THE RESEARCH EDITION
01 02 03 04
From the Desk of Alicia Rowell, Vice President AIM at Melanoma Foundation
How Did Jimmy Carter Live So Long?
Carter’s Entire Family Died from a Rare Cancer – How Was His Life Different?
Inheriting Cancer Risk Factors
A Personal Story Shared by Our Current President and the Daughter of our Founder
Genetic Testing Performed in Melanoma
A Q&A with an Investigator at the National Institutes of Health
HFROM THE DESK OF A l i c i a R o w e l l
VICE PRESIDENT | AIM AT MELANOMA FOUNDATION
ere at AIM we had a enjoyable holiday season, and then we went right back to work doing what we love and what we do best: supporting research and the melanoma community.
Our Walks team, Risa and Jenna, are working closely with our coordinators to plan and execute the 2025 Steps Against Melanoma Walks—nine in the spring alone! Our Director of Community Engagement, Ann, has set up 11 symposiums at cancer centers across the nation for 2025, all of which are both livestreamed and recorded for you to view at your convenience. Our Director of Medical Education, Mandi, has been busy writing the articles you see here, new website pages, materials for healthcare providers, and more. Our Director of Marketing, Kathleen, brings our messaging and materials to you via the website, social media, email, and newsletters like this one. And Sam and I—AIM’s President and VP—are continuing to run our research projects, such as the International Melanoma Tissue Bank Consortium (IMTBC) and the International Melanoma Working Group (IMWG); advocate for patients and caregivers; and find the best ways to educate the melanoma community on what’s new in research and treatment.
Our focus for this newsletter is genetics and melanoma.
At least three times per year we send out a research-themed newsletter like this one. And your response has been gratifying: Our last research edition garnered over 12,000 reads!
In this edition we have focused on genes. You’ll find two articles about genetic testing in melanoma. One is a general overview of genetic testing along with the personal story of our president Samantha Guild and the genetic testing she went through. The other is an interview with Dr. Michael Sargen M.D.—an Assistant Clinical Investigator in the Clinical Genetics Branch and Division of Cancer Epidemiology and Genetics at the National Cancer Institutes, which is part of the National Institute of Health—specifically about the POT1 mutation.
You’ll also find an article about the late President Jimmy Carter, who was diagnosed with melanoma in his early nineties, and his family. President Carter long outlived his immediate family, all of whom died of cancer— but not melanoma. For some families with a history like the Carters, the cancers are all related to a gene mutation.
As always, thank you for your support of AIM.
HOWDIDJIMMY CARTERLIVESOLONG?
Carter’sEntireFamilyDiedfromaRareCancer–HowWasHisLifeDifferent?
Imagine all of your immediate family members your dad, mom, brother, and two sisters died from pancreatic cancer. You would certainly live your life wondering if you, too, might be diagnosed
That’s the reality lived by former President Jimmy Carter Emory University Hospital in Atlanta scanned his pancreas twice a year for most of his life, looking for early signs of pancreatic cancer.
His first family member to die from pancreatic cancer was his father, James Earl Carter, Sr , at age 58 Then, his brother, Billy Carter, died at age 51 from pancreatic cancer His sisters, Gloria and Ruth, died from pancreatic cancer at ages 63 and 54, respectively
His mother, Lillian Carter, fared better She survived breast cancer but succumbed to pancreatic cancer at age 85 Altogether, the average life span of his immediate family members was 62 years
Carter died on December 29, 2024, in Plains, Georgia, at the age of 100 years He was never diagnosed with pancreatic cancer. He was, however, diagnosed with metastatic melanoma in his early nineties Still, he avoided the same fate that took his entire immediate family
Upon his death, he had spent two years in hospice care and even out-survived his wife of 77 years, Rosalynn. In recent years, he had fallen and broken a hip after being diagnosed with melanoma in 2015
Although not all causes of cancers are known, melanoma is strongly associated with exposure to harmful ultraviolet radiation (UV) that damages DNA For some, it’s the everyday exposure to the sun’s UV rays and/or periodic sunburns that damage DNA. For others, the exposure and DNA damage may come through the use of indoor tanning beds Pancreatic cancer has no known direct causes.
