Mayo Clinic Researchers Report Apparent Father-Daughter Genetic Link for Colorectal Cancer

Jacquelyn K. Beals, PhD

October 29, 2009

October 29, 2009 (Honolulu, Hawaii) — An unusual pattern of genomic imprinting has been reported in a multi-institutional study of parent–offspring pairs with colorectal cancer (CRC). The study, presented here at the American Society of Human Genetics 59th Annual Meeting, found that in families in which a parent is diagnosed with CRC, the age at diagnosis for affected daughters of affected fathers is younger than for other parent–child pairings. The mechanism of inheritance is, at yet, unexplained.

CRC is the third most common cancer in the United States, leading to approximately 50,000 deaths per year — the second highest rate of cancer mortality. Many cases involve hereditary syndromes, with an age of onset typically 20 years earlier than for sporadic CRC.

Among families in the current study, some met the Amsterdam criteria for hereditary CRC: CRC occurred in at least 3 family members; CRC affected 2 generations; 1 affected person is a first-degree relative of another affected person; 1 affected person was diagnosed before 50 years of age. Other families studied demonstrated normal DNA mismatch repair in the tumors.

"Some studies have indicated parent of origin effects in rare cancers — for example Wilms' tumor," said Kari G. Rabe, MS, from the Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic College of Medicine, in Rochester, Minnesota, in her presentation. "So we asked: What is the role of imprinting on age of onset in colorectal cancers?" The investigators hypothesized that genomic imprinting affects age at CRC diagnosis in offspring with parents affected by the disease.

The study reviewed 2628 parent–offspring pairs. After excluding those with known Mendelian syndromes, Lynch syndrome, and certain known gene mutations, the final sample included 2061 parent–offspring pairs. Statistical tests (t tests) were used to compare age at diagnosis in affected father–offspring pairs and affected mother–offspring pairs (53.7 vs 55.8 years of age; P = .0003).

When the sex of the offspring was considered, this difference was "driven entirely" by a significantly younger age at diagnosis in affected daughters of affected fathers (52.3 years) than in affected sons of affected fathers (55.1 years; P = .0004).

Imprinting is involved in many genetic diseases. Among the best known are Prader-Willi and Angelman syndromes, in which the effect of the same gene depends on its parent of origin. However, such imprinting is not affected by the sex of the offspring. "This is the first report of something odd like this," Ms. Rabe told Medscape Pathology & Lab Medicine.

The findings could not be explained by bias, site of cancer, DNA mismatch repair, or Amsterdam II criteria status, noted Ms. Rabe in her presentation.

"We said it could be an imprinted gene on the pseudo-autosomal region of the X chromosome, and another option may be an imprinted gene on an autosomal gene that affects a sex-specific pathway," continued Ms. Rabe. "For example, the estrogen pathway . . . would explain the father-to-daughter transmission, perhaps." A third possibility is an X-linked gene being unmasked by preferential inactivation of the maternal X chromosome in colonic tissue.

Some sociological factors could lead to daughters being screened and diagnosed before sons. "We thought, too, that maybe the care of the parent falls more on the female than it does on the male. But that wouldn't explain why the mothers and the fathers [have a different effect]. You would think that women outlive men, so again we don't know. We're as perplexed as everybody is now," said Ms. Rabe. "It would be great if we could find an independent study of colorectal cancers in which we could replicate this," she said. Her group has currently exhausted all the cases in their cohort.

"The concept of a parental effect is becoming more and more interesting. . . . There are groups that are starting to explore it for other genes," session comoderator David Malkin, MD, associate chief of research (clinical), senior staff oncologist, senior scientist, and codirector of the Cancer Genetics Program at The Hospital for Sick Children, Department of Pediatrics, Division of Oncology, in Toronto, Ontario, told Medscape Pathology & Lab Medicine.

"But that's the direct parental effect, whether it's specifically daughter or specifically mother. . . . We are seeing in this meeting, and in the cancer research meetings, particularly, more of these parental effects, with some of the classic tumor suppressors and other cancer genes," said Dr. Malkin.

"Part of it is that technologies now are more available to be able to do that kind of directional mapping, if you will, of which allele is coming through," Dr. Malkin pointed out. "It's an interesting new direction."

Ms. Rabe and Dr. Malkin have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 59th Annual Meeting: Abstract 112. Presented October 23, 2009.

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