Hereditary cancer syndromes involve the inheritance of germline mutations from either or both parents, dramatically increasing the risk of developing cancer. Inherited mutations are suspected to account for up to 10% of all diagnosed malignancies — and that estimate might grow with additional genome-wide sequencing studies.1-4

Gene variants associated with cancer syndromes include oncogene gain-of-function mutations (and other types of mutations), which actively contribute to tumorigenesis, and pathogenic variants in tumor suppressor loci like TP53 or DNA mismatch repair (MMR) genes (such as MLH1, MSH2, MSH6 and PMS2). High-risk BRCA1 and BRCA2 gene variants are infamously associated with breast and ovarian cancer risk; like MMR mutations, they hinder DNA repair (See Figure 1).

“By definition, the term ‘Lynch syndrome’ refers to when a patient has a known MMR mutation, and hereditary nonpolyposis colorectal cancer [HNPCC] is when they have a family history consistent with Lynch but have no identified MMR mutation — a bit of semantics there,” noted cancer surgeon Paul E. Wise, MD, of the Washington University School of Medicine in St Louis, Missouri.

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While more than a dozen such germline mutations have been tied to familial cancer syndromes, TP53 in particular appears to be one of the most important. It is the most-frequently mutated gene in human cancers overall and has been likened to a “master switch” for tumor growth.5 The p53 protein is a DNA sequence-specific transcription factor binding protein that modulates expression of other genes to regulate cellular proliferation; inactivating mutations disrupt its role in tumor suppression.6

Most patients with Li-Fraumeni syndrome harbor germline TP53 mutations, sharply increasing patients’ risks of developing sarcomas and breast, lung, brain, and other cancers.3,4,6-8 (Li-Fraumeni can also stem from CHEK2 tumor suppressor gene mutations.)

Figure 1: Examples of Hereditary Cancer Syndromes

Syndrome

Mutation(s)

Most common tumor types

Cowden

PTEN

Breast, thyroid, endometrial

Familial adenomatous polyposis (FAP)

APC

Colorectal, GI, CNS, Gastric, Bone, Skin

Hereditary breast-ovarian cancer

BRCA1, BRCA2

Breast, ovarian, prostate, pancreatic

Lynch

MSH2, MLH1, MSH6, PMS2, EPCAM

Colorectal

Li-Fraumeni

TP53

Sarcomas, breast, lung, brain, adrenal gland

Von Hippel-Lindau

VHL

Kidney

Turcot

MSH2, MLH1, MSH6, PMS2 (biallelic)

Large intestine, CNS

Multiple Endocrine Neoplasia Type 1

MEN1

Pancreatic islet cell, adenomas of parathyroid and pituitary

Multiple endocrine neoplasia Type 2A

RET

Thyroid, pheochromocytoma, parathyroid adenoma

Retinoblastoma

RB1

Retinal, pineal, osteosarcoma, melanoma, sarcoma

“Various genotypes can have more or less aggressive phenotypes,” Dr Wise noted. “For example, FAP [familial adenomatous polyposis] due to a heritable APC gene mutation has essentially 100% lifetime risk of colorectal cancer while the MMR mutations have colorectal cancer risks varying from less than 10% to greater than 60%.”