ICARE Newsletter Summer 2018

Refining Cancer Risks Among Individuals with Lynch Syndrome

Over the past year, multiple studies have refined risks and types of cancer among individuals with Lynch syndrome. Through a Scandinavian study, risks for 13 types of cancer (with colorectal cancers being excluded), were reported to be elevated with differences related to gender, age, and the gene in which mutation was present. Incidence rates of cancer peaked by age as follows: between age 30-49, ovarian cancer; between age 50-69, endometrial, breast, renal cell and brain cancers; after age 70, urothelial, small bowel, stomach, pancreatic cancer and skin tumors. This is yet another study that may eventually be used to individualize cancer risk management among patients.

Therkildsen C, et al. Br J Cancer. 2017 Nov 21. PMID: 29065108.

ICARE Newsletter Summer 2017

What Are New and Subsequent Cancer Risks Among Patients with Li-Fraumeni Syndrome?

Although individuals with Li-Fraumeni Syndrome (LFS), due to mutations in the TP53 gene, have a very high lifetime risk of cancer, risks of initial and subsequent cancers are not well defined. Through a group of patients with the classic form of LFS, researchers at the National Cancer Institute estimated their cancer risks. They evaluated a total of 286 individuals with TP53 mutations from 107 families, and found of women 50% had developed cancer by age 31 and of men 50% had developed cancer by age 46. This suggests that on average women with LFS tend to develop cancer earlier than their male counterparts. For women, cancer risk was the contributing highest after age 20, mainly due to high risks of breast cancer. This differed in men, where the risk was highest in childhood and later adulthood. Among both sexes, almost 100% of individuals had developed cancer by age 70. Cancer risks outlined by type of cancer developed by age 70 among women and men with LFS are shown in the table below.

Cancer Type

Cancer Risks by Age 70



Breast cancer



Soft tissue sarcoma



Brain cancer






Of individuals who developed cancer, about half went on to develop at least one more cancer after an average timeframe of 10 years.  Furthermore, having been diagnosed with one cancer did not lower their risk of developing a subsequent cancer.  The new information from this study helps to refine cancer risk estimates among those with LFS, which is needed to guide their cancer risk management strategies.

Mai et al. Cancer. 2016 Dec 1;122(23):3673-3681. PMID: 27496084.

ICARE Newsletter Winter 2016

Improving Our Understanding of Cancer Risks Among Individuals with Li-Fraumeni Syndrome

A recent study from France included over 400 patients with Li-Fraumeni Syndrome (all of whom had an inherited TP53 gene mutation). Cancer types among children and adults differed, with the main cancer types among children being osteosarcomas, adrenocortical carcinomas, central nervous system (CNS) tumors and soft tissue sarcomas; whereas among adults, the main cancer types were breast cancer and soft tissue sarcomas. 

The study also evaluated whether the type of mutation was associated with a specific presentation of cancer.  What they found was that average age at which cancer presented was substantially lower among those who had a ‘dominant negative’ missense mutation (21.3 years) compared to those with all types of loss-of-function mutations (28.5 years) or genomic rearrangements (35.8 years).  With the exception of children with adrenocortical carcinoma, most affected children had dominant-negative missense mutations.

Among women ages 30 or younger with breast cancer, TP53 mutations were detected in 6%.  Breast cancer pathology reports were evaluated in a group of TP53 carriers, and showed that 55% were HER2 receptor positive and 37% were triple positive (i.e., ER, PR and HER2 receptor positive).  Among women with breast cancer and a TP53 mutation, the development of contralateral breast cancer (cancer in the opposite breast) was very high at 31% compared to an estimated 10% contralateral breast cancer risk among women in the general population.

There was a high rate (43%) of multiple primary cancers among TP53 mutation carriers, the majority of which were cancers that developed following an initial cancer diagnosis.  Treatment records were available on a subset of patients who received radiation treatment for their first tumor which showed that 30% developed secondary tumors in the radiation field, within 2-26 years (mean, 10.7 years) following their initial cancer treatment.

With the increasing use of multi-gene tests, mutations in TP53 are unexpectedly being identified in individuals without a family history characteristic of Li-Fraumeni Syndrome.2

Consequently, clinicians and researchers are pursuing efforts to better understand the expanding cancer risks and how cancer presents among some of these individuals who are unexpectedly found to have a TP53 mutation, which is needed to further tailor their medical care.

1Bougeard G et al. J Clin Oncol. 2015 Jul 20;33(21):2345-52. PMID: 26014290
2Kamihara J,et al. Hum Mutat. 2014 Jun;35(6):654-62. PMID: 24706533