Add broken DNA repair to the list of inherited colorectal cancer risk factors

February 23, 2018 by Tom Ulrich, Broad Institute of MIT and Harvard
Add broken DNA repair to the list of inherited colorectal cancer risk factors
Credit : Susanna M. Hamilton

An analysis of nearly 3,800 colorectal cancer patients—the largest germline risk study for this cancer to date—reveals opportunities for improved risk screening and, possibly, treatment.

Thirty percent of a given person's risk of colorectal is hereditary. The genetic roots of that heritability, however, remain murky; the current list of colorectal cancer susceptibility genes only explains about 10 percent of the genetic risk.

To expose some of that "hidden" heritability, a multicenter team led by researchers at the Broad Institute of MIT and Harvard Cancer Program and Dana-Farber Cancer Institute screened nearly 3,800 colorectal cancer for inheritable (a.k.a. ) in 40 genes involved in DNA damage repair and not already linked to colorectal cancer risk.

Their results, reported in the American Journal of Human Genetics, reveal that a small but significant subset of patients do harbor inherited mutations in DNA repair genes not previously linked to colorectal cancer risk.

Of the 680 patients the team initially screened, 31 carried inherited disease-promoting mutations in known colorectal cancer risk genes such as APC or TP53. Unexpectedly, an additional 33 carried at least one germline mutation in 21 of the 40 DNA repair genes examined. Three and five, respectively, of those patients carried mutations in ATM or PALB2, two elements of a DNA repair process called homologous recombination (HR). Previous studies have linked inherited mutations affecting HR to breast, pancreatic, and prostate cancer risk, but not colorectal cancer. Together, the inherited ATM and PALB2 mutations helped explain increased disease risk in an additional 20 percent of colorectal cancer patients than the current list of risk genes.

Also noteworthy, the team found no difference in age at diagnosis or family history between germline mutation-carrying and non-carrying patients. At the moment age and family history are two key factors doctors consider when deciding whether to screen colorectal cancer patients for germline risk mutations.

The team validated their results from the first 680 patients in another 3,117—making this the largest germline risk mutation study in colorectal cancer to date.

Taken together, the team's findings suggest four things:

  1. Inherited ATM and PALB2 mutations should be added to the list of colorectal cancer risk and to standard tumor genetic testing panels.
  2. Breast and prostate tumors with germline HR defects often respond to a class of drugs called PARP inhibitors. Colorectal cancer patients whose tumors harbor similar mutations may also benefit from these treatments.
  3. According to the Exome Aggregation Consortium browser, between 1 in 400 and 1 in 1000 people of European ancestry carry germline ATM or PALB2 mutations, opening opportunities for improved risk and prevention screening.
  4. It may be that germline risk mutation screening should be standard for all patients, regardless of age or family history.

Explore further: Germline TP53 mutations in patients with early-onset colorectal cancer

More information: Saud H. AlDubayan et al. Inherited DNA-Repair Defects in Colorectal Cancer, The American Journal of Human Genetics (2018). DOI: 10.1016/j.ajhg.2018.01.018

Related Stories

Germline TP53 mutations in patients with early-onset colorectal cancer

March 12, 2015
In a group of patients diagnosed with colorectal cancer at 40 or younger, 1.3 percent of the patients carried germline TP53 gene mutations, although none of the patients met the clinical criteria for an inherited cancer syndrome ...

New cancer type with PIK3CA mutations

August 16, 2016
A newly defined type of colorectal and endometrial cancer involves at least two somatic mutations in the mismatch repair genes (MMR): MLH1, MSH2, MSH6, PMS2. This double somatic MMR cancer has no germline mutations in the ...

Patient study suggests broader genetic testing for colorectal cancer risk

January 30, 2017
A new study among more than 1000 colorectal cancer patients at Dana-Farber Cancer Institute has revealed that a surprising number of patients, about 10% in total, show mutations in genes thought to increase the susceptibility ...

Searching for the 'signature' causes of BRCAness in breast cancer

August 21, 2017
Breast cancer cells with defects in the DNA damage repair-genes BRCA1 and BRCA2 have a mutational signature (a pattern of base swaps—e.g., Ts for Gs, Cs for As—throughout a genome) known in cancer genomics as "Signature ...

Two new breast cancer genes emerge from Lynch syndrome gene study

January 18, 2018
Researchers at Columbia University Irving Medical Center and NewYork-Presbyterian have identified two new breast cancer genes. Having one of the genes—MSH6 and PMS2—approximately doubles a woman's risk of developing breast ...

Researchers propose new approach to identify genetic mutations in men with prostate cancer

June 29, 2017
Scientists have had limited success at identifying specific inherited genes associated with prostate cancer, despite the fact that it is one of the most common non-skin cancers among men. Researchers at University of Utah ...

Recommended for you

Psychiatric disorders share an underlying genetic basis

June 21, 2018
Psychiatric disorders such as schizophrenia and bipolar disorder often run in families. In a new international collaboration, researchers explored the genetic connections between these and other disorders of the brain at ...

Deep data dive helps predict cerebral palsy

June 21, 2018
When University of Delaware molecular biologist Adam Marsh was studying the DNA of worms living in Antarctica's frigid seas to understand how the organisms managed to survive—and thrive—in the extremely harsh polar environment, ...

Genetic variation in progesterone receptor tied to prematurity risk, study finds

June 21, 2018
Humans have unexpectedly high genetic variation in the receptor for a key pregnancy-maintaining hormone, according to research led by scientists at the Stanford University School of Medicine. The finding may help explain ...

Shared genetics may shape treatment options for certain brain disorders

June 20, 2018
Symptoms of schizophrenia and bipolar disorder, including psychosis, depression and manic behavior, have both shared and distinguishing genetic factors, an international consortium led by researchers from Vanderbilt University ...

Scientists unravel DNA code behind rare neurologic disease

June 20, 2018
Scientists conducting one of the largest full DNA analyses of a rare disease have identified a gene mutation associated with a perplexing brain condition that blinds and paralyzes patients.

Simple sugar delays neurodegeneration caused by enzyme deficiency

June 20, 2018
A new therapeutic approach may one day delay neurodegeneration typical of a disease called mucopolysaccharidoses IIIB (MPS IIIB). Neurodegeneration in this condition results from the abnormal accumulation of essential cellular ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.