Early-Onset Colorectal Cancer

OSUCCC – James researchers recommend screening all early-onset cases for hereditary cancer syndromes


Heather HampelLynch syndrome is the most common cause of hereditary colorectal cancer (CRC) in the United States, accounting for about 8 percent of CRC patients under age 50 and 3-4 percent of all CRC patients. The syndrome arises from mutations in one of four genes, called MLH1, MSH2 (including EPCAM deletions), MSH6 and PMS2. All are involved in DNA mismatch repair.

People with Lynch syndrome (LS) mutations are at high risk for developing cancer. The risk is greatest for CRC, followed by endometrial, stomach, ovarian and other cancers.

“People with LS need intensive surveillance, with annual colonoscopies beginning at age 20-25,” says Heather Hampel, MS, LGC, associate director for the Division of Human Genetics and for Biospecimen Research at The Ohio State University. “This increased monitoring can save lives by catching precancerous polyps early, before cancer develops.”

What hasn’t been known is the prevalence of other hereditary cancer syndromes among early-onset CRC patients. “That hasn’t been possible because next-generation gene sequencing, which allows us to test multiple genes at the same time for a lower cost, was not available until recently,” Hampel says.

Hampel helped lead a study by researchers at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) that used next-generation sequencing to determine the prevalence and spectrum of germline mutations in 25 genes associated with LS and other hereditary cancer syndromes.

The prevalence study (ClinicalTrials.gov identifier NCT01850654) was part of the Ohio Colorectal Cancer Prevention Initiative (OCCPI), an ambitious, statewide CRC screening and prevention effort that began in 2013. Fifty Ohio hospitals worked together with the common goal of screening all newly diagnosed CRC patients in the state for LS. Funding for the OCCPI was provided by Pelotonia, an annual bicycling event held in Columbus, Ohio, to raise money for cancer research at the OSUCCC – James.

The prevalence-study findings were published in the journal JAMA Oncology in December 2016. Germline DNA was tested using next-generation sequencing; tumors were also studied for characteristics of LS using microsatellite instability, immunohistochemistry or both.

Colorectal Cancer 2The new analysis involved 450 early-onset CRC patients under age 50. It is the first detailed report of the prevalence and spectrum of mutations in 25 genes associated with hereditary cancer syndromes in early-onset CRC patients, says Hampel, who also serves as associate director for biospecimen research at the OSUCCC – James. Overall, 75 mutations in cancer susceptibility genes were identified in 72 patients, or 16 percent. Also:

  • 36 patients (8 percent) had LS only;
  • Two patients (0.4 percent) had LS plus another hereditary cancer syndrome;
  • One patient had two hereditary cancer syndromes, neither of which was LS;
  • 34 patients (7.6 percent) had a different hereditary cancer syndrome.

Surprisingly, a third of patients (24 of 72) who had one or more pathogenic mutations did not meet National Comprehensive Cancer Network guidelines for at least one of their mutated genes and would have remained undetected by single-gene testing. Many of these mutations occurred in genes that have known links to CRC, but 13 patients had mutations in genes not usually associated with CRC, including ATM, PALB2, BRCA1 and BRCA2 (see table at the bottom of the article).

One family’s story

Dale S. and his family, of Lima, Ohio, provide a powerful example of how knowledge about inherited genetic risk factors can affect a person’s life.

After learning a family member had enrolled in the OCCPI and then tested positive for an LS mutation, Dale scheduled genetic counseling and testing for himself. He learned that he also had LS. A colonoscopy found stage 1 colon cancer, and he is expected to do very well.

“I had my first screening colonoscopy at age 45 due to my family history – just one year before learning I also had Lynch syndrome and an early tumor,” says Dale. “The aggressiveness of this form of colon cancer is scary, but I think it is better to know. Now I know I have to stay vigilant for the rest of my life.”

More than 126 members of this family have been tested for Lynch syndrome through the OCCPI. Forty of them learned they have Lynch syndrome. Dale, a father of six, hopes that his children also will choose to get tested once they are of age.

Statewide to nationwide

Rachel PearlmanAs of Dec. 30, 2016, the OCCPI screening effort had enrolled 3,343 newly diagnosed CRC patients. As of November 2016, 96 CRC patients and 116 of their relatives had tested positive for LS; 69 additional CRC patients were found to have a hereditary cancer syndrome other than Lynch syndrome.

“The OCCPI and our work over the past four years demonstrate that it is possible to screen all newly diagnosed colon cancer patients for genetic risk factors through a statewide hospital collaboration,” Hampel says. “And the findings of our research study demonstrate the need and value of screening early-onset CRC patients.”

Hampel and her colleagues estimate that the OCCPI will save 1,000 years of life and provide $32 million in benefit to the community because of the lives it saved in the state of Ohio through the early diagnosis of LS and the reduced need of cancer treatment.

“We are now working to launch this approach nationally and to promote the screening of the 136,000 colorectal cancer patients expected to be diagnosed in 2017,” Hampel says. “We believe the OCCPI can serve as a roadmap for other states to implement Lynch syndrome screening for their newly diagnosed colon cancer patients at the time of diagnosis.”

Based on their new data, the OSUCCC – James research team recommends genetic counseling and a broad, multi-gene panel test of cancer susceptibility genes for all early-onset colorectal cancer patients, regardless of family history or the results of tumor screening for LS.

This differs from current professional guidelines, which recommend all colorectal cancer patients be screened for LS, with referral for genetic counseling and LS-specific genetic testing if the tumor screening test is abnormal.

“We expected to find a high rate of Lynch syndrome among early-onset colon cancer patients,” says Rachel Pearlman, MS, LGC, first author of the paper and statewide study coordinator. “What was surprising were some of the other gene mutations found, including mutations in genes traditionally linked to breast cancer risk, even in patients whose family history was not suggestive of those mutations.

“Until multi-gene panel testing, we typically would not have tested patients with colorectal cancer for mutations in those genes unless they met criteria based on their family history.

“We know that the spectrum of mutations in early-onset colorectal cancer is much broader than we originally thought—both in the number of different gene mutations causing this disease and the rates at which they occur,” Pearlman says. “We believe this data offers additional support for complete genetic testing for all early-onset colorectal patients. This information can save lives by identifying at-risk family members who can then benefit from intensive cancer surveillance and prevention options.”

Colorectal Cancer 3

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