Carter grew up on a peanut farm in Georgia that later became a larger farm supply business. His family owned hundreds of acres of farmland. The Carter Library has a picture of shirtless little boy Carter on his farm in 1928 It shows him outside petting a pony named Lady.
For the first 40 years of his life, effective sunscreen wasn’t available. In those days, some used tannins and chestnut extract on the skin as a crude form of sun protection Later, tanning oils with UV radiationfiltering properties were more popular, once the first modern sunscreen, with a sun protection factor (SPF) rating of 2, was commercialized in 1946 The use of sunscreen increased during the 1960s and 1970s.
Carter’s Life Choices
Carter lived to become a centenarian – a rare feat for anyone, but especially a male with his family history The Pew Research Center estimates that just 0 03% of the U.S. population are centenarians, and 78% are female
His familial connection to cancer was so significant that he and his surviving relatives gave blood to researchers looking for a genetic connection to pancreatic cancer If a gene were found, it could become a game-changing finding for a deadly disease with an unknown cause. (Note: individual results derived through clinical studies are kept confidential )
When Carter was asked what might have been the difference between his life choices versus his family members, he responded by suggesting cigarette smoking. Carter never smoked cigarettes, but all of his family members did
It is well known that cigarette smoking contributes to the development of many cancers Still, it lacks evidence for being the direct, sole cause of pancreatic cancer Nonsmokers can receive a diagnosis of the disease.
More importantly, providing cigarettes during the First World War and encouraging soldiers to smoke did not lead to an increase in the incidence of pancreatic cancer after the wars Cancer-associated death rates among men dramatically peaked for lung cancer following the popularization of cigarette smoking, but not pancreatic cancer nor melanoma
Melanoma and Pancreatic Cancer Statistics
Melanoma diagnoses and pancreatic cancer deaths continue to rise annually in the U S In 2025, mortality from pancreatic cancer rose to the fourth cause of cancerrelated deaths among men and the third cause among women in the U.S.
Whereas many cancers are in decline, melanoma is now among the most common cancers for men aged 85 and older in the U S The graph appearing here, from the American Cancer Society, illustrates the decline in prostate, colon & rectum, and lung & bronchus for this group with a corresponding rise in melanoma of the skin
Over the past ten years, many new therapies have been approved to treat melanoma a welcome change from the dismal situation patients with melanoma faced not too long ago: In 2009 without having any effective treatment options approved, the 1-year survival for metastatic melanoma varied between 55-25%, depending on whether the patient had metastasis to distant lymph nodes or visceral metastasis in the bones, brain, and liver, respectively
Median survival rates were usually described in months. For those same groups, the 5-year survival rate varied between ~28-10%, respectively
With effective treatment in 2025, we do not describe the median survival for Stage IV melanoma in months. We have data showing 10year survival rates For example, a clinical study using a single drug, pembrolizumab (Keytruda), showed 34% of patients who received it were alive after ten years. This drug belongs to the class of drugs we refer to as immunotherapy
In 2015 when Carter was diagnosed with Stage IV melanoma, he received a then-new drug called nivolumab (Opdivo), also an immunotherapy, to treat his cancer. He lived for nine years following his diagnosis of metastatic melanoma
CA A Cancer J Clinicians, 2019;69(6):452-467.
Cancer incidence rates for male adults in the U.S. aged 85 and older.
The current standard of care for melanoma now includes two immunotherapy drugs, nivolumab (Opdivo) plus ipilimumab (Yervoy). Recent survival outcome data showed that 43% of patients treated with these drugs were alive after ten years
Considering all this, Carter was born in 1924 when sunscreen did not exist He died in 2024 when therapy for melanoma could keep patients alive for over a decade.
Other Families With Genetics Causing Both Melanoma and Pancreatic Cancer
Although we have no idea about the genetic background of the Carter family, there is a rare condition that materializes as melanoma and/or pancreatic cancer in families This condition is called familial atypical multiple mole and melanoma syndrome or FAMMM
A leading tell-tale sign of an inherited cancer gene occurs when multiple family members are diagnosed with cancer before age 40 Sometimes, these appear as different types of cancer that share the same causative genetic mutation
FAMMM occurs by inheriting a mutated gene, called CDKN2A, that drives the development of both melanoma and pancreatic cancers Although pancreatic cancer is usually rare in the population (<1.5%), it can increase by 40 times with the presence of mutated CDKN2A. People with FAMMM also have multiple dysplastic nevi and melanomas
An individual with FAMMM that inherits the mutated CDKN2A has a 50-85% chance of developing melanoma They are likely to struggle with repeated diagnoses of suspicious skin lesions throughout their life, which are often confirmed as melanomas One patient had over 50 primary melanomas and 100 lesions removed since initial diagnosis in their 30s.
Many of the mutations that cause inherited medical syndromes, like inherited cancers, arise from our ancestors For example, a specific mutation in CDKN2A called the p16-Leiden founder mutation, was traced back to a Dutch individual from the town of Leiden, Netherlands, in 1707 Since this gene is dominant, many descendants will express the signs of cancer
After his presidential service, Carter joined the faculty of Emory University in Atlanta, where he shared his knowledge with Emory’s students. He then established the Carter Center in Atlanta in collaboration with Emory University
The Carter Center allowed him to flourish as a global advocate for human rights and well-being For his efforts, former President Bill Clinton awarded him the Presidential Medal of Freedom, and later, he received the Nobel Peace Prize
Maybe the secret to living a full life is the threat of a deadly pancreatic cancer diagnosis at your next appointment Maybe that threat pushes you to live life to the fullest.
Carter outlived his parents, siblings, and wife, and became the oldest president in U S history, setting a new record against all other leaders of the Executive Branch His life is a battle that cancer lost! In Conclusion – Carter Defeated Cancer
Former President Carter lived a life in defiance of his high risk for cancer
He grew up in a peanut-farming family and served in the U S Navy He also served as a Georgia state senator and later as the governor of the state Carter became the 39th president of the U.S. and the only one from Georgia.
Carter served as president from 1977 to 1981 and became active in humanitarian causes and monitoring elections after leaving office. He won the Nobel Peace Prize in 2002
In 2015, Carter was diagnosed with Stage IV melanoma. Despite the challenges, the former president lived a life that boldly defied the odds of his high cancer risk.
References
1 Grady D In a Former First Family, Cancer Has a Grim Legacy The New York Times Aug 7, 2007 Available at: https://www nytimes com/2007/08/07/health/07jimm html
2 Rojas R, Morales C, and Boone C In Carter’s Hometown, a Long Vigil Ends With Sorrow, but Also Uplift The New York Times Dec 30, 2024 Available at: https://www nytimes com/2024/12/30/us/jimmy-carter-hometown-vigil-plains-georgia html
3 Drissi M Carr E and Housewright C Sunscreen: a brief walk through history Proc (Bayl Univ Med Cent) 2021;35(1):121–123 doi: 10 1080/08998280 2021 1966602
4 Schaeffer K U S centenarian population is projected to quadruple over the next 30 years The Pew Research Center Jan 9, 2024 Available at: https://www pewresearch org/shortreads/2024/01/09/us-centenarian-population-is-projected-to-quadruple-over-the-next-30-years/
5 Siegel R, Naishadham D, and Jamal A Cancer statistics, 2012 CA Cancer J Clin 2012; 62(1):10-29 doi: 10 3322/caac 20138
6 Siegal RL Kratzer TB Giaquinto AN et al Cancer statistics 2025 CA Cancer J Clin 2025;1-36 doi: DOI: 10 3322/caac 21871
7 DeSantis CE, Miller KD, Dale W et al Cancer statistics for adults aged 85 years and older, 2019 CA Cancer J Clin 2019;69(6):452-467 doi: 10 3322/caac 21577
8 Balch CM, Gershenwald JE, Soong S et al Final Version of 2009 AJCC Melanoma Staging and Classification J Clin Oncol 2009;27(36):6199-206 doi: 10 1200/JCO 2009 23 4799
9 Robert C Carlino MS McNeil C et al Pembrolizumab vs Ipilimumab for Advanced Melanoma: 10-Year Follow-Up of the Phase 3 KEYNOTE-006 Study ESMO Congress 2024 Oral presentation presented on September 15 2024
10 Larkin J, Chiarion-Sileni V, Gaudy-Marqueste C et al 10-year survival outcomes from the phase 3 CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma ESMO Congress 2024 Oral presentation LBA43 presented on September 15 2024
11 Wolchok JD, Chiarion-Sileni V, Rutkowski P et al Final 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma N Engl J Med 2024
12 Broseghini E Venturi F Veronesi G et al Exploring the Common Mutational Landscape in Cutaneous Melanoma and Pancreatic Cancer Pigment Cell Melanoma Res 2025;38(1):e13210 doi: 10 1111/pcmr 13210
13 Begg CB Orlow I Hummer AJ et al Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample J Natl Cancer Inst 2005; 97(20): 1507–1515
14 Gu K, Van De Velde R, Pitz M et al Recurrent melanoma development in a Caucasian female with CDKN2A+ mutation and FAMMM syndrome: A case report SAGE Open Med Case Rep 2020:8:2050313X20936034 doi: 10 1177/2050313X20936034
15 Hille ET van Duijn E, Gruis NA et el Excess cancer mortality in six Dutch pedigrees with the familial atypical multiple mole-melanoma syndrome from 1830 to 1994 J Invest Dermatol 1998;110:788–92
16 Emory celebrates President Jimmy Carter at 100 Accessed 12 31 24 Updated 10 1 24 Available at: https://news emory edu/features/2024/09/er 100 years with carter 27-092024/index html
INHERITING CANCER RISK FACTORS
A
Personal Story Shared by Our Current President and the Daughter of our Founder
Despite having a sister who passed away from melanoma, Sam Guild was originally directed to genetic testing because of her mother’s ovarian cancer
“Genetic testing was initially suggested to me after my mother was diagnosed with ovarian cancer,” Sam said “It was suggested that I get tested to see if I had any genes that would put me at high risk for ovarian cancer But once they understood that my sister died from melanoma and that I had other cancer in my family, I ended up doing a whole panel to see if I had mutations that would put me at risk for other cancers ”
When the genetic testing results came back, one of the things she learned was that she had a mutation that puts her at high risk for melanoma “I already knew I had many risk factors for melanoma But the testing confirmed I had a familial risk ”
Only a fraction of melanomas are categorized as familial, meaning that the disease was genetically inherited from relatives
Inheriting a gene that causes melanoma occurs in fewer than 10% of all melanoma cases, and it’s different from simply inheriting risk factors For example, if your mother had very light skin, and you have very light skin, you’ve inherited a risk factor for melanoma And if your father has blue eyes, and you have blue eyes, you’ve inherited another risk factor for melanoma But a mutated gene that is passed on from one family member to another is something coded into your DNA You cannot see this mutation and may have no idea whether you or other family members inherited it
Why Do Genetic Testing?
Wanting to understand one’s genetic makeup is a primary reason for seeking genetic testing, especially among adopted children who may have little information about their background Others, like Guild, may get testing to help guide their health care and personal decisions “If you have a gene that puts you at higher risk for a particular cancer, you could change certain behaviors,” she said
Guild’s late mother, Valerie, started the AIM at Melanoma Foundation after her daughter, Charlie, was diagnosed with metastatic (Stage IV) melanoma in her lungs at only 25 years of age Charlie died from the disease not long after her diagnosis Valerie promised to do everything she could to educate others about melanoma, including about prevention and early detection
Since her sister’s death, Sam says she has been very attentive to her skin and regularly schedules skin checks with her dermatologist. But this new information about her genetics has compelled her to be even more vigilant about early detection. “My dermatologist and I live by this mantra: If skin lesion is potentially precancerous and could turn into a skin cancer – remove it.”
For those individuals who have already been diagnosed with cancer or survived cancer, there is a fear of reoccurrence. Having more information about their inherited risk may help them make decisions. For example, they may decide to enroll into a clinical trial or set up an advanced care plan for themselves.
Also, knowing whether a familial gene exists can help other family members Sam has a sibling and two children She has shared her results with her sibling and will share her results with her children when they’re older. “Testing gives individuals information to share with their loved ones. Then, those family members have the information to make informed decisions about their own care, such as being vigilant about early detection or getting their own genetic testing,” Sam said.
The Limitations on Genetic Testing
Testing to determine whether a gene exists that could increase the risk of cancer is not for everyone In fact, The American Society of Clinical Oncology (ASCO), the largest group of physicians treating people with cancer, has three recommendations about when and whether to offer genetic testing to an individual. In order for a provider to offer genetic testing, the individual should have 1) a strong family history of cancer with an early age of onset (i.e., younger than 40 years of age); 2) resources to accurately interpret test results; and 3) the ability to use the results for medical management of the individual or family.
One concern that physicians and others may have about testing just anyone is that identifying genes that may increase the risk for cancer can come with a psychological and emotional toll For some people, the potential anxiety that comes along with knowing their genetic predisposition to cancer may outweigh any benefit of this knowledge because often there is nothing a person can do with the news beyond surveillance Knowledge, without any tangible way to improve the situation, may cause undo anxiety
“I don't have a high sense of fear, but if it’s possible, I am now even more careful about my skin and my kids’ skin,” Sam said “For example, I always avoided the sun, but I avoid it even more now ”
Other Factors to Consider
In the U S , Congress passed a law against discrimination for health insurance or employment based on the results of a genetic test This was called the Genetic Information Nondiscrimination Act It also prohibits disclosing genetic information without consent
But life insurance underwriting was not included in the Genetic Information Nondiscrimination Act Congress left states to decide whether to enact protections on consumers to limit the use of genetics for life insurance companies providing coverage, premiums, and variable costs Therefore, some states have set limitations, and others have not
One consideration, then, if you’re interested in genetic testing, may be whether your state allows your results to be factored into life insurance plans Depending on the results, there could be coverage and premium consequences
If you’re interested in genetic testing, ask your doctor about your options.
For Sam, the genetic results confirmed that her vigilance is exactly what’s needed. “With my sister’s death, and my light skin, blue eyes, and very mole-y skin, my dermatologist and I were already very attentive to my skin. The testing reaffirmed that our vigilance is warranted.”
References:
1) American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility J Clin Oncol 2003;21(12):2397-406 doi: 10 1200/JCO 2003 03 189
2) U S Congress THE PUBLIC HEALTH AND WELFARE CHAPTER 21FPROHIBITING EMPLOYMENT DISCRIMINATION ON THE BASIS OF GENETIC INFORMATION Updated 12 29 24 Accessed 12 30 24 Available at: https://uscode house gov/view xhtml?req=(title:42%20section:2000ff1%20edition:prelim)
3) U S Congress THE PUBLIC HEALTH AND WELFARECHAPTER 21FPROHIBITING EMPLOYMENT DISCRIMINATION ON THE BASIS OF GENETIC INFORMATION Updated 12 29 24 Accessed 12 30 24 Available at: https://uscode house gov/view xhtml? hl=false&edition=prelim&req=granuleid%3AUSC-prelim-title42section2000ff-
5&num=0&saved=%7CKHRpdGxlOjQyIHNlY3Rpb246MjAwMGZmLTEgZWRp dGlvbjpwcmVsaW0p%7C%7C%7C0%7Cfalse%7Cprelim
4) Yanes T, Tiller J, Haining CM et al Future implications of polygenic risk scores for life insurance underwriting npj Genomic Medicine 2024;9(25) https://doi org/10 1038/s41525-024-00407-x
5) Rothstein MA Time to End the Use of Genetic Test Results in Life Insurance Underwriting J Law Med Ethics 2018 Sep;46(3):794–801 doi: 10 1177/1073110518804243
THE GENETICS OF SKIN CANCER
HostedbyKristaRubinMS,FNP-BC
NursePractitioner,CenterforMelanoma,MassachusettsGeneralHospital, AIMatSkinCancer’s“AskaSkinCancerNurse”
In this informative webinar on skin cancer, nurse practitioner Christa Rubin welcomes Dr Kenneth Tsai, from Moffitt Cancer Center & Research Institute.
The discussion revolves around the critical differences between genetics and genomics in relation to skin cancers
Key topics include: familial predispositions to skin cancer environmental risk factors like sun exposure the significance of genomic changes in cancer development advancements in treatment options such as immunotherapy
Special Guest
Kenneth Y. Tsai, MD, PhD
Vice Chair, Research, Department of Pathology
Senior Member, Departments of Pathology and Tumor Microenvironment & Metastasis
Co-Director, Donald A Adam Melanoma and Skin Cancer Center of Excellence
H Lee Moffitt Cancer Center & Research Institute
GENETIC TESTING PERFORMED IN MELANOMA
A Q&A WITH AN INVESTIGATOR AT THE NATIONAL INSTITUTES OF HEALTH
AIM at Melanoma interviewed Dr. Sargen, who is leading a clinical study (NCT00040352) to investigate how genetic and environmental factors contribute to the development of melanoma
Dr Michael Sargen MD is an Assistant Clinical Investigator in the Clinical Genetics Branch and Division of Cancer Epidemiology and Genetics at the National Cancer Institutes, which is part of the National Institute of Health. He completed his M.D. at the University of Pennsylvania in Philadelphia and then a dermatology residency at Emory University in Atlanta and a fellowship in dermatopathology at Stanford University in Stanford, California. His research focuses on melanoma and nonmelanoma skin cancer, looking into prevention, environmental or genetic risk factors, and biomarkers He frequently publishes literature describing inherited mutations among cancerprone families
The link to the study details, including eligibility, exclusion, and inclusion criteria, is here
Footnotes in this interview provide further reading material on the concepts in Dr. Sargen’s answers.
What is genetic testing?
MS: Genetic testing is a laboratory test that evaluates for genetic alterations that increase risk for specific conditions such as cancer. This testing often involves analyzing genetic material, also known as DNA, extracted from blood or saliva.
What is the role of genetic testing in skin cancer?
MS: Genetic testing can help identify individuals who may be genetically predisposed to developing skin cancer Individuals who are at elevated risk can benefit from increased skin surveillance by a dermatology healthcare provider Skin changes that are associated with cancer can then be identified at an early stage and removed.
Does genetic testing occur among families at high-risk for melanoma?
MS: In the United States, we generally recommend genetic testing for families in which three or more members have been diagnosed with melanoma However, other factors may impact genetic testing decisions, including age at melanoma diagnosis in affected family members and other types of cancer in the family that might suggest a specific cancer predisposition syndrome It is best to discuss genetic testing with melanoma specialists in dermatology, oncology, or clinical genetics to determine whether or not testing is appropriate.
Among individuals with a melanoma predisposition syndrome*, many dermatologists perform skin exams every 6-12 months over the course of their lives with initial exams starting around the onset of puberty
However, the frequency of skin exams can vary based on other risk factors including whether or not a person has previously had a melanoma and their prior history of sun exposure including the use of tanning beds Dermatologists will consider all of these factors when developing a surveillance plan
Individuals who carry alterations in certain high risk melanoma susceptibility genes can also be at elevated risk for other types of cancer. For this reason, genetic testing can potentially identify individuals who may benefit from other types of surveillance besides skin exams For some individuals, the potential anxiety associated with knowing of their genetic predisposition to cancer may outweigh the potential benefits of testing It is best to discuss these concerns with a genetic counselor before pursuing testing
What is Protection of Telomeres 1 (POT1)?
Loss of POT1 activity due to a variation in the gene can lead to chromosomal damage, which can result in a cascade of genetic events that contribute to cancer formation
Besides POT1, what other genes are a part of a highrisk panel for familial melanoma?
MS: The most commonly altered gene in melanomaprone families is CDKN2A about 20-30% of US families with familial melanoma carry a variant in CDKN2A. Other less commonly altered genes in <2% of melanoma-prone families include CDK4, BAP1, TERT, ACD, and TERF2IP These genes are often included on melanoma testing panels
There are additional genes (eg, TP53, PTEN) that increase risk for melanoma, but melanoma is often not the predominant cancer type in these individuals/families
Why does the gene POT1 matter with regards to melanoma?
MS: Individuals with a harmful variation in the POT1 gene appear to have a substantially increased risk for melanoma of the skin, compared with the general population Therefore, it is important to identify affected individuals early in life so they can receive routine skin surveillance to detect melanoma at its earliest stage when it is most treatable.
3,4
MS: Your genetic code is packaged together into discrete units called chromosomes. The Protection of Telomeres 1 (POT1) gene codes for a protein that protects the ends of chromosomes, also known as “telomeres,” from damage during cell division.
