Ashkenazi Jews

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My Semicolon Life: Tracing my family’s cancer history – by Brian Mansfield


My Semicolon Life: Tracing my family’s cancer history –


USA Today

USA Today (Photo credit: Wikipedia)


When USA TODAY‘s Nashville music critic Brian Mansfield was diagnosed with colon cancer at age 48, he figured that a lifetime of Southern-fried foods, extra-large sodas and stress eating on deadline had brought it on. Turned out he had a genetic syndrome that gave him an 80% chance of developing colon cancer. He’ll chronicle his life with the disease — and with only a small part of his colon — in a series of weekly installments.


Every time my older son gets an upset stomach, he gets a little spooked.


This summer, he didn’t seem worried. My surgery and recovery went well enough that he didn’t have to spend much time wondering if things might go badly. Besides, people brought food.


Now that he’s back at college and on his own, he’s thinking less about my short-term issues and more about his long-term ones.


Like, when’s he going to get cancer?


COLUMN: Last week’s installment


MORE: Follow Brian on Twitter


MORE: ‘Music that makes me want to live’ playlist


As the son of someone with Lynch syndrome — a hereditary genetic disorder that exponentially increases one’s susceptibility to cancer — it’s not an unreasonable question. He knows he’s got a 50/50 chance of carrying the same mutation I do, and he knows that my own digestive problems led to my colon cancer diagnosis. He wants to get screened for Lynch, and he’d rather do it sooner than later.


So this week I went to see someone who could help me get a handle on the genealogical aspect of the situation. An advanced practice nurse in genetics, she’d typically walk someone — my son, for instance — through his likelihood of having a genetic disorder, then take a DNA sample to have it tested. Since I already had tested positive for Lynch, she created a family tree showing our cancer history, then outlined the steps I should take to alert and protect both my immediate and extended family.


In order to rule out additional syndromes, she asked questions about sebaceous skin tumors, thyroid glands, fibroid tumors and my ancestry of origin. Lynch doesn’t appear to be a respecter of ethnicities, but other mutations are: For instance, the BRCA mutations, which can produce a hereditary breast-ovarian cancer syndrome, are common among Ashkenazi Jews. She also measured my head: A larger-than-normal measurement could signify Cowden syndrome, a much rarer hereditary disorder that often results in multiple benign tumors and an increased cancer risk.


As for the family history, cancer showed up occasionally on my mother’s side, like the great-aunt who died of breast cancer in the mid-1950s after having worked in the Oak Ridge, Tenn., nuclear program during World War II, but no patterns emerged. My father’s side of the family, however, told a different story.


On our own, my family had focused the search on the Carter/Geralds side of my father’s lineage. When we put the Mansfields on paper, though, there was plenty of evidence to suggest troubles of their own. My grandfather, a heavy smoker, had oat-cell lung cancer when he died at 62. He had two brothers — and maybe a third — who died from colon cancer. Also, I have a second cousin on that side diagnosed with colon cancer at age 50.


Still, it’s my paternal grandmother’s branch that most strongly suggests Lynch. When Granny was in her 50s, she had a hysterectomy. She didn’t talk about it then, and she can’t tell us much about it now. As we’ve pieced together family lore, we’ve come to believe her doctors were concerned about uterine or ovarian cancer (both Lynch-related), so they removed the organs most at risk. One sister also had a hysterectomy after being diagnosed with endometrial cancer; when a malignancy recurred in her kidneys, it spread throughout her body and took her life. A brother died of lung cancer in 2009. Ovarian took the youngest sister this spring.


In the next generation, colon cancer hit three first cousins, all when they were in their 40s. Now, there’s me.


Facebook helped me gather these stories. This weekend, it’ll help me spread a message that’ll read something like this:


Dear ______,


As you know, I had surgery for colon cancer this summer. During the course of my treatment, I learned that I carry an hereditary genetic mutation called Lynch syndrome that greatly increases the likelihood of developing cancer in the colon, stomach, uterus, ovary and other places.


After looking through our family’s history with a cancer genetics professional, we’ve determined that the disorder came from my father’s side of the family. You probably already know how prevalent those cancers have been across our generations. Because of that, I’d like to suggest that you contact a cancer genetics professional in your community to help you assess your own risk of carrying the mutation.


