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Background on Hereditary Cancer

Learn about the most common hereditary cancer syndromes, their genetic causes, and why early testing matters for patients and their families.

Last updated on 25 May 2026

Background on Hereditary Cancer

Hereditary cancers makes up around 5–10% of all cancers. Though rare, a timely diagnosis is important – as not only do patients require long-term care from a young age, but their relatives also require management. In the past decades, enormous strides have been made to unravel the genetic basis of cancer, and this knowledge has been used to develop targeted treatments for hereditary forms of cancer. 

Germline genetic testing for patients and their families with suspected hereditary cancer syndromes is therefore a vital component of the practice of preventative oncology and should become routine clinical care.

There are more than 400 hereditary cancer syndromes described with three of the most common ones being Hereditary Breast and Ovarian Cancer (HBOC), Lynch syndrome (LS) and Familial Adenomatous Polyposis.

1. HEREDITARY BREAST AND OVARIAN CANCER

Hereditary breast and ovarian cancer syndrome (HBOC) is one of the most common hereditary cancer syndromes. It follows autosomal-dominant inheritance – which means that inheriting one copy of a mutated gene, either from the mother or father, is sufficient to increase the risk of cancer as children have a 50% chance of inheriting the faulty gene.

The faulty gene is associated with early-onset breast and ovarian cancer, but individuals with HBOC are also at higher risk of developing male breast cancer, prostate cancer, pancreatic cancer and melanoma.2 It accounts for around 5-10% of all breast cancer cases, 10-15% of ovarian cancer cases and 3-5% of pancreatic and prostate cancers.3-6

Causes

HBOC is primarily caused by pathogenic variants in the BRCA1 and BRCA2 genes which play a crucial role in repairing damaged DNA.1, 2, 7, 8 There are other genes associated with HBOC, including but not limited to PALB2, TP53, PTEN and RAD51C/D.2, 9, 10 These genes encode for components of multi-protein complexes (e.g., PALB2 is a partner and localiser of BRCA2) and are vital to repairing DNA double-strand breaks.

2. LYNCH SYNDROME

Lynch syndrome (LS) is the most common cause of hereditary colon cancer.11 Following autosomal-dominant inheritance, it is associated with early-age onset colorectal cancer without polyposis; endometrial, ovarian, gastric, small-bowel, renal pelvis, pancreatic and bladder cancers; and other cancers.12 It accounts for around 3% of all colorectal cancer diagnoses.

Causes

It is caused by pathogenic variants in: 13, 14

  • The mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS2

    • MMR is a system that recognises and repairs errors that occur during DNA replication and plays a crucial role in maintaining genomic stability.15

  • The epigenetic regulator EPCAM

    • EPCAM pathogenic variants result in silencing of the MMR gene MSH2, thereby disturbing the MMR system.16

Cancer risk varies by gene, supporting the use of gene-specific screening and surveillance recommendations for LS.

For example, individuals with a MLH1 pathogenic variant should be offered earlier and more frequent colonoscopies than a PMS2 carrier who can start screening later.

3. FAMILIAL ADENOMATOUS POLYPOSIS

Familial adenomatous polyposis (FAP) is a common hereditary cancer syndrome with high penetrance.

Types and polyp/cancer risk

  • Classic FAP

    • Classic FAP is characterised by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, often starting in the teenage years or early adulthood. If left untreated, these polyps have a nearly 100% chance of becoming cancerous by the age of 40.17

    • In addition to colorectal cancer, people with FAP may also develop polyps in other parts of the gastrointestinal tract.

  • Attenuated familial adenomatous polyposis (AFAP)

    • AFAP is a variant of FAP, but is characterised by a milder presentation, typically with fewer polyps and a later onset of symptoms. In AFAP, affected individuals usually develop fewer than 100 polyps in the colon and rectum, as opposed to the hundreds to thousands seen in classic FAP.

    • Additionally, the polyps tend to develop later in life, often in one’s 30s or 40s, compared to the teenage or early adulthood onset seen in classic FAP.18

Causes

FAP and AFAP are caused by pathogenic variants in the adenomatous polyposis coli (APC) gene and are also inherited in an autosomal dominant pattern. 

The APC gene plays a crucial role in regulating cell growth and division, particularly in the lining of the colon and rectum. Its main function is to act as a tumour suppressor. The specific genetic mutations present in the APC gene determine whether an individual has AFAP or classic FAP.17

Overview of Other Hereditary Cancer Syndromes

Other hereditary cancer syndromes described include Li Fraumeni, Cowden syndrome, Peutz-Jeghers syndrome, Hereditary Diffuse Gastric Cancer and Neurofibromatosis type 1 (NF1). 1,19 They are all passed on in an autosomal dominant fashion but are caused by pathogenic variants in different genes.

