer mu­ta­tions due to ‘bad luck’

Ran­dom DNA er­rors blamed; other cancer re­searchers skep­ti­cal.

Austin American-Statesman - - VIEWPOINTS - By Lau­rie McGin­ley Wash­ing­ton Post

More than two-thirds of cancer-caus­ing mu­ta­tions are the re­sult of ran­dom mis­takes in DNA repli­ca­tion that oc­cur when nor­mal cells di­vide, ac­cord­ing to a paper pub­lished Thurs­day. The study is sure to re­new a vig­or­ous de­bate over how much in­di­vid­u­als can do to pre­vent cancer and how much is un­avoid­able.

The re­searchers, math­e­ma­ti­cian Cris­tian To­masetti and cancer ge­neti­cist Bert Vo­gel­stein, both of Johns Hop­kins Univer­sity, set out to de­ter­mine what pro­por­tion of cancer mu­ta­tions are due to un­pre­dictable DNA-copy­ing er­rors — as op­posed to the two other main contributors to cancer, in­her­ited genes and en­vi­ron­men­tal fac­tors, such as smok­ing and obe­sity.

For their study, pub­lished in Science, the sci­en­tists used a math­e­mat­i­cal model that an­a­lyzed genome se­quenc­ing and epi­demi­o­log­i­cal data for 32 types of cancer. Over­all, they con­cluded, 66 per­cent of mu­ta­tions that con­trib­ute to cancer are due to un­avoid­able DNA-repli­ca­tion mis­takes, while 29 per­cent are at­trib­ut­able to en­vi­ron­men­tal fac­tors and 5 per­cent to hered­ity. That doesn’t mean that two-thirds of cancer cases are caused by ran­dom copy­ing er­rors, they said; it can take three, four or more mu­ta­tions to make a cell turn ma­lig­nant.

More­over, the pro­por­tion of mu­ta­tions due to ran­dom copy­ing er­rors varies de­pend­ing on the cancer, the re­searchers said. Ran­dom DNA-repli­ca­tion mis­takes ac­count for about 77 per­cent of crit­i­cal mu­ta­tions in pan­cre­atic cancer, and vir­tu­ally all child­hood cancer, they said. By con­trast, they con­cluded that more than two-thirds of the mu­ta­tions in lung cancer were due to en­vi­ron­men­tal fac­tors, mostly smok­ing.

Hu­mans have tril­lions of cells, which are con­stantly re­gen­er­at­ing by di­vid­ing and mak­ing new cells. But each time DNA is copied, the sci­en­tists said, an av­er­age of three ran­dom mis­takes will oc­cur. While most are harm­less, a small num­ber af­fect genes that will pro­mote cancer.

The new re­search builds on a 2015 study that high­lighted the role of “bad luck” — ran­dom DNA er­rors — in de­vel­op­ing cancer. That study drew ve­he­ment protests from some cancer physi­cians and re­searchers who wor­ried it would en­cour­age people to take a fa­tal­is­tic ap­proach to cancer rather than try­ing to re­duce their cancer risk by main­tain­ing a healthy weight, ex­er­cis­ing reg­u­larly, eat­ing a good diet and avoid­ing cig­a­rettes.

The Hop­kins re­searchers have said their ear­lier work was widely mis­in­ter­preted. Nev­er­the­less, in a news brief­ing this week, they took pains to stress that their study was con­sis­tent with es­ti­mates that 40 per­cent of can­cers can be pre­vented, and urged the pub­lic to pur­sue healthy life­styles.

But they also said it was im­por­tant for sci­en­tists and the pub­lic to rec­og­nize that a large per­cent­age of cancer mu­ta­tions oc­cur no mat­ter how pris­tine the en­vi­ron­ment or how laud­able some­one’s life­style choices.

“Most of the en­e­mies are inside us — they are al­ready here,” Vo­gel­stein said, re­fer­ring to the ran­dom cancer-caus­ing mu­ta­tions. He said that science needs to find bet­ter ways to de­tect cancer early, when there is a greater chance of cur­ing it.

Vo­gel­stein also ar­gued that the new re­search about ran­dom mu­ta­tions should of­fer com­fort to people who de­velop cancer despite hav­ing “near-per­fect life­styles,” as well as to par­ents who are wor­ried that they some­how “gave” their chil­dren cancer, ei­ther by pass­ing on a harm­ful gene or in­ad­ver­tently ex­pos­ing them to an en­vi­ron­men­tal toxin. “We don’t need to add guilt to an al­ready tragic sit­u­a­tion,” he said.

To­masetti said the work rep­re­sented a par­a­digm shift be­cause it marked the first time that re­searchers had mea­sured the re­spec­tive con­tri­bu­tions of the three dom­i­nant causes of cancer mu­ta­tions.

Some re­searchers were skep­ti­cal, echo­ing the crit­i­cism of the 2015 work. “They say ran­dom­ness is a ma­jor cause of cancer, and they said it last time,” said Anne McTier­nan, an in­ternist and epi­demi­ol­o­gist at Fred Hutchin­son Cancer Re­search Cen­ter. “But the data doesn’t con­vince me.”

She said that en­vi­ron­men­tal causes of cancer have long been un­der­es­ti­mated, and that es­ti­mates on their con­tri­bu­tion to cancer will in­crease as more is learned.

Yusuf Han­nun, direc­tor of the Stony Brook Univer­sity Cancer Cen­ter, agreed, ar­gu­ing that the 66 per­cent con­tri­bu­tion of ran­dom DNA er­rors to mu­ta­tion was “way ex­ag­ger­ated.” In late 2015, a team he led re­ported that the vast pro­por­tion of life­time cancer risk is due to en­vi­ron­men­tal fac­tors.

Oth­ers wel­comed the new Hop­kins study. Brian Druker, direc­tor of the Ore­gon Health and Science Univer­sity’s Knight Cancer In­sti­tute, said it pro­vided a data frame­work “to un­der­stand much of what we al­ready know about cancer epi­demi­ol­ogy.” Of­ten, he said, he sees cancer pa­tients who have had a healthy life­style and are look­ing for an ex­pla­na­tion for their dis­ease. “Of­ten there isn’t one,” he said.

In their 2015 study, To­masetti and Vo­gel­stein com­pared cancer in­ci­dence in the United States to the to­tal num­ber of cell di­vi­sions to dif­fer­ent kinds of tis­sues in the body. They wanted to de­ter­mine why, for ex­am­ple, cancer is more likely to de­velop in the colon than in the brain. They found a strong cor­re­la­tion be­tween cancer in­ci­dence and the num­ber of times the stem cells in the tis­sues di­vide. They fig­ured that the more cells di­vide, the higher the po­ten­tial for ran­dom DNA-copy­ing mis­takes — and at­trib­uted the er­rors to “bad luck.”

But crit­ics dis­liked the “bad luck” ex­pla­na­tion and com­plained that the study was limited to the United States and didn’t in­clude the most com­mon can­cers — breast and prostate.

In a new anal­y­sis also re­ported Thurs­day, which in­cluded in­for­ma­tion on breast and prostate can­cers, To­masetti and Vo­gel­stein said they had done ad­di­tional work that con­firmed and broad­ened their 2015 con­clu­sions.


A mi­cro­scope im­age shows a cul­ture of hu­man breast cancer cells. New re­search raises ques­tions about how much you can do to pre­vent cancer.

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