While a Lynch diagnosis can be a scary thing, it also brings empowering knowledge. With proper screening, the most common Lynch-related cancers can be discovered early, even prevented.


The National Center for Biotechnology Information website has a section that you can use to find cancer genetic counseling near you. If you decide to get screened, I’ll be happy to send you a copy of my genetic test result and my pathology report. Soon, I should also have a pedigree that shows our family cancer history.


Since my surgery, I have recovered nicely. But few things would make me feel better than knowing I kept somebody else in our family from going through the same thing I did.






Meanwhile, I’m calling my father and my sons to help them make their own appointments. They’ve got tests to take.




Hereditary Breast and Colorectal Cancer – what is the genetic link?

The association between breast and colorectal cancer in not clear.  There is an increased incidence of breast cancer and colorectal hamartomas which may lead to colorectal cancer in PTEN-mutation spectrum disorders such as Cowden’s Syndrome, and in Peutz-Jeghers Syndrome.  Data from genome-wide association studies demonstrates association of a common but low penetrance (weak) risk locus at chromosome 8q24.

Lynch Syndrome
The link between Lynch Syndrome has been controversial, but two recent studies have added weight to Lynch Syndrome as a risk factor for breast cancer.  A recent study in JNCI (Win et al 2012) suggests that amongst Lynch Syndrome patients the risk of breast cancer as a second cancer after a diagnosis of colorectal cancer may be increased by about 76%.  An earlier study this year suggests that their is molecular evidence for this association (Buerki et al Genes Chromosomes Cancer 2012).


Some studies in Li-Fraumeni Syndrome families identified mutations in CHEK2 as possible cause for this condition (Bell et al Science 1999).  This link has not been reproducible but the variant 1100 may be a population variant which increases risk in Ashkenazi Jewish populations.

Families with Li-Fraumeni Syndrome and CHEK2 mutations

Evidence demonstrates that a subset of families with hereditary breast and colon cancer may have a cancer family syndrome caused by a mutation in the CHEK2 gene. Although the penetrance of CHEK2 mutations is clearly less than 100%, additional studies are needed to determine the risk of breast, colon, and other cancers associated with CHEK2 germline mutations. One large study showed that truncating mutations in CHEK2 were not significantly associated with CRC; however, a specific missense mutation (I157T) was associated with modest increased risk (odds ratio [OR], 1.5; 95% CI, 1.2–3.0) of CRC.

Similar results were obtained in another study conducted in Poland. In this study, 463 probands from LS and LS–related families and 5,496 controls were genotyped for four CHEK2 mutations, including I157T. The missense I157T allele was associated with LS–related cancer only for MMR mutation-negative cases (OR, 2.1; 95% CI, 1.4–3.1). There was no association found with the truncating mutations. Further studies are needed to confirm this finding and to determine whether they are related to familial CRC type X.

Hereditary mixed polyposis syndrome (HMPS)

Hereditary mixed polyposis syndrome (HMPS)

Hereditary mixed polyposis syndrome (HMPS OMIM 601228) is a mixed colorectal tumour syndrome which was originally linked to the CRAC1 locus on 15q13-14 (Thomas et al. 1996; Jaeger et al. 2003). It is a rare condition found in a few families of Ashkenazi descent, with an autosomal dominant inheritance, mixed juvenile, adenomatous and hyperplastic polyps, as well as colorectal cancer (Whitelaw et al. 1997). The best screening protocol for polyps in HMPS is not clear as the condition is rare.

Genome-wide association revealed common low-penetrance predisposition alleles at the CRAC1 locus which are linked to sporadic colorectal cancer risk (Jaeger et al. 2008). The gene which causes HMPS was subsequently identified as a 40kb duplication upstream of the gene GREM1 at the CRAC1 locus (Jaeger et al 2012) which causes disruption of the BMP / TGF-beta signalling pathway, a pathway also disrupted in Juvenile Polyposis Syndrome.

Simon Leedham showed that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps (Davis et al. 2015).  They also elucidated the synergistic interaction of GREM1 with an activated Wnt signalling pathway.

Duplication upstream of GREM1

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