5
POT1 mutations have been associated with the development of spitzoid melanoma, a rare subtype of melanoma Harmful variants in POT1 also appear to contribute to other cancer types, including chronic lymphoid leukemia, glioma, and angiosarcoma
6-8
If an individual carries the disease-causing variant for POT1, describe the evidence associated with the risk for earlyonsetofcancer.
MS: Multiple studies have identified associations between disease-causing variants in POT1 and an increased risk for melanoma, chronic lymphocytic leukemia, glioma, sarcoma, and potentially other cancers. While these cancers appear to have an earlier onset in individuals with a POT1 variant, compared with the general population, larger population studies are needed to confirm this Determining when to begin screening for a specific cancer type is dependent on multiple factors including the earliest age of diagnosis for that cancer in the family and whether the individual has additional risk factors for disease
346-9
*Melanoma Predisposition Syndrome – An inherited or family cancer syndrome occurring when you have a genetic mutation(s) which increases the chance of developing melanoma, compared to individuals without a mutation
GENES INHERITED IN MELANOMA-PRONE FAMILIES
GENESYMBOL
GENENAME FOUNDINMELANOMA-PRONE FAMILIES
CDKN2A Cyclin dependent kinase inhibitor 2A
Cyclin-dependent kinase 4
receptor
Melanocyte inducing transcription factor <28% POT1 Protection of telomeres 1 <20%
SOURCE: BROSEGHINI E, VENTURI F, VERONESI G ET AL 2025
References:
1 Leachman SA, Carucci J, Kohlmann W et al Selection criteria for genetic assessment of patients with familial melanoma J Am Acad Dermatol 2009;61(4):677 e114 doi: 10 1016/j jaad 2009 03 016
2 Leachman SA, Lucero OM, Sampson JE et al Identification, genetic testing, and management of hereditary melanoma Cancer Metastasis Rev 2017;36(1):77-90 doi: 10 1007/s10555-017-9661-5
3 Shi J, Yang XR, Ballew B et al Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma Nat Genet 2014;46(5):482-6 doi: 10 1038/ng 2941
4 Robles-Espinoza CD, Harland M, Ramsay AJ et al POT1 loss-of-function variants predispose to familial melanoma Nat Genet 2014;46(5):478-481 doi: 10 1038/ng 2947
5 Sargen MR, Pfeiffer RM, Elder DE et al The Impact of Longitudinal Surveillance on Tumor Thickness for Melanoma-Prone Families with and without Pathogenic Germline Variants of CDKN2A and CDK4 Cancer Epidemiol Biomarkers Prev 2021;30(4):676-681 doi: 10 1158/1055-9965 EPI-20-1521
6 Speedy HE, Kinnersley B, Chubb D et al Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia Blood 2016;128(19):2319-2326 doi: 10 1182/blood-2016-01-695692
7 Bainbridge MN, Armstrong GN, Gramatges MM et al Germline mutations in shelterin complex genes are associated with familial glioma J Natl Cancer Inst 2014;107(1):384 doi: 10 1093/jnci/dju384
8 Calvete O, Martinez P, Garcia-Pavia P et al A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families Nat Commun 2015:6:8383 doi: 10 1038/ ncomms9383
9 Savage SA Telomere length and cancer risk: finding Goldilocks Biogerontology 2024;25(2):265-278 doi: 10 1007/s10522-023-10080-9
The Language of
Familial Melanoma
Inherited melanoma with at least two firstdegree relatives (i.e., parent, sibling, or child) with clinically diagnosed melanoma.
DNA
Deoxyribonucleic acid (DNA) contains the instructions for our design. We inherit approximately 50% from mom and 50% from dad. This miniature material makes us what we are and contains all our genetic information. A portion (~50%) will be passed along to our children.
Gene
An individual gene is one tiny piece or segment of DNA. Each gene contains the instructions for one specific thing or purpose in the cell Our DNA contains at least 20,000 genes that’s at least 20,000 pieces or segments of instructions, each with varying purposes
A change in the instructions for making a gene. Some changes lead to disorders or an increased risk for a disease.
WHAT INSPIRES LEADING MELANOMA RESEARCHERS?
Olivier