Li Fraumeni syndrome increases the risk of multiple tumours such as soft tissue sarcoma and breast cancer and is caused by a germline pathogenic variant in TP53 1,19,20.

Cowden syndrome is caused by pathogenic variants in the cell cycle control gene, PTEN 22-24. Whilst relatively rare, it is characterized by both benign and malignant neoplasms and increases the risk for breast cancer, endometrial cancer, colon cancer, thyroid cancer amongst others 1,19,20,21.

Peutz-Jeghers syndrome is caused by germline mutations in the tumour suppressor gene STK11 which increases the risk for breast cancer, ovarian sex cord stromal cancer and many others 1,20.

Hereditary Diffuse Gastric Cancer is associated with germline mutations in the tumour suppressor gene CDH1 and is characterized by an increased risk of diffuse gastric (stomach) cancer, lobular breast cancer and colorectal cancer 19,20,25.

 Lastly, Neurofibromatosis type 1 (NF1), caused by a NF1 pathogenic variant is known to increase the risk of multiple benign and malignant tumours such as sarcomas, ovarian cancer, and melanoma21. 

References:

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  2. Yoshida R. Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis. Breast Cancer. 2021;28(6):1167-80.

  3. Szabo CI, King MC. Inherited breast and ovarian cancer. Hum Mol Genet. 1995;4 Spec No:1811-7.

  4. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994;343(8899):692-5.

  5. Swisher E. Ovarian cancer associated with inherited mutations in BRCA1 or BRCA2. Curr Womens Health Rep. 2003;3(1):27-32.

  6. Hemel D, Domchek SM. Breast cancer predisposition syndromes. Hematol Oncol Clin North Am. 2010;24(5):799-814.

  7. Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016;18(8):823-32.

  8. Kast K, Rhiem K, Wappenschmidt B, Hahnen E, Hauke J, Bluemcke B, et al. Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer. J Med Genet. 2016;53(7):465-71.

  9. Kobayashi H, Ohno S, Sasaki Y, Matsuura M. Hereditary breast and ovarian cancer susceptibility genes (review). Oncol Rep. 2013;30(3):1019-29.

  10. Velazquez C, Esteban-Cardenosa EM, Lastra E, Abella LE, de la Cruz V, Lobaton CD, et al. A PALB2 truncating mutation: Implication in cancer prevention and therapy of Hereditary Breast and Ovarian Cancer. Breast. 2019;43:91-6.

  11. Imyanitov EN, Kuligina ES, Sokolenko AP, Suspitsin EN, Yanus GA, Iyevleva AG, et al. Hereditary cancer syndromes. World J Clin Oncol. 2023;14(2):40-68.

  12. Vasen HF, Wijnen JT, Menko FH, Kleibeuker JH, Taal BG, Griffioen G, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. 1996;110(4):1020-7.

  13. Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 1999;81(2):214-8.

  14. Kuiper RP, Vissers LE, Venkatachalam R, Bodmer D, Hoenselaar E, Goossens M, et al. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat. 2011;32(4):407-14.

  15. Pecina-Slaus N, Kafka A, Salamon I, Bukovac A. Mismatch Repair Pathway, Genome Stability and Cancer. Front Mol Biosci. 2020;7:122.

  16. Huth C, Kloor M, Voigt AY, Bozukova G, Evers C, Gaspar H, et al. The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors. Mod Pathol. 2012;25(6):911-6.

  17. Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009;4:22.

  18. Yen T, Stanich PP, Axell L, et al. APC-Associated Polyposis Conditions. 1998 Dec 18 [Updated 2022 May 12]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1345/.

  19. Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol. 2005;23(2):276–292.

  20. Lim A, Ngeow J. The skin in Cowden syndrome. Front Med (Lausanne). 2021;8:658842.

  21. Courtney E, Chan SH, Li ST, et al. Biallelic NF1 inactivation in high-grade serous ovarian cancers from patients with neurofibromatosis type 1. Fam Cancer. 2020;19(4):353–358.

  22. Lim A, Ngeow J. The Skin in Cowden Syndrome. Front Med (Lausanne). 2021;8:658842.

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  24. Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16(1):64-7.

  25. Tan RY, Ngeow J. Hereditary diffuse gastric cancer: What the clinician should know. World J Gastrointest Oncol. 2015;7(9):153